Multiple Myeloma Update, Issue 1, 2018 (Video Program)
Multiple Myeloma Update, Issue 1, 2018
Proceedings from video interviews with Drs Edward A Stadtmauer, Sarah A Holstein, Paul G Richardson and Shaji K Kumar on the treatment of multiple myeloma, Waldenström macroglobulinemia and amyloidosis.
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Evolution of B-cell maturation antigen (BCMA) targeting in multiple myeloma (MM) DR STADTMAUER: As you know, immunotherapy for myeloma has actually been going on for perhaps the last 20 years. Myeloma is a disease of immune dysregulation. And there are abnormal T cells and B cells. And in many ways, the first real demonstration of success of immunotherapy were the immunomodulatory agents, lenalidomide and thalidomide and pomalidomide. Certainly we know that there is an aspect of how those work by directly targeting the myeloma cells. But I think a great extent and the reason why they’re called immunomodulatory agents is because they’re stimulating the microenvironment of the bone marrow of patients with myeloma. And that’s really a major aspect of how they work. We’ve been trying for a long time to make vaccines to stimulate an anti-immune response, immunologic response. The problem is, the vaccines that we’ve used, these single antigen-directed vaccines have just not — they’ve definitely demonstrated immune responses, but the clinical responses have been very minimal. So one of the major developments has been these genetically modified T cells. And as you know, the target of the T cell is really one of the major first points of how to make these things work. And the logical initial target for cancers was CD19, the marker that’s on most of the B cells, and so the CART-19 or the CD19-directed genetically modified T cells. I think it was back in 2011 was the first time that bringing together molecular biology, creating these chimeric antigen receptors, inserting them into viral vectors and then infecting a person’s own T cells to modify the cells so that they put on their surface this warhead was demonstrated to really be successful first in chronic lymphocytic leukemia and then acute lymphocytic leukemia and then non-Hodgkin’s lymphoma. The problem is, as B cells differentiate, they lose the CD19. And so in multiple myeloma, most of the cells are not CD19-positive. So there has been a search for other targets for multiple myeloma. And the most promising one that has come out is called the BCMA, the B-cell maturation antigen. So this marker is on the surface of most plasma cells and most malignant plasma cells even though — so as the B cells differentiate, there’s less CD19 and more BCMA. And so over the last couple of years, there’s now been very exciting results where a patient’s own T cells are removed. They’re genetically engineered to put an anti-BCMA warhead on their surface and then simply infusing these cells into patients with relapsed and refractory multiple myeloma. In some experiments, maybe half of the patients have had beautiful responses. And in some of the recent reports, the majority of patients have had nice responses. So in our particular institution, we have a patient now who had relapsed and refractory disease where it was basically a patient who was dying of myeloma. And we simply infused these genetically engineered T cells, and within a month the patient went from having active myeloma to complete remission. And that was 18 months ago. And the patient is still in a strict complete remission 18 months later with very minimal side effects, though there are potential toxicities to these therapies. The most notable one is that cytokine release syndrome, where patients can get an inflammatory response as these T cells proliferate in their system that mimics sepsis. So patients can have low blood pressure and fever and respiratory distress. But, fortunately for most patients, this is a self-limiting process. And we actually have the antidote of the CRS, which is really an IL-6-driven inflammatory process. And tocilizumab, which is a medication that lowers the levels of interleukin-6, miraculously reverses this syndrome within hours in the vast majority of patients. Chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome and neurotoxicity DR LOVE: And I wanted to ask you about both aspects of the things that you’re talking about, both the efficacy as well as the toxicity. But as long as you just brought up the toxicity, another thing we’ve heard a lot about are CNS issues. What has been seen there? And what’s the pathophysiology, also cytokine release? DR STADTMAUER: CNS issues, delirium, seizures, confusion, these are real potential side effects. We do not really understand the mechanism of this. We’ve seen similar symptoms in patients getting the other anti-CD19 monoclonal antibody, blinatumomab. In general, these are self limiting and reversible, but there have been some fatalities from the CNS toxicity. But we don’t understand the CNS toxicity as well, and we don’t clearly have an antidote for it as well as the CRS. DR LOVE: So I mentioned to you that David Porter from your institution, who’s done so much of the work in this field, particularly in leukemia and lymphomas, is actually working with us on a program right now. And I’d interviewed him a couple of years ago, and he told me some of the stories of the initial patients, some of the cytokine release syndromes and severe problems that were seen. I’ve heard it said that this is less with BCMA. Is that true in myeloma? DR STADTMAUER: The experience is still much less with BCMA in myeloma. And so it’s still an evolving story. And I would say that we have definitely seen Grade 3 — we’ve seen some significant CRS in our myeloma patients. I think there is a relationship between the burden of the disease and probably some relationship, though it’s not clear, between the success and how well the cells are popping from the therapy about the incidence of CRS. But you’re correct that some of the reports have really shown relatively minimal toxicities. And we’ll still have to see. I mean, I think that currently the use of CAR T cells for myeloma is exciting, but it still remains experimental. I think we have a lot of proof of principle in that there are certainly patients who’ve had nice responses. But I think that we’re now in an engineering aspect of this where we really have to figure out what are truly the best targets and the best way of targeting the myeloma cells. There seems to be a lot of relationship between the expansion of these cells within the patient’s body and how well to maximize the expansion of these cells, and persistence. It really seems like these cells need to stay in a person’s body for a while so they can act as what Carl June, who was our great physician scientist at Penn, who has done a lot of this work — he calls them serial killers, that you want to keep them around at low levels so that, should the antigen — meaning the disease — start growing again that they’ll be around to proliferate and attack and get rid of the disease. Clinical management of cytokine release syndrome DR LOVE: So you mentioned the issue of IL-6 blocking with tocilizumab. Do you, kind of, when you see a patient having cytokine release, do you go right to that? Or you use corticosteroids and then if it doesn’t work you bring it in? DR STADTMAUER: We try to avoid medications that will kill the T cells unless we really have to. So we keep that in our back pocket. If we really get a sense that these T cells are proliferating and causing lots of toxicity and our routine mechanisms or approaches to try to improve the patient are not working, then we’ll go quickly to steroids. And we have had the greatest success — we had this one patient who had a horrible CNS toxicity where she basically became obtunded. And it was somewhat clear that the engineered T cells were proliferating in her CNS. And for her, we simply gave her a dose of cyclophosphamide. And within hours of that, the process reversed and she actually woke up completely and had one of the best responses that we saw to it. But currently we tend to use these approaches only as a last resort. There is some debate as to whether the tocilizumab is, in any way, anti-effective. And there are some studies, which are using it right from the get-go to see if they can eliminate the CRS without ameliorating the response rate. But that remains an experiment. Our approach has always been to be ready with the medication but to not use it unless it’s really needed. DR LOVE: So I’m curious. Your patient that you referred to had this great response. What kind of toxicity issues, if any, did he have? DR STADTMAUER: The average time to have a toxicity from the infusion of the cells is somewhere in the neighborhood of about 1 to 2 weeks after the infusion. And he did require — we’re very quick. We actually do these treatments as outpatients, but then we’re very quick to admit the patient should they have any signs of sepsis or the CRS syndrome or CNS toxicity. And so he did require admission and actually experienced what we call a Grade 3 CRS and did receive tocilizumab — in fact received 2 doses of it approximately in that first week of therapy but recovered from that, did fine and has not had any clear toxicity from the treatment since then. DR LOVE: What actually happened? He had fever or — what, clinically — DR STADTMAUER: Yes. Yes. So fever is usually the first sign of some sort of toxicity. Sometimes it’s actually the CRS. Sometimes, like any other infusion of activated cells, you can get a transfusion or an infusion reaction that can be the issue. But he had low blood pressure. He had some hypoxia. He required some oxygen. And low blood pressure. But other than — and fever. So fever, low blood pressure, hypoxia, pretty classic. And there are serum markers that suggest this cytokine release syndrome. It’s a macrophage activation syndrome. So the ferritins tend to rise. And CRP, the C-reactive protein, is a surrogate for interleukin-6. And that tends to rise, too. And his numbers did go up along with these symptoms. And then with the infusion of tocilizumab, very quickly these symptoms resolved. DR LOVE: Did he have any CNS issues? DR STADTMAUER: I would say he had mild ones, but it’s always tricky when you have fevers to 103 whether if you’re a little bit confused or lethargic, is that a CNS problem or is it just related to the symptoms. DR LOVE: I was going to ask you, most of these are generalized, not focal neurologic problems? DR STADTMAUER: Correct. Correct. Durable remissions with BCMA CAR T-cell therapy in relapsed/refractory (R/R) MM DR LOVE: Fascinating. So, of course, the thing everybody wants to know is, where do we stand right now in terms of efficacy? How many people have you actually treated at Penn? DR STADTMAUER: So we still have an ongoing Phase I trial. And we have somewhere in the neighborhood of about 20 patients that have been treated. But the cohort that we’ve reported is actually a very remarkable cohort. It’s a group of patients — 9 patients were the first group of patients — where we’re one of the few centers that decided we’d like to try just to give the T cells. Most of these genetically modified T-cell protocols first give the patient what we call lymphodepleting chemotherapy, a slug of cyclophosphamide or fludarabine, to eliminate the innate T cells so that we can then infuse cells into an empty bone marrow that then will proliferate these cells. But we wanted to have — at least our first cohort — without any of that lymphodepleting therapy to really separate any potential response from the lymphodepleting therapy versus the infusion of the cells. So this patient that I’ve been describing, and 9 other patients, just received an infusion of the cells without any lymphodepleting therapy. In our experience — and, I guess another thing that’s different from our experience than a lot of the other studies is, we also did not assay the patients for BCMA expression, since, in our experience, virtually every plasma cell or every patient with myeloma has BCMA expression. We decided that we would just infuse the all comers and then use that to help see if we can differentiate who might have the best responses and see if there’s anything that can be correlated with that. So anyway, this first group of 9 patients just received the cells, were not selected and were very heavily pretreated and, nevertheless, 44% of those patients had a very nice response, including, I guess, our star patient and our first patient, which is now 18 months in this strict complete remission, doing great. Initial efficacy and safety results with BCMA CAR T-cell therapy DR LOVE: Any estimate of the total number of patients that have been presented or reported at this point and, globally, what we know about it in terms of efficacy? DR STADTMAUER: I just came back from the ASCO meeting, where there was an update of one group of studies and then another group of studies from China, actually. And China basically, the United States and China are the primary countries where this activity have been done. And both the results were very remarkable, very high response rates and relatively low toxicities, as you suggested. They report low incidences of the CRS. But both of them are relatively preliminary reports. I would say in terms of numbers, we’re talking about 100 or fewer patients that have been treated with this anti-BCMA cellular immunotherapy. But, certainly, the preliminary results are very promising, though much more work needs to be done. In virtually all the studies that have been presented so far, the infusion of these cells has been done in patients who are really very relapsed and refractory. You could argue, given that this is an immunotherapy approach, that maybe a more intact immune system, as would be seen in an earlier group of patients or perhaps a less refractory and resistant malignant myeloma cell, may even be more amenable to this therapy. And so studies are beginning in an earlier group of patients. DR LOVE: You correctly said that a lot more work needs to be done. On the other hand, it also brings up an issue that’s happening a lot in oncology, where you see a novel therapy that’s given by itself and you start seeing people who have no options regaining their health, so to speak, like your patient. And from a, I guess, regulatory perspective, what’s it take to get that in practice? Oncologists may wake up and see that it’s approved. I would guess that it’s only going to be approved to be utilized in specialized centers. But it kind of gets into the overall issue of — I mean, how many people would you need to see to want to give this therapy? You’re talking about 100, whatever, 200, whatever. And then if that does become available, do we have the capacity to treat all the patients? And who’s going to treat them? DR STADTMAUER: No. Feasibility of administering CAR T-cell therapy in a community setting DR LOVE: At this point, do you think that community-based oncologists can manage these patients? DR STADTMAUER: Right, I think there’s a learning curve, like any new therapy. Right now I would say cellular therapy is in the realms of maybe an autologous bone marrow transplant, that it will be helpful to have some comfort level and expertise with patients potentially having sepsis syndrome, having the ability to admit the patients to the hospital, have some rapid turnaround of blood work so you can see what’s happening. And so, of course, initially the centers that will be doing cellular therapy, I think, are the same tertiary centers where you refer for autologous transplant or stem cell transplant. But I think that will be how it starts. But just like any other therapy and technology, as the community becomes more and more comfortable with it and as standard operating procedure protocols become more and more clear, I think that definitely community physicians and community hospitals — the same hospitals that are doing leukemia induction therapy or inpatient infusional chemotherapies for lymphoma, let’s say, I can’t see why those physicians wouldn’t do a fine job of caring for these patients. DR LOVE: That's an interesting thought, though. In other words, obviously, there are transplant centers in the community, that maybe it’ll be the transplant centers that this kind of starts through, cellular therapy. Is that what you’re thinking? DR STADTMAUER: Yes. But, now, remember, certainly at Penn, and we generate these cells ourselves at our institution. But for most of the studies, the cells are being generated at a central facility that’s external to the institution. And, really, all you need at your institution is the capability of doing peripheral blood lymphocyte collection, sending the lymphocytes to whatever central facility. The central facility is what’s creating the cells and engineering the cells. And then they send back — currently they send back a pack, a frozen bag that’s much smaller than a packet for autologous transplant. And once the cells have been engineered and frozen, they’re good for a period of time before they need to be utilized. So really, I think, as long as that process gets greased and — I think that it will be a relatively straightforward process in terms of collecting the cells and administering the cells. I think there needs to be a — there’re, like I said, standard procedures for how to give — what type of lymphodepleting therapy, where to give the lymphodepleting therapy, what — there should be standard ways of monitoring these patients with ferritins and CBCs, et cetera. And again, as with anything, there’s going to be a learning curve with the first patient or so. But I think after a while, you become very comfortable. Dr Porter, who you mentioned, he and his team has done a really good job of analyzing the toxicities, particularly the CRS, has developed a whole algorithm of how to manage the cytokine release syndrome and how to observe it. And I think that’s really become a standard practice not just at Penn but throughout the institutions that have been doing this work. Mechanism of action of monoclonal antibodies; daratumumab-associated infusion-related reactions DR LOVE: Yes. I remember a couple of years ago, we were doing a symposium on melanoma when the combination data of ipilimumab and nivolumab was coming out. And everybody was like, “Oh, can we do this in the community?” And, of course, now people kind of do it routinely. So as you say, there really is a capability to handle complicated therapies. Where do you think this is going to land? When you talk about immunotherapy in general, people are always thinking about the concept of up front. I know we’re a long way from that. DR STADTMAUER: Sure. DR LOVE: But could you envision up-front cellular therapy? DR STADTMAUER: Yes. And exactly what you say. Sometimes we confuse all of this. So remember, cellular immunotherapy is what we’re talking about. What we haven’t spoken about is, there’s other forms of immunotherapy. Just as the checkpoint inhibitors have been very active in solid tumors, more and more we’re seeing that the checkpoint inhibitors are active in myeloma, usually not as a single agent but in combination, particularly with the immunomodulatory agents. Those combinations have been very active. And there’s some suggestion that adding checkpoint inhibition to the cellular therapies might even further improve those. But ultimately, this is still a hope rather than a proven thing, but if we find that the cellular therapies really can overcome resistance and really eliminate every single malignant cell, then obviously it has the potential of being the brass ring, that this will be something that if you give it early to the patients and since it doesn’t — we talk a lot about the genetic biology of myeloma cells and how certain genetics lead to much more resistant clones. When you’re targeting something that’s on the surface of every one of these malignant cells, then it almost doesn’t matter what’s inside the cell if it really is capable of destroying every cell that it attacks. And then if it continued — if it can persistent — be a serial killer, then doing this therapy early in the course of the disease may be a way of really leading to long-term remissions in these patients. But that, of course, remains to be determined. DR LOVE: So I want to go through your cases. And the first one I want to ask you about is this 54-year-old man who’s a pharmacist. But before you go through the case, I see that he got daratumumab. And before we get into that, I’m just thinking about what you were saying about immunotherapy, checkpoint inhibitors and cellular therapy. What’s your vision about how daratumumab and elotuzumab work? DR STADTMAUER: I would say probably for the last — ever since rituximab was created and found to be effective for B-cell non-Hodgkin’s lymphoma, of course, we’ve been looking for the rituximab for every disease that we can find and, in particular, myeloma just really being another B-cell malignancy, we’ve been looking for a rituximab for myeloma. And just like with the cellular therapy, BCMA is a logical target for plasma cells. And, in fact, there are anti-BCMA monoclonal antibodies that are under current investigation. And, in fact, they’ve latched immunoconjugates or — so toxins — to anti-BCMA and have seen very remarkable responses with that work. But the more common or markers that are on myeloma cells include the CS1, or the SLAMF7 antigen, as well as a CD38 antigen. In fact, CD38 is one of the ways that we use flow cytometry to isolate and identify plasma cells. So looking for, or creating, antibodies. And both the CS1 and the SLAMF7 and the CD38, in particular, are primarily on plasma cells. I mean, that’s one of the key ingredients or criteria for being a good target. It has to be something that’s primarily on the tumor cell and not particularly on other cells. And so with the CS1/SLAMF7, the elotuzumab monoclonal antibody, which was really the first one that was being used, as a single agent it had actually very little activity. But when again, combined with immunomodulatory agents, lenalidomide being in particular, there’s been a very nice randomized trial that shows clear improvement in response and particularly survival when elotuzumab is added to the lenalidomide and dexamethasone. Exactly what aspect of how that’s working is really the primary aspect. We still are not 100% certain. But it doesn’t seem like it is the direct toxic effect of elotuzumab on the myeloma cell that leads to the destruction. It does look like — in my mind, I see it as elotuzumab latches onto the tumor cell, and it acts as a flag for the innate immune system, which is being activated by the lenalidomide, to help destroy those myeloma cells. And daratumumab, I think that’s a little different. I mean, daratumumab definitely as a single agent shows remarkable responses. And, in fact, in one of the patients who I gave you, this pharmacist who I gave you as a case, he had received many therapies, including some investigational therapies, and was really like my patient with the CAR T cells, was really progressing and relapsed and really getting very sick from his myeloma. Fortunately, we had opened the single-agent daratumumab clinical trial. So he was one of the patients on that trial and just receiving, in the standard way that we give daratumumab, the weekly dosing for 8 weeks and then going to every other week for 4 months and then going to monthly. He went into a beautiful remission. And that remission, with the single-agent daratumumab, lasted for about a year and a half, which is pretty remarkable. And so single-agent activity was definitely helpful in his case. And again, exactly how single-agent activity works, it seems like it’s a combination of different immunological events, though there is a direct apoptosis and destruction of the cells by the latching on of the antibody, but in addition, it does seem like it modulates the NK cells and other immune cells to help destroy the myeloma. DR LOVE: So at ASCO, we were getting ready to do a myeloma session. And one of the docs in the audience came up and handed me an abstract and said, “What’s this all about?” And it was a paper looking at daratumumab and a checkpoint inhibitor, atezolizumab, in lung cancer. What’s the thinking there in terms of outside of myeloma? DR STADTMAUER: I can’t speak as much for outside of myeloma, but there certainly is the — if you can turn off the anti-immuno immune stimulation and then also give an immune stimulant, you can side effect how the whole checkpoint inhibitor story is fascinating and tremendous. I mean, we sometimes forget that our immune system evolved. And it really does come down to evolution that our immune system evolved to basically destroy foreign invaders, microbes and things like that. The problem with cancer is that cancer looks very much like us. And our immune system evolved to not kill “us,” to proliferate and destroy “other” but not “us.” And so the only way, though, that we can use our innate immune system to kill cancer is to turn off the process that protects “us.” And that’s where these checkpoint inhibitors — the whole concept is fascinating and brilliant and has really remarkably led to beautiful responses in many diseases. And so now we’re going the extra step of not only turning off checkpoints but also stimulating immunity even further. DR LOVE: So your patient who did so well on the daratumumab, this 54-year-old man, how did he do in terms of tolerability? The one thing we’ve heard about are infusion reactions. I’m curious what happened with him and also what you know about, what you think about and whether you’ve even tried subQ dara. DR STADTMAUER: So in many ways, the biggest issue when it comes to daratumumab is, number one, the potential for infusion reactions or, quote-unquote, allergic reactions, which leads us to be very cautious, particularly in the initial infusions of these patients, to a very slow infusion like rituximab, where we started at a very slow rate and then go faster and faster so that the first infusions can frequently be 8-hour-long infusions. We’ve learned that there’s a number of ways to decrease the likelihood of reactions. And there’s a whole standard operating procedure now to decrease that. And I think probably the most important thing has been, the use of montelukast the day or so before the initiation of the infusion can significantly decrease any respiratory distress or fevers and allow for a more rapid infusion. For the vast majority of patients, though, by the second infusion the duration of the infusion can be reduced to maybe 5 to 6 hours. And I would say the average infusions are probably 4- to 5-hour infusions at this point and are well tolerated. There is some suggestion that there’s an increase in infections in patients who get the monoclonal antibodies. Exactly how that’s all sorting itself out is still being determined. But in general, just like as we were saying, the daratumumab is now being used in most community practices and with a lot of safety and effectiveness. But it is still — it’s somewhat of a barrier to have a treatment that takes 5 hours of infusion. Subcutaneous delivery of daratumumab DR STADTMAUER: And so fortunately, there have been clinical trials of the subcutaneous infusion of this agent. In order for that to work there, it has to be connected with an enzyme that actually allows the tissue to break down a little bit to allow for the infusion of this agent. But in early clinical trials, infusions of 30 minutes to an hour and a half have been very safe and equally effective to the longer infusions. And I would guess that we’re going to see maybe a transition from these long intravenous infusions to the subcutaneous infusions within the next year or so. DR LOVE: What’s the volume of the infusion, and where is it given? DR STADTMAUER: It tends to be given in the thigh or in the abdomen. And the volume, it’s real volume. But in the preliminary reports, it has been very well tolerated, not a particularly vesicant or not particularly an irritant infusion. DR LOVE: You said you use montelukast? DR STADTMAUER: Yes. DR LOVE: This is the anti-asthma pill? DR STADTMAUER: Yes. Yes, because a bronchospastic toxicity was relatively common in the initial patients. And by doing that the day before, that has significantly reduced that and allowed for the infusions of the daratumumab. DR LOVE: Is that in the package insert? Is that widely done? DR STADTMAUER: I’m not 100% certain, but I think — DR LOVE: I’ve never heard that. DR STADTMAUER: — yes, there is a — I don't know if it’s in the package insert or whether it’s in recommendations of how best to give it. DR LOVE: Do you think — I mean, honestly, maybe I never thought to ask it or nobody ever thought to mention it. Do you think a lot of investigators do that? DR STADTMAUER: I’m not certain. I must admit, when it comes to the nuances of administering these agents, we have this whole specialty of our nurse practitioners. And really, in many ways, our nurses have become the experts when it comes to this — DR LOVE: Interesting. DR STADTMAUER: — and are really skilled. Both the chemotherapy nurses and our practitioners have really focused on reducing these toxicities. And so I rely on them to really monitor this. Case: A 56-year-old man with R/R MM and t(11;14) receives venetoclax/bortezomib/dexamethasone DR LOVE: So maybe we can go through some of your other cases. I’m just looking at these other ones here. Right. And again, maybe without going through it from A to Z, just kind of say what, basically, the situation is and what’s the teaching point. So one thing that kind of came out of the blue in myeloma that I wasn’t thinking about — we’ve been talking about venetoclax, obviously, in CLL/mantle cell. Now, all of a sudden, we’re hearing about it in myeloma. Maybe you can talk a little bit about your 56-year-old white male pharmacist. DR STADTMAUER: So this has really, in many ways, become the story of our patients with myeloma. And I purposely put him in there for this purpose, in that the field keeps evolving so quickly that even though many of the therapies that we use are not curative, we’ve been able to find new and novel therapies for patients even who have really relapsed and refractory disease with conventional therapies by utilizing the new developments. So daratumumab came just in time, in fact, for him to have a nice response. But, nevertheless, after a year and a half, his disease started progressing. And we went through a number of options. But venetoclax, as you know, the Bcl-2 inhibitor, has been tremendously effective in chronic lymphocytic leukemia and lymphoma, but particularly chronic lymphocytic leukemia, so effective. Whenever you have a therapy that leads to a tumor lysis syndrome, you know that it’s a pretty effective thing. And, fortunately, we’ve been able to manage these patients by watching them closely and anticipating tumor lysis. And the CLL patients have tremendously benefited from it. Given that, once again, myeloma is a B-cell malignancy, whenever you have a new therapy for a B-cell malignancy, it’s reasonable to think of trying it in multiple myeloma. And there’s a subset — it literally is about 10% to 15% of patients with myeloma — who have an 11;14 translocation. And traditionally we call this the lymphoma phenotype of myeloma. And, also traditionally, we’ve thought of it as not a negative prognostic chromosomal abnormality. In fact, it’s probably a bit — a better prognosis, to some extent. But these patients ultimately become resistant and have issues. And so in some preliminary trials of multiple myeloma with the venetoclax, there was a response rate even in patients without an 11;14 translocation, but it became clear very quickly that the subset of patients who had an 11;14 translocation seemed to have a much higher response rate. I think upwards of maybe 40%, even 50% of the patients who took single-agent venetoclax respond to the agent. And then there are a number of studies that have been adding venetoclax to bortezomib and dexamethasone, et cetera. And so to me, though, I think it’s worthy of investigating in all subsets of myeloma, I think the preponderance of the data now suggests if you have an 11;14 translocation, you have a real chance of responding to this. And so it turns out that this same patient, on further review, did have an 11;14 translocation. And so once again, his disease was really getting active and very limited options. Fortunately we were able to obtain, on a compassionate basis, the venetoclax. And unlike chronic lymphocytic leukemia, the incidence of tumor lysis syndrome has actually been very low in the multiple myeloma experience, and yet some real responses. And so he’s been taking 400 mg of the venetoclax and has been showing a very nice response even though other therapies haven’t been working. DR LOVE: He’s getting venetoclax alone or with bortezomib? DR STADTMAUER: So he’s been getting it with bortezomib and dexamethasone. That combination seems to have the highest response rates and, interestingly, the studies show that patients who were refractory, who had been exposed to bortezomib in the past and progressed on it, if you add the venetoclax, then a subset of those patients will respond nicely even though they were not responding to bortezomib in the past. DR LOVE: Where do you see venetoclax heading, particularly in the subset of 11;14? Are there studies looking at it earlier? DR STADTMAUER: Yes. Yes. So there’s a number of studies of various combinations. For instance, we are participating in a protocol of venetoclax/carfilzomib and dexamethasone. And so we’ll see — of course there’s always the hope that when you add other agents or do this treatment earlier in the course of the disease, then even patients without the chromosomal abnormality might have responses that are beyond what you’d expect with the conventional therapy. But I definitely see that that subset of patients, which is the minority of myeloma, are the most promising with the treatment of venetoclax. And, fortunately, and again, in the myeloma patient population there’s been low toxicity with that agent. Case: A 54-year-old man with R/R MM receives ixazomib/lenalidomide/dexamethasone DR LOVE: I wanted to ask you about your 54-year-old man who currently is receiving for relapsed disease ixazomib and lenalidomide and dex. And I want to ask you about what happened there. But I noticed something in his history I was curious about, that I guess maybe when he presented, he had bone infarcts. How do they present clinically? What happened with him? What do you see when you see bone infarcts in myeloma? DR STADTMAUER: Yes. No. That’s a very good question. I mean, most of the time when we have patients with myeloma, the bony disease that we see is lytic bone lesions, mainly from the cytokines that are released by the plasma cells that lead to the osteoclasts eating holes in the bones. Very occasionally, in the POEMS syndrome we see osteosclerotic lesions. But I would say the reports of this have been greatest in acute leukemia or maybe lymphoma, like high-grade lymphoma, in bone marrow diseases, even though you think of the bone marrow as a very vascular structure. If you have a very rapidly growing high-risk disease or high growth-rate disease, these cells can outstrip their blood supply. And you can actually get a necrosis of the bone marrow. And it’s usually a very poor prognostic finding in all diseases, but we see it in myeloma also relatively infrequently. But it’s usually a sign of a packed marrow of rapidly growing cells, which, remember, in myeloma, even though we see an aggressiveness to a lot of these diseases, they really don’t have as rapid division as certain lymphomas and leukemia. And so seeing a necrosis is really much less common in this disease. DR LOVE: And what do you see clinically? What happened with him? Do they have pain? DR STADTMAUER: Pain. DR LOVE: Pain. DR STADTMAUER: Yes, pain. Pain. That’s usually the main thing that — so it’s, I guess, in the differential diagnosis of why people will have pain. It can be a necrosis occurring in the bone marrow. And, sometimes, radiation to that area will be helpful. Probably the most important thing is, though, successful treatment and making the disease better. Depending on where — usually the osteonecrosis occurs not in the joint but in the longer bones. If it occurs in a joint, though, just like a vascular necrosis, ultimately if the pain persists even though the disease is improved, potentially a joint replacement or something like that might be helpful. DR LOVE: So I was curious about your clinical experience with ixazomib. As I mentioned, it looked like that’s what he’s on right now. What was going on when you started him on therapy, and how did he tolerate it? DR STADTMAUER: And as of this moment, I see ixazomib as an alternative to bortezomib. That’s the primary way. And I know that it is a completely different medication and potentially has different activities. But most of the clinical data that we have right now is that it is not clearly — though there hasn’t been a head-to-head comparison — better or worse than bortezomib. And so the primary use that I have is in people where the convenience of taking an oral agent rather than a subcutaneous agent would warrant it. Occasionally, though, there is a neuropathy associated with ixazomib similar to the neuropathy in bortezomib — but there is an occasional person who did not tolerate well bortezomib but responded where I will try ixazomib. I think the data of using the IRd regimen, the ixazomib/lenalidomide and dexamethasone regimen, early in the course of the disease is excellent. I think in the patient that we’re talking about, it was a patient who had had initial therapy, an autologous stem cell transplant, lenalidomide maintenance therapy. And then when the disease biochemically started progressing, we — he’s a very active guy. He travels a lot. And so rather than using a bortezomib-containing regimen, we decided to initiate the ixazomib/lenalidomide/dexamethasone at that point. And he’s tolerated it very well. DR LOVE: No GI problems? DR STADTMAUER: I wouldn’t say no GI problems. That, of course, is where we think of bortezomib as neuropathy being the primary issue. We think of ixazomib as GI toxicity being the primary issue. But for the majority of patients that we’ve treated with either — obviously depending on what the issue is, some loperamide, sometimes cholestyramine, which has been the miracle agent for lenalidomide diarrhea, sometimes taking an antiemetic. Most of the patients are able to tolerate the agent well. Occasionally we do a dose reduction. Four milligrams is the standard dose. I have patients on 3 mg who tolerate it just fine and have real activity. DR LOVE: And how long has he been on treatment, and how’s he responding? DR STADTMAUER: He’s responding nicely to it. And I think he’s been on it for somewhere in the neighborhood of about 5 to 6 months, something like that. DR LOVE: It’s interesting that you chose to really add the ixazomib. He was progressing on lenalidomide and dex. Did you increase the dose of the lenalidomide? DR STADTMAUER: He didn’t tolerate — lenalidomide actually gave him more toxicity. And I did, actually. He was on 10 mg, which is the standard maintenance. I brought it up to 15 mg and added the 4 mg of the ixazomib and 20 mg of dexamethasone. I’ve found, in general, dexamethasone, less is more in order — remember, so much of myeloma and so much of the decision-making is not so much as much which regimen is going to be the most active, because, obviously, we want to see responses when we do this. The whole point is that the only reason why we’re making changes is because we expect we are going to have a symptomatic progression. And we want to avoid that from happening or turn around the symptoms as quickly as possible. But there’s also a very important aspect of durability. We want to be able to get a regimen that patients can take for a long period of time, because if the patients can’t tolerate it, then they’re not going to benefit from that. And so I’m very much of a tweaker of doses and schedules. And the great thing about myeloma that we’ve learned is the full dose on time approach is not as essential in this disease, as like acute lymphocytic leukemia or something like that, as making sure that the patient tolerates the regimen for a long period of time. Treatment approach for patients who experience relapse while receiving post-transplant lenalidomide maintenance therapy DR LOVE: So it’s interesting. So this patient got VRd, RVd, as most do, transplant and then len maintenance, relapsed on len maintenance, very common scenario. And you chose to add in ixazomib, increase the dose of lenalidomide. But there are other approaches to these types of patients. One is to increase the dose of lenalidomide and add elo. Another is car/pom/dex. There are other combinations that can be considered and, of course, daratumumab. How do you go about deciding specifically what to do for a patient who relapses on len maintenance? DR STADTMAUER: Sure. That’s, of course, the $64,000 question. And it’s the question that we are confronted with virtually every day multiple times, especially if you have a large myeloma practice. And what I do is what I’ve done for the last 20 years in caring for patients with myeloma. Any time I have a decision point, what I do is I review all of the treatments that the patient’s had in the past, whether they responded or didn’t respond, but, even more importantly, what the toxicities were, to see if patients will tolerate things. I also have a strong philosophy that, unlike maybe breast cancer or lung cancer or other diseases, that each combination of therapy should be thought of as a different drug, that len/dex is different than bortezomib/len/dex is a different drug than elo/len/dex. The combination is magic, that there’s something to the combination. So then what I do is I list, just like you just did, all the potential options for the patient. And, of course, there’s a lack of studies, because they are very difficult studies, that look at sequence of regimens. So that’s why, until there is more data about sequence, I really think in terms of toxicity. I want to use the same philosophy. I’m looking for regimens that have a high chance of working, that if they work, that there’s a high chance that the patient will be able to continue the regimen for a period of time. So you negotiate. It’s always a negotiation with the patient. Do they live far away, in which case oral agents would be better than infusions. Are they frail, in which case it would be better to have a regimen where they’re being seen frequently in the clinic, so that you can keep an eye on them and make adjustments quickly. And then let’s — some patients, they’ve had lenalidomide, they have had horrible diarrhea. So there’s no way that you should do a lenalidomide. I’m not a very strong believer in classes of medicines that — which, I think, again, is maybe a difference in the solid tumor oncology, that if the patient’s progressing on an immunomodulatory agent, then you must not use immunomodulatory agent the next time. I don’t think that holds true in myeloma. I think that pomalidomide can be very effective in a patient where lenalidomide has lost its activity. I think there is a lot of data now to suggest that triple therapy is superior to doublets. And so if patients can tolerate it — that’s why I like the idea of rather — though I do have patients who have just been on lenalidomide, and I’ll just increase the dose and add some dexamethasone as the initial therapy. But I do think that that has been proven in randomized trials to be inferior to adding elotuzumab to lenalidomide and dexamethasone, for instance, or bortezomib to lenalidomide and dexamethasone. So I think triple therapy, as a rule, is better, but you have to take into consideration so much of the patient’s preferences, and then, occasionally, you have to take into consideration insurance and what is covered and what’s not covered and what’s going to have huge copays and what’s not going to have huge copays. Case: A 76-year-old man with previously treated Waldenström macroglobulinemia (WM) experiences a prolonged response to ibrutinib DR LOVE: Let’s talk a little bit about Waldenström’s. And maybe we hear about your 76-year-old man. DR STADTMAUER: Waldenström’s is a disease — so it’s really different from myeloma. I’m a believer that Waldenström’s is more lymphoma than myeloma. But it’s a low-grade, indolent lymphoma that is associated with a monoclonal protein and can be associated — and has, generally, a very indolent course. And I have patients who I’ve been following for 25 years who have never been on any therapy. But it also can have some very devastating problems of kidney dysfunction and low blood counts and infections and hyperviscosity. So the hardest or maybe the most important first decision always is, should the patient be treated at all? And in general, I have a slow hand to treat Waldenström’s patients, that the vast majority of patients putter around for a long period of time. And they really have to be symptomatic or have a clear evolution of their disease in a negative way for me to start treating them. But, fortunately, we’ve got some really good treatments. Of course, we have the traditional treatments of chemotherapy. And, just like any other low-grade lymphoma, the bendamustine-containing regimen, like bendamustine and rituximab, is a very active and reasonable and relatively well-tolerated regimen. Frequently I’ll start off with rituximab as a single agent. The problem with rituximab as a single agent, though, is there is this bump in the IgM monoclonal protein that occurs relatively frequently after single-agent rituximab. So if a patient is borderline hyperviscous to begin with, you have to be very cautious about that. So if I see someone like that, I’ll watch them, of course, very closely. And frequently I’ll give them some dexamethasone or maybe even, the first time, a couple of plasma phoresis procedures to reduce the likelihood that that will happen. When you give chemotherapy along with rituximab, then it significantly decreases the likelihood of that bump in the IgM. But in the patient that I presented, however, he received that, but he did not have a particularly prolonged or good response. So we’re very fortunate, particularly because of the work of Steve Treon from Dana-Farber, is that it turns out that ibrutinib, again utilizing a drug that had been created in many ways for chronic lymphocytic leukemia, the MYD88 mutation is very common in Waldenström’s macroglobulinemia. And there are tremendous response rates and prolonged responses just by taking 3 pills or so of ibrutinib daily. And so that’s what this patient did. He received the bendamustine and rituximab, did not have a prolonged response and so has now been on ibrutinib for a year or so and is doing beautifully. And those responses to ibrutinib with relatively low toxicity and high response rate have led to the debate as to whether ibrutinib should become the first-line therapy for — and I believe that there’s clinical trials that are ongoing that looking at this. And I think it’s a very reasonable thing to consider, but I guess the great thing about using a chemotherapy approach is that it tends to be a very limited therapy, that you’ll receive maybe 6 cycles of something, go into remission — and those remissions can last for years — versus taking a continued set of pills for indefinitely. And though ibrutinib has been very well tolerated, there’s always some potential toxicities of rashes, of bleeding disorders, et cetera. But I think the outlook for patients with Waldenström’s, number one, it started off not too horrible to begin with. Less is more. And many of these patients can be monitored for many years. But should they run into trouble, I think we have a number of really good options for them, and that leads to responses that are prolonged and well tolerated. DR LOVE: Yes. I mean, it’s interesting. You have a 76-year-old man. I mean, he got through the bendamustine/rituximab, but he did have some problems. You can imagine somebody, 85 to 90 and more frail. Are there clinical situations where you would attempt to use ibrutinib up front? DR STADTMAUER: Definitely. No. I think that’s a very good point, that given the low toxicity and a pill regimen, it makes a lot of sense to consider frailty, et cetera. Incidentally, he’s a 76-year-old gentleman. He has a 45-year-old girlfriend, so I think he’s maybe a special case. DR LOVE: That sounds interesting. In any event, let me see. There was something else I was going to ask you. Yes. And it’s interesting, this dilemma about do you want to give short-term rituximab/chemo versus ibrutinib. The same argument goes on in CLL. It’s interesting, though. They still use, particularly for younger patients, chemo/rituximab with the idea of avoiding long-term treatment, although other people say, “Hey, it’s just another pill.” DR STADTMAUER: Yes. For CLL, obviously, it’s a whole different topic. But yes. To me, that is one of the harder decisions for a young patient with CLL, the, like, FCR versus doing something else. And so it’s an evolving area. Again, as I said, myeloma and for CLL, also toxicity is maybe even more important a determination of what you should give than response, since we see such nice responses with many different agents. And the fludarabine-based regimens really lead to an immunologic dysfunction. And that is lifelong in these patients. And ultimately, that might be a toxicity that we’d like to avoid, given the newer agents. DR LOVE: That's interesting. You’re saying that the immune suppression from fludarabine lasts after treatment’s stopped? DR STADTMAUER: Yes. Yes. So I would say those sorts of adenosine deaminase inhibitor-type medicines really do lead to a — they’re so good at killing lymphocytes that you can detect real immune dysfunction for years, if not decades, in this group of patients. And now that the patients are living longer and longer, is that something that might either limit their therapies in the future or lead to secondary problems in the future? Case: A 58-year-old man with newly diagnosed high-risk MM experiences a very good partial response and moderate peripheral neuropathy with lenalidomide/bortezomib/dexamethasone (RVd) induction → autologous stem cell transplant (ASCT) but is unwilling to receive bortezomib maintenance therapy because of concerns about further neuropathy DR HOLSTEIN: So I saw this 58-year-old gentleman shortly after he had been diagnosed with myeloma. He came to me as a second opinion. This was obviously quite a surprise for him, and he wanted to see a myeloma specialist and just learn a little bit more about his disease before he committed to starting therapy that had been recommended by his local oncologist. So when he presented, he did have a diagnostic bone marrow and they did do FISH, which didn’t show, at the time, any true high-risk abnormalities. So it showed a deletion 13q, 1q-positive, as well as some trisomies. The FISH done on the outside did report some sort of IGH rearrangement, but they really couldn’t identify the partner, so nothing more was done with that. So when I saw him, we discussed standard treatment for newly diagnosed myeloma, because he was 58 and otherwise healthy. We talked about the role of consolidation with autologous stem cell transplant. And I strongly encouraged him to do that following his induction therapy. DR LOVE: What was his life situation and work, et cetera? DR HOLSTEIN: So he was working full time and really was otherwise healthy. And so he wanted to go through therapy kind of as quickly as possible and get back to work as quickly as possible. DR LOVE: And what was the first opinion, and what were your thoughts about that? DR HOLSTEIN: The first opinion also talked about the same induction regimen that I ultimately recommended, which was RVd, or lenalidomide/bortezomib and dexamethasone. He had had kind of minimal discussion about the role of autologous stem cell transplant, kind of knew a little bit about it, but it hadn’t really been clear to him whether this was something that should be done following induction or whether this could be done sometime later in his disease course. DR LOVE: So what happened? DR HOLSTEIN: So after discussing with him the data that are out there for the role of up-front transplant, he ultimately went back to his local oncologist, because he does live several hours away from where we are. And he received his 4 cycles of lenalidomide/bortezomib and dexamethasone, or RVd induction therapy, and he achieved a partial response. I had set him up with one of the bone marrow transplant colleagues at my institution, and he underwent a standard melphalan 200 autologous stem cell transplant in May. And then I saw him again for his post-transplant evaluation after he had completed the day-90 bone marrow biopsy and all of the other laboratory studies. DR LOVE: And what did his evaluation show at that point? DR HOLSTEIN: So at that point he would be judged as a very good partial response, because he did still have a very small M spike left in his serum. But, really, the reason that the bone marrow transplant colleague wanted me to see him again was that the FISH that was done on this marrow now was able to provide more clarification about that possible IHG rearrangement. And, in fact, our cytogenetics lab identified a translocation 14;16, which, of course, is associated with high-risk disease. And so my colleague really thought that it would benefit the patient to talk more with me as to whether or not just single-agent lenalidomide maintenance was sufficient or whether we should do something a little bit more aggressive, given the high-risk cytogenetic disease. DR LOVE: So what did you decide to do? DR HOLSTEIN: So I talked to him at length. When he first started talking to me and I hadn’t seen him since, again, before he received treatment, so I really hadn’t had a chance to see how he had done with his induction therapy. He told me that induction therapy had gone horribly. He felt very sick. He had lots of side effects that he attributed to lenalidomide, to bortezomib, and he didn’t think he wanted any additional treatment. But we had a very long conversation about the role of maintenance therapy in general and, of course, what studies show when you look at taking placebo or observation versus taking lenalidomide. And then we had an even longer discussion about high-risk features and, in general, how their duration of remission is significantly shorter. DR LOVE: Could you talk a little bit more about the problems that he had with RVd? And do you think he had more problems than other people, or he was more sensitive to them? DR HOLSTEIN: I think he was more sensitive. So one of the problems, which, of course, is significant when we think about what to do post-transplant, was neuropathy, peripheral neuropathy, primarily in his feet but somewhat in his hands as well. And this started occurring partway through his induction therapy and then really seemed to worsen after the transplant, although he did admit, kind of, the further he got out from transplant, the better the neuropathy was getting in his feet. That was expected. DR LOVE: He got subQ bortezomib? DR HOLSTEIN: He did. DR LOVE: Weekly? DR HOLSTEIN: Yep, in the standard dosing. DR LOVE: And again, looking at him objectively, would you say that the amount of neuropathy he had was more than you typically see? DR HOLSTEIN: Not more than you typically see, but I think he was just sensitive to that sort of side effect. So it really bothered him at night when the covers were brushing his feet. It really bothered him to have any light touch sensation on his feet. But he really wasn’t having burning pain sensation that you see with the more severe bortezomib-induced peripheral neuropathy. He wasn’t having balance issues. I think he had been one of those individuals who was previously very, very healthy and hadn’t had side effects, because he wasn’t really on medicines before and so was just a little bit more sensitive. He did note that he had started wearing compression stockings about 2 weeks before he saw me and that that seemed to be helping. Again, whether it was the compression stockings or simply just more time away from the melphalan, it’s a little bit hard to know. DR LOVE: Interesting. Ixazomib as a component of maintenance therapy for high-risk MM DR LOVE: So what did you decide to do? DR HOLSTEIN: So I presented him with all the information, talked about, “Look. If you don’t do anything, here’s my best guess as to when you will relapse,” and that best guess was probably 12 to 18 months. “If you take lenalidomide, here’s my best guess as when you will relapse.” And then we talked at length about the fact that we don’t have Phase III data supporting the use of triplet maintenance therapy post-transplant but that we know from both newly diagnosed and relapsed/refractory setting that the combination of an IMiD and a proteasome inhibitor can at least partially abrogate the effects of high-risk disease and that if the goal is to really try to keep his disease under control for as long as possible, my recommendation would be to use triplet maintenance therapy. Now, the kind of standard out there at this point in time is based on a manuscript out of Emory by Nooka et al, where they used kind of a modified lenalidomide/bortezomib/dexamethasone maintenance regimen for their high-risk patients for up to 3 years. Because of the peripheral neuropathy and because of the patient’s very strong opinion that he never wanted to get treated with bortezomib again, I recommended that we substitute ixazomib for bortezomib. I of course discussed the fact that we don’t really have data supporting this but that we do know, at least in the relapsed/refractory setting, that lenalidomide and ixazomib can at least partially overcome the adverse events associated with high-risk disease and counseled him that hopefully that this regimen would not increase his existing neuropathy and that he should be able to tolerate it. He was still a little bit on the fence about therapy, but we discussed that you could always start, kind of see what his quality of life was and, if it was acceptable to him, then continue for as long as possible. DR LOVE: So what happened? DR HOLSTEIN: I saw him just about 2 months ago, so as far as I know, he has started therapy. I told him that if he was not able to tolerate it that he should come back and see me. Again, he is following with his local oncologist on a regular basis and not me. So I’m assuming that right now, no news is good news. Benefits of post-transplant maintenance therapy DR LOVE: So can you talk a little bit — because, obviously, you’ve been very involved with the research on post-transplant maintenance, where we are today in terms of what we’ve learned about post-transplant maintenance, both with lenalidomide and maybe go a little bit more in depth when we start talking about triplets but also what we know about the benefits of maintenance based on cytogenetic status and how much, for example, the number that you gave him, if he didn’t have any maintenance, how that would, in your best guess, best estimate, how that would be actually affected by lenalidomide, for example, without a proteasome inhibitor and then your best guess about if you used the triplet? DR HOLSTEIN: Sure. So at this point in time, I think we have really excellent data supporting the use of single-agent lenalidomide maintenance, but really that’s in all comers. So, of course, CALGB-100104 was conducted in a time when we really did not have cytogenetic data available. The recently updated analysis, again, despite extensive data-cleaning efforts, we really were not able to include any cytogenetic data, because it simply wasn’t done at that time when patients were being enrolled in around 2005 or so. So we really can’t comment on that, but we can comment, of course, is that through multiple Phase III studies, lenalidomide maintenance significantly prolongs progression-free survival, almost doubles it in most cases, and that if you look at the studies in aggregate through the recently published meta-analysis, there is an overall survival benefit as well. The best data so far for the role of lenalidomide maintenance across all cytogenetic risk factors, risk groups, really comes from the Myeloma XI study, which thus far has only been presented in abstract form. But there we have really lovely data showing the difference in outcomes between high-risk disease patients and standard-risk disease patients. And, of course, not surprisingly, those patients with standard risk do better than those patients with high risk. But, importantly, the data that was presented at ASH for this study showed that the addition of lenalidomide improved outcomes regardless of whether you were high risk or standard risk. Now, lenalidomide does not bring the high-risk patients up to the standard risk. There is still definitely an adverse risk associated with high-risk disease. But the data clearly showed that patients with high-risk disease do obtain some benefit with lenalidomide. And so I think that’s really important, because previously there’s always been this bias, I think, against lenalidomide maintenance, saying that, “It works for patients who are standard risk, but it doesn’t work for high risk.” And now we finally have high-quality data from the Myeloma XI study showing that that’s not the case, that, in fact, patients with high-risk disease do benefit. But again, the overall problem remains that it’s not enough to convert high risk to standard risk. RVd consolidation and maintenance therapy for high-risk MM DR LOVE: And you referred to the data from Emory. Can you talk a little bit more about that as well as other attempts to look at triplet therapy in the maintenance setting, or even consolidation, for that matter? DR HOLSTEIN: Right. And so I think the consolidation is a little bit different than the maintenance. Certainly there are studies out there, for example with carfilzomib/lenalidomide/dex, looking at kind of a fixed number of cycles post-transplant. And you can see improved depth, so there’s responses, improved deepening of MRD negativity, but in general those are fixed numbers of cycles and not prolonged duration. Really the best data we have for that is the Emory study, which again was really more of a single-institution experience, where they took their high-risk patients and gave them this modified RVd regimen for up to 3 years. And if they still hadn’t progressed after 3 years, then the idea was to convert them to single-agent lenalidomide. Certainly the outcomes were good, but, of course, this was not a randomized study. And, of course, in real life it’s sometimes difficult to try to convince patients to stay on triplet therapy for years at a time. DR LOVE: But, on the other hand, the first time I started to — I remember hearing about oral proteasome inhibitors — and we have ixazomib, which this man received, and there’s also oprozomib, which is not approved. My first thought was maintenance. It doesn’t seem like it would make that much difference, oral versus IV for a few courses up front. But when you start thinking about 1 and 2 years, it seems like that’s where an oral agent really would come to be useful. Selecting among options for maintenance therapy DR LOVE: What do we know right now about oral proteasome inhibitors, including ixazomib, as maintenance? DR HOLSTEIN: So we know that it’s feasible. I think that’s the main thing that we know. Really at this point in time, we don’t have Phase III data available telling us that it’s better than placebo or better than lenalidomide, better as a single agent versus some sort of doublet or triplet. But we do know that prolonged therapy with ixazomib is feasible, which I think is a really important point. There was obviously a lot of concern that perhaps GI side effects from ixazomib would make it difficult to have a patient stay on long term, but the studies that have been done thus far show, again, the feasibility of it. The question obviously is whether or not ixazomib is equivalent to lenalidomide, whether there are subgroups of patients who would benefit more from ixazomib than from lenalidomide. Here I think it gets down to interesting philosophical questions about what we think lenalidomide is really doing in the postmaintenance setting. So is lenalidomide simply achieving antimyeloma effect and that’s why patients do well for longer, or is lenalidomide really modulating the immune system and providing kind of an immune context that allows for disease control for longer periods of time? There’s been all sorts of discussions amongst the myeloma physicians about whether the dose of lenalidomide that’s used in the maintenance, which is usually somewhere between 5 and 10 mg, is really sufficient to cause significant antimyeloma effects or, again, whether the benefit that we see is from immune modification, which, of course, we know that lenalidomide has those properties. On the flip side, certainly ixazomib has antimyeloma effects, but we think that ixazomib has far less immunomodulatory effects than lenalidomide. So from a maintenance perspective, ixazomib long term, are we achieving benefit from simply antimyeloma effect or immunomodulating effect? That I think we don’t know. DR LOVE: I’m curious what your thoughts are in terms of the question you posed about the lenalidomide and specifically whether in your mind it’s an exciting opportunity or a research thought to combine other immune strategies with lenalidomide in the maintenance setting. And, of course, the one obvious one would be elotuzumab. What are your thoughts about that kind of strategy? DR HOLSTEIN: Oh, it’s something that we are very excited about. And I’ll just say that through the Alliance Cooperative Group, that’s actually a study that we have been trying to get up off the ground for quite some time looking at lenalidomide with a variety of different partners and really asking the question, “What happens from an immunomodulatory perspective, looking at immune subsets in peripheral blood and marrow, looking at response rates?” I think there are many different agents out there, which we know from the relapsed/refractory setting have better activity when you combine them with lenalidomide. And it’s the number one question right now. Which agent should we be using in combination with lenalidomide, or should we be using any combinations? Elotuzumab is a perfect example. Clearly it’s a medication that does not produce a lot of side effects, so from a long-term feasibility perspective, it should be relatively safe and easy to manage for patients once you get past the fact that they will be required to go into their infusion centers a couple of times a month. From an immunomodulatory perspective, elotuzumab has a lot of attractive properties because of its effects on not only myeloma cells but on natural killer cells. So again, if we think that there is some sort of immune milieu that’s really optimal for maintaining disease control, perhaps elotuzumab can contribute to that. But, obviously, elotuzumab isn’t the only option out there. Obviously we could add a proteasome inhibitor like ixazomib that we’ve been discussing. You could add other monoclonal antibodies like daratumumab. There are newer agents that are starting to be studied, such as HDAC inhibitors, some of which, such as the HDAC6 inhibitors, which are oral and which also have potential as maintenance therapies. So there’s a lot of potential out there. I think the question is, how do we go about designing studies to get answers as quickly as possible? DR LOVE: And I guess one other immune potential additive, particularly to an IMiD, that has been looked at, but I don't know if it’s been looked at in the maintenance setting, would be checkpoint inhibitors. Is there an interest in looking at that in the maintenance setting? DR HOLSTEIN: There is, absolutely. And, in fact, the study that we’ve been trying to get up off the ground through the Alliance, one of the arms does contain a checkpoint inhibitor. And I know there are some smaller institutional-based studies that are starting to look at that. But thus far I haven’t seen any data yet. Perhaps this upcoming ASH. Ixazomib-associated gastrointestinal toxicity DR LOVE: So I want to go back to a couple of other aspects of the case that you just presented and get into it a little bit more. One is, you mentioned the issue with GI toxicity with ixazomib. And I’m curious what your experience has been with that. Do you start patients on preemptive GI medication, antiemetics, for example? What kinds of GI problems? Is it dose related? DR HOLSTEIN: So my experience is that primarily it’s diarrhea in nature. I’ve really not seen patients experience nausea and vomiting. I generally will have antinausea meds available to the patient at home. But in my experience, they really have not needed it. In the relapsed/refractory setting, when my institution participated in the placebo-controlled study of lenalidomide/dexamethasone versus lenalidomide/dexamethasone and ixazomib, to be honest I really couldn’t tell which patients were receiving active drug versus placebo. So in general, my experience has been, the GI side effects are not overwhelming, but you do have patients who sometimes have diarrhea. In general, that, however, is easily managed with over-the-counter medication. DR LOVE: So another issue with the proteasome inhibitors in general — and this man had problems with neuropathy from the bortezomib — what about ixazomib in terms of neuropathy? And where would you put in carfilzomib? DR HOLSTEIN: So I would say ixazomib causes a very low frequency of neuropathy based on the clinical trials and also just based on my experience in clinic. For the patients who have bortezomib-induced neuropathy and then get switched over to ixazomib, my experience is that their neuropathy does not worsen. So I think that’s an attractive feature of ixazomib. I really have not seen any carfilzomib-induced neuropathy. So from a neuropathy perspective, both ixazomib and carfilzomib seem to be very good. Bortezomib still, that’s its biggest problem with respect to long-term administration is the development of the peripheral neuropathy. Carfilzomib- versus bortezomib-based induction therapy DR LOVE: So I was also going to ask you about carfilzomib as an up-front treatment. Looking back at this man’s course, particularly because he was unhappy about the neuropathy, what’s your take right now? I mean, carfilzomib has its own set of risks. I mean, obviously there’s a randomized study looking at carfilzomib versus bortezomib as induction therapy. But right now based on the research data that we have and your own clinical experience, how would you weigh out indirectly the risks and benefits of these two drugs as part of induction? DR HOLSTEIN: I think that there’s still a lot for us to learn. And I’m eagerly awaiting the results of the ECOG KRd versus RVd study when it’s finished. I think what we’ve seen so far is that there is a toxicity profile for carfilzomib that we did not expect, based on all the relapsed/refractory studies that have been done previously. I think that there’s a cardiopulmonary, kind of, thromboembolic profile in the newly diagnosed setting. The numbers of patients that are experiencing these serious adverse events are low, but when they do experience them, these events are very serious. So for me that’s been enough to say that I don’t start somebody out preemptively on lenalidomide/carfilzomib/dex. I really want to see the safety data to make sure that we understand and can manage these patients appropriately. But what I will sometimes do is, if patients do not have an optimal response to up-front lenalidomide/bortezomib/dexamethasone — let’s say they’ve maybe achieved a PR or maybe still have 20% of plasma cells left in their bone marrow and we’re trying to get them to transplant — I’ve found that switching over to KRd, so lenalidomide/carfilzomib/dexamethasone, really in all cases thus far that I’ve attempted gets the patient to that very good partial response or a bone marrow less than 10% plasma cells and gets us moving on to consolidation with transplant. So that’s really my practice thus far. I won’t offer KRd up front until we have Phase III data showing at least equivalency with respect to efficacy, but also a safety profile that’s acceptable. But I will switch patients over if they haven’t achieved the optimal response with up-front RVd. DR LOVE: Can you drill down a little bit more in terms of what your take is on the toxicity profile of carfilzomib? It’s always been kind of difficult for me to sort out what’s going on. I hear about a dyspnea syndrome. I hear people saying there’s a small incidence of actual cardiac dysfunction. You said “thromboembolic,” which I’m not sure I’ve heard at all. But what specifically do you think is associated with this drug? DR HOLSTEIN: I’m not sure that I’m smart enough to answer that. I think what we are learning so far is some vague vascular injury, but that’s pretty nonspecific, and I recognize that when I’m answering. I know that there has been interest in obtaining additional correlative studies from the ECOG study, so that we can learn more about this. But the adverse events that we haven’t quite predicted have included things like heart attacks, serious PEs. Now, you could say that that’s the IMiD, but generally these days we know how to manage IMiDs and prevent thromboembolic events associated with IMiDs. And so to have serious pulmonary emboli occur on patients receiving KRd suggests that perhaps this is coming from the carfilzomib, although obviously hard to prove. I don’t think we know what it is, but if you’re taking somebody who’s relatively young and fit and transplant eligible and exposing them to a risk of a serious cardiopulmonary side effect, you really have to be sure that you’re doing that for a good reason. And I think right now, we just don’t have enough data to tell us that this is, in fact, safe enough to become the new standard of care. DR LOVE: How often do you see a patient who’s getting carfilzomib, who talks to you about the subjective experience of dyspnea during the infusion? And if they do say that to you, what do you do? DR HOLSTEIN: So it’s, I would say, maybe 25% of the time — DR LOVE: Wow! DR HOLSTEIN: — I see it. And it’s always hard to know what to do. You first make — obviously you know whether these patients have underlying lung disorders, they’re baseline COPD, et cetera. Are they managing that as they should? I’m usually pretty strict about not giving a whole lot of prehydration fluids. And I really only do it with the first cycle, so I usually don’t worry that this is iatrogenic in terms of salt overload from too many fluids pre/postcarfilzomib. The discussion varies from patient to patient in terms of how much it’s actually bothering them. On occasion I will do more workup, kind of make sure that there haven’t been changes in PFTs, check an echocardiogram. But I’ve never really found anything objective in those types of evaluations. Ultimately, it’s up to the patient if they’re — usually if they’re responding well, or if their disease is responding well — we kind of talk about having them alert me if their symptoms worsen in any way, immediately — they feel comfortable continuing on. Duration of lenalidomide maintenance therapy DR LOVE: So one other aspect of the trial that you mentioned is comparing KRd to RVd, if — I believe that there’s another randomization to 2 years versus indefinite len maintenance. And I’m curious about your thoughts about the rationale behind that and whether you have any hesitancy about putting a patient on that study. I’m going to guess, off study, do you use indefinite len maintenance? DR HOLSTEIN: Yes, I do use indefinite. And that’s because it’s based on multiple Phase III studies and, of course, most notably in this country, CALGB-100104, in which the lenalidomide was continued until progression. What CALGB-100104 does not directly address is whether indefinite maintenance is needed. So it definitively answers the question of yes, lenalidomide maintenance versus placebo confers improved outcomes. But do you get the same improved outcomes for 2 years of len versus 3 years, versus 5 years, versus indefinite? And we simply don’t know the answer to that. So I think it’s an interesting question to ask. There’s, of course, a financial cost to staying on len long term. There’s just the daily side effect cost to the patient of staying on len long term. That should be considered. If we think, though, that either of the two things we talked about earlier, that either len is manipulating the immune system to create an immune environment that somehow maintains disease control and/or if we think that len’s inducing antimyeloma effect, then I think it makes sense that continued lenalidomide would provide better outcomes. But we need to do the study to prove it. We’ll also have some more indirect, kind of, study-to-study comparison for the IFM 2009 study versus the Dana-Farber one conducted in this country, where lenalidomide on the French side is continued just for 1 year for maintenance and, of course, in this country lenalidomide is being continued until disease progression. Here if you look at the French data, I think you can already start to get a signal of that. Relapses start to happen once you stop lenalidomide maintenance. And that’s even in the case if you look at the curves that were published, where they’re looking at the patients who achieved MRD negativity. You start to see those curves kind of tick off after the patients stopped lenalidomide maintenance. So I guess my personal bias is that continued therapy will provide better long-term outcomes, but again, we absolutely need the studies to prove that. DR LOVE: But, obviously, you’re comfortable to put a patient on a study like that. DR HOLSTEIN: Yes. Yes. Early versus delayed ASCT after induction therapy for MM DR LOVE: So another kind of related question to this case is the issue of was his transplant really necessary? Or could it have been delayed? I don't know what his life situation was and how much of a problem it caused him work wise or whatever, to have to go through a transplant. But I’m curious what you say to patients about the benefit of transplant. For example, do you believe there’s a survival benefit to doing it? Do you believe that patients would do just as well with delayed transplant? And from a practical point of view, do you think there could be a role right now for MRD measurement in trying to make that decision? DR HOLSTEIN: So all those are absolutely fantastic questions. First, with respect to the data supporting the use of up-front transplant versus delayed, so I generally will have a discussion about the fact that at this time, there are 4 relatively recent Phase III studies, which have all addressed that question. You can argue that a few of them done in Europe perhaps used suboptimal induction regimens and, therefore — and suboptimal chemotherapy versus transplant arms. But even so, the signal across all 4 studies has been very consistent in terms of the PFS benefit. The survival benefit yes, in some studies. The IFM 2009 study we simply don’t have long enough follow-up yet to look at survival differences right now. There’s no difference between up-front and delayed transplant, but both arms are doing exceedingly well. I really tell patients that I believe at this time that up-front transplant should be considered standard of care. Practically speaking, when you have patients who choose to collect their stem cells and perhaps stay on some sort of maintenance therapy, whether it’s len alone, lenalidomide/dexamethasone, their quality of life up front might be better because they didn’t go through transplant, but their disease is oftentimes difficult to manage once they do start to progress. So you’re progressing on, let’s say, len alone or lenalidomide and dexamethasone. At this point, then you need to offer some sort of salvage therapy to try to get them to transplant. And it’s not always an easy thing to get them to that transplant. And so I think the likelihood of a patient getting a transplant is much, much higher if it’s done following induction versus waiting until time of first relapse. I also think that the disease sensitivity is improved. In general, we have retrospective data suggesting that the fewer therapies that a patient sees up front before going to a melphalan-based transplant, the better the outcomes are post-transplant. And so I think it’s difficult once you start treating a relapsed patient and trying to clean up their disease, get them to transplant. I think in general the duration of benefit post-transplant in the delayed setting is shorter than the benefit in the up-front setting. So we talk about all of that. And so I sometimes say that it’s up-front pain for hopefully long-term gain. Whether that’s true for every single patient, it’s hard to say. We only have aggregate data. We’re not very good at individualizing therapy at this point. But I think right now in the absence of any other studies showing true prolonged remissions without a transplant, I would still offer transplant following induction therapy. This question of MRD negativity is a really interesting one. Obviously we know that achieving MRD negativity is a good thing. There’s no question about that. But where I think it gets murky is whether is it just MRD negativity times one? Is it MRD negativity over a period of a year, over 2 years? What’s really important? We all have had patients who achieve MRD negativity and then relapse 6 months later. So MRD negativity does not equal cure. And until we get to the point where we can confidently say that achieving MRD negativity equates to long-term remission, I don’t think we can use it to pick which patients don’t need a transplant or which patients should go to transplant. DR LOVE: So I’m just kind of curious, though, if a patient like this one, for example, a young patient, says to you, “Will I live longer by taking an immediate transplant as opposed to collecting my cells,” how would you answer that? DR HOLSTEIN: I would say I honestly don’t know. I think the answer is yes, but we just don’t know. Based on the study which is most applicable to him, the IFM 2009 study, the answer is in the short term no, based on 3-year survival data. But long term my suspicion is still that up-front transplant is going to confer better survivals. So I’m always very honest with my patients and try to discuss the available data and then try to distinguish between what my recommendation is, whether it’s based on data or whether it’s based on kind of personal judgment. Clinical utility of minimal residual disease (MRD) assessment in MM DR LOVE: And we’ve been talking a little bit about MRD measurement. Could you talk a little bit about what we know right now about the clinical utility of that strategy and whether you think it’s worth doing for a general oncologist in community-based practice? DR HOLSTEIN: So I think right now, MRD measurement is not ready for prime time. I think it really should just be confined to the use in clinical trials. Part of that is because we still are trying to figure out what the best way is to measure it. We’re still trying to get uniformity in how we measure it. And mostly it’s because we don’t truly know what to do with the data. So yes, we know that achieving MRD negativity is good. But we don’t know how to use that to individualize treatment decisions. And if you’re getting a piece of information that you don’t know how to use, then I’m not sure that we should be getting it in the day-to-day practice. DR LOVE: So I want to go on to your next case, but one final question about this case, which is kind of what your trigger finger is to use ixazomib. So if you think about the possibility of using ixazomib, everything from starting with up-front as part of induction to maintenance, as we’ve been talking about, to relapsed disease, what does it take for you to consider it? For example, maybe the patient’s very well informed. The patient might be a physician, whatever, and says to you, “I know there’s an oral drug out there. And I just don’t really like coming into clinic. I’d rather take a pill.” Is that enough for you to go, “Okay,” or do you need it to be, it’s a 2-hour drive, or they’ve had some kind of complication? How interchangeable do you think ixazomib and bortezomib is in the spectrum of disease? DR HOLSTEIN: I don’t think we know the answer to that yet. Much of my use has been in the relapsed/refractory setting. Obviously it’s not approved yet for the up-front setting. And so I really have not used it for any newly diagnosed patient. I have, on occasion, made the substitution after patients have started getting neuropathy with bortezomib. It’s a little bit difficult to piece out the benefit of ixazomib in patients who have progressed on bortezomib. There I worry that you aren’t going to get a lot of disease benefit. But for patients who are still sensitive to bortezomib but perhaps either couldn’t tolerate it because of side effects or it’s just inconvenient because of travel distance, I think it’s probably acceptable to switch out, but we just don’t know that yet. And to be honest, I think we aren’t even sure yet what the optimal dosing schedule is of ixazomib. Obviously it was approved in the weekly dosing, 3 weeks on, 1 week off of lenalidomide. But obviously there’s been more recent data going back to the type of dosing schedule that was studied in one of the Phase I studies, where it’s twice weekly. And so I’m a little bit hesitant to, especially, offer it to a newly diagnosed transplant-eligible patient when we know what to expect with RVd for response rates and we’re still a little bit unsure in the transplant-eligible population what to expect with lenalidomide/ixazomib/dex and whether we should be giving it once weekly or twice weekly. Again, in the relapsed/refractory setting, I would mainly use it in patients who, for some reason, did not receive lenalidomide with their up-front treatment and who were still bortezomib sensitive. Case: A 59-year-old man with R/R MM and high-risk cytogenetics receives pomalidomide/daratumumab/dexamethasone DR LOVE: So I want to try to go through your other cases. And we went into a lot of detail about this first case, because it seemed like a really good case to do that. But we’ll probably pick up the pace a little bit and focus on some of the key teaching points from each one of these cases, beginning with your 59-year-old man. DR HOLSTEIN: Right. So he’s a gentleman who I met late last year after he was relapsing post-transplant. So he’s a gentleman with IGA kappa myeloma. He had been diagnosed in late 2014 with his myeloma. He did have a translocation 4:14 at time of diagnosis. He received induction therapy with lenalidomide/bortezomib/dex, achieved a complete response with that. There were some delays with respect to collecting his stem cells and then getting him to transplant, but he eventually did get to transplant in September 2015. His post-transplant eval showed that everything looked good. He was still in a complete response. And he started len maintenance. In reviewing his records when he was referred to me, there was evidence of biochemical relapse by May 2016, so really only 5 or 6 months after being placed on len maintenance he already relapsed from a CR, which, of course, is not ideal. He then had some difficulties. They kept him on the lenalidomide maintenance. He had an episode of pancreatitis. His treating oncologist decided to stop the lenalidomide and, not surprisingly, he had further evidence of disease progression, and that’s when he was referred to me. So at that time, checked his marrow again. He had 13% plasma cells, no new findings really on FISH. And so we talked about the fact that with the translocation 4:14, that’s really considered a higher-risk cytogenetic problem. And we ultimately ended up recommending the combination of pomalidomide/daratumumab and dexamethasone. And so after 4 cycles of that, he achieved a serological CR. We have not repeated a bone marrow biopsy to confirm the CR, but he remains on it and is doing quite well from a myeloma perspective. DR LOVE: Just to go back to one point, I was going to ask you when we were talking about maintenance before. But I think this case brings that up, which is — before we get into the therapy on him in relapse — was the decision to use len maintenance in spite of the fact that he was in CR? What do we know about the benefit of len maintenance in patients who are in CR? And, for that matter, I don’t know, but what do we know about the benefit of maintenance in patients who are MRD-negative? DR HOLSTEIN: So excellent question. CALGB-100104, that’s one of the things that we looked at. And the short answer is that if you were in a CR and you get len maintenance, you do even better than if you were in CR and got placebo. So it’s not uncommon to hear from the community the perception that if you’re in a CR you don’t need maintenance. And that’s simply not true based on the available data. Again, 100104 clearly demonstrates that you do benefit from maintenance even if you are in a CR. In addition, I think what we know so far about MRD negativity is that you do benefit from maintenance there as well, but we clearly have less data at this point. Triplet therapy options for R/R disease DR LOVE: So can you talk a little bit about what your thought process was about the various options that were available at the point that you decided to treat him with the pom/dara/dex? What were the other thoughts that you had about possible therapies in that situation? And how do you approach the issue of first relapse in myeloma? DR HOLSTEIN: It’s really becoming more and more complex, because we have more and more good triplet therapies. We of course know that in general triplets are better than doublets, so that answer is relatively easy. But the question of which triplet to use and when is very complicated. Many of the Phase III studies that we have aren’t necessarily relevant to the US population with respect to all the Phase III studies that looked at len/dex versus len/dex plus something else, all of which showed that the triplet was better than the doublet. And that’s primarily because most of these studies did not include len-refractory patients. You can always argue whether relapsing on len maintenance truly makes you refractory to len. I think sometimes the answer is yes, and sometimes the answer is no. But with him, he had a very, very short disease control duration following transplant despite being on len maintenance. And I just was not willing to kind of risk the strategy of putting him on higher-dose len plus something else and then kind of wasting that other partner. And so I really wanted to switch gears completely and use a triplet that would be completely novel to him. Whether or not that’s the right approach I don't know. Again, I tend to be a little bit more aggressive in patients with high-risk disease or patients who are behaving like they have high-risk disease, namely, relapsing very quickly after a transplant despite maintenance therapy. The thought process for pom/dara/dex included possibly using pomalidomide/carfilzomib/dexamethasone instead. Obviously that’s also a very potent triplet therapy. Again, we know that the combination of IMiDs and proteasome inhibitors together can confer improved outcomes for high-risk patients. My problem with using pomalidomide/carfilzomib/dexamethasone is that once you progress on that, it’s not clear what you do after that and how you partner daratumumab. So the idea with picking pomalidomide/daratumumab/dexamethasone was that it would leave carfilzomib for another partner for the next line of therapy. DR LOVE: What would you be thinking about if this man does develop another disease progression? DR HOLSTEIN: I would probably — assuming we didn’t have any good clinical trials, because clinical trial is always an excellent option. I would probably think about cyclophosphamide/carfilzomib/dexamethasone. I’ve found it to be a very well-tolerated triplet regimen. And it’s a way to get another drug in with carfilzomib. Advantages of subcutaneous daratumumab DR LOVE: Can you talk a little bit about the pragmatic issues of using daratumumab, particularly related to the infusion, what your thoughts are about subQ daratumumab and how this man has done on it? DR HOLSTEIN: So the first infusion of daratumumab is always a little bit tricky. I think it really helps to have personnel who are familiar with the drug giving it. A lot of times what I’ll do when I’m partnering with community oncologists is offer to have their patients get their first dose in our center. We’re open 24 hours a day, so there’s not this issue of is the infusion going to be done before 5:00 rings? And again, experience of nursing with the infusions really helps as well. I think that appropriately premedding does help with some. Uniformly now we’ll add in montelukast as a premedication. Again, if patients have any COPD history, I’ll make sure that they are using their inhalers and nebulizing treatments. But even despite doing everything possible, most patients will still have some sort of infusion reaction. And I usually counsel the patients that it’s just really going to be mostly a boring day for them. So it’s not necessarily that these infusion reactions are scary. They aren’t, at least in my experience, like first-time rituximab infusions. But it’s just a matter of kind of slogging through the infusion, starting-stopping, starting-stopping until all of their little reactions, which really can be as, kind of, simple as a runny nose or a sniffly nose, kind of calms down. In general, after the first infusion, things go very smoothly. I’ve really not had issues with second-dose infusions. Having said all that, of course I’m excited about the potential for subQ daratumumab. It’s, of course, difficult, even in a larger center, to be able to get those 8- to 12-hour chairs for daratumumab. And, obviously, for patient experience it’s going to be much more preferable to have a shorter infusion time. DR LOVE: What do we know about subQ daratumumab in terms of efficacy? And I don't know if you know anything about the actual technical aspects of how it’s done, how much volume, the fluid, involves. DR HOLSTEIN: Yes. So my understanding is that that’s still a little bit in flux based on what was described at this last ASH in terms of how it was administered versus what was recently described to me in a presite study visit for a study that’s going to involve subQ dara. So I think that they’re still working a little bit on it. At least when they presented it at ASH, I think there were multiple injection sites. I think there might have been some sort of pump that was used, actually. And I don't know if they have been able to decrease the volume. It’s definitely more than just a simple 5-cc subQ shot. But with respect to efficacy, it looks like so far the preliminary numbers look to be equivalent to what we saw with the initial Phase I/II data with IV daratumumab. Obviously it’s perhaps already in progress — a larger study that’s directly comparing the efficacy of the two preparations. DR LOVE: Where do you think daratumumab is heading? Ever since I first started hearing about it, people talked about it maybe becoming the rituximab of myeloma, being added to everything up front, et cetera. And I think there were some data presented at ASCO looking at it. I think it was up front with RVd. What do we know about using it earlier, and do you think that’s where we’re heading? DR HOLSTEIN: I think that’s probably where we’re headed. The initial kind of feasibility shows that it is feasible. An important study that is being done partnering with the Alliance is a study that is a Phase II randomized study looking at RVd followed by transplant followed by RVd and lenalidomide maintenance versus the same backbone but with daratumumab added at every point. And so it would not surprise me if that becomes the new standard of care, so that we’re seeing daratumumab in the up-front setting, in the maintenance setting. What that then means in the relapsed setting I don't know. I don't know if it should be used the way we use rituximab in the lymphoma world, which is, okay, you switch out the chemo but you still leave in the rituximab. I think at this point we don’t fully understand the mechanisms for resistance for daratumumab. And obviously we need to understand that to be able to know whether we should keep it on board for second-line therapy, third-line therapy, et cetera. And, of course, with the other types of monoclonal antibodies out there, should we be combining them, or should we simply be removing daratumumab once the patient becomes refractory to their current line of therapy? I don't know. Case: A 41-year-old woman presents with lambda light chain MM and bone marrow amyloidosis DR LOVE: So you have several patients here under the category of interesting patients. They all look kind of complicated, but maybe you can from a teaching point of view summarize kind of what happened with the patient and, from your point of view, what the key teaching point is, maybe beginning with this 41-year-old lady. DR HOLSTEIN: Sure. So she’s an extraordinarily complex patient. And it’s just a good example of sometimes what you can see at a teaching institute. So she presented last year. So everything that’s going to have happened will have happened in just a little over a year’s period of time. But she was diagnosed with lambda light chain myeloma, but she also had evidence of amyloid in her bone marrow. So she presented with high calcium and evidence of lytic disease, so pretty typical newly diagnosed myeloma. She didn't have anything particularly worrisome on FISH. And she didn’t appear to have obvious evidence of cardiac involvement with her amyloid. And so the decision was made by her local oncologist to start standard induction therapy with lenalidomide/bortezomib/dexamethasone. She initially had evidence of response based on her light chains but then appeared to plateau. At that point, a follow-up bone marrow was done, and she had gone from about 85% plasma cells at time of diagnosis to 40%, so a good response but not really ready to be collected and proceed with transplant. The treating oncologist then decided to use daratumumab/bortezomib/dexamethasone as second-line therapy. And again, she had evidence of response based on light chains and decreasing plasma cell content in her marrow, but it was kind of a slow response. And, notably, on cytogenetics, every time she would have a bone marrow there would be new clones evident, so a little bit concerning that her disease was becoming more aggressive. Her daratumumab therapy with bortezomib was complicated by development of pleural of a unilateral pleural effusion. And she had multiple taps initially, which showed no evidence of malignancy. She was referred to me with the question of, should they continue the daratumumab/bortezomib/dex? She was still technically responding, so I said yes. And we eventually got her to the point where she was at 20% plasma cells. And in discussion with the transplant team, we thought perhaps we should just call this good and try to move ahead. But while she was off therapy, she developed back pain. And she was found to have new extramedullary disease, which was causing spinal cord compromise. She was having increasing problems with her pleural effusion. She required radiation and just ended up having a very complicated course along the way, as well as she presented with a stroke. And we still don’t understand what led to that. She ended up getting some bendamustine, with initial response. And then again, progression. And her progressions are very aggressive. So she has extramedullary disease, medullary disease. Again, on her marrow you keep finding new clones. And her performance status has unfortunately significantly worsened throughout all of this, including with the stroke. So at this time, I have her on pomalidomide/ixazomib/dexamethasone with the thought that we’re getting a proteasome inhibitor and an IMiD in. I was really not willing to offer carfilzomib because of her amyloidosis and all of her pulmonary issues. And at this point, we’re really just trying to control the disease, but we unfortunately don’t have a long-term plan. She’s clearly not an allogeneic stem cell transplant patient. And she’s not even an autologous stem cell transplant patient. So I thought this was just a good example of how you can have a young patient in today’s era of having all these therapies available, and you can still have very bad outcomes. DR LOVE: What’s her family situation? Does she have children? DR HOLSTEIN: She does not. She’s single. And her mother always comes with her for all of her appointments. Until recently, though, she has been still working. DR LOVE: So, I mean, myeloma is not an easy disease to treat in general, although as you say, it’s certainly gotten a lot better. But this really sounds like a very, very challenging situation. What’s it been like for you to take care of her, at a personal level? DR HOLSTEIN: It’s been difficult. She’s somebody who remains very positive throughout this. I know you don’t want to be all doom and gloom every time I see her, but I really feel that especially early on when I was just seeing her periodically and the local oncologist was kind of doing the day-to-day things, I always felt like my job was just to deliver bad news over and over again. And that’s really difficult. She’s very young. And I don’t have any long-term options for her. Case: A 72-year-old man develops myelodysplastic syndrome after receiving post-transplant consolidation RVd and subsequently receives multiple lines of therapy for R/R disease DR LOVE: Hmm. Maybe we can move on and talk about your 72-year-old man. DR HOLSTEIN: Sure. So this is a gentleman that I met within the last year as well, but his story starts back about 5 years ago when he presented with some back pain and was found to have an L1 fracture. He received therapy initially with some CyBorD. And then they had to interrupt that to deal with more spinal disease. And after that, his treating oncologist ended up just giving him bortezomib/dexamethasone. And he underwent a transplant then in 2012. He only achieved a partial response post-transplant. He still had 25% plasma cells remaining. They did try to kind of clean him up with some consolidation of lenalidomide/bortezomib/dexamethasone, which at least worked based on the marrow showing postconsolidation less than 5% plasma cells. And then they started len maintenance. Now, I will just note a little detail that in his postconsolidation marrow, there was nothing new on the myeloma FISH panel, but he was noted to have a new deletion 20q. He stayed on len for a little over a year. It wasn’t quite clear to me what the decision was behind stopping the len, but I think it had something to do with concerns about cytopenias. Because of that he had some additional marrows, which ultimately showed MDS. So then he was just watched from a myeloma perspective until the time when he clearly needed treatment for the myeloma. So at that time, they first started trying to give him just a little bit of steroid. That did not control his disease. Bortezomib was added in. That really didn’t control his disease. And then he was offered daratumumab. He had some unusual pulmonary issues with daratumumab that were thought potentially to be due to the study drug at that time, and so the daratumumab was stopped. And he then eventually came to me with evidence of disease progression, so he is a little bit older, but his performance status was still good. He plays golf several times a week. He goes to the gym almost every day to do some sort of physical activity. His MDS has not appeared to progress since time of diagnosis. And he’s had minimal cytopenias. He’s really not required any treatment for the MDS. So the question was, what could I do from a myeloma perspective that would be effective, hopefully, but also not cause issues with his MDS? So right or wrong, I chose to use just doublet therapy of pomalidomide and dexamethasone. I, up front, dose reduced the pomalidomide just because of concerns about his cytopenias, and he’s really had a fantastic response. He’s had a complete normalization of his light chains, and he’s been on therapy now since about March or April and has been doing really well. DR LOVE: From your point of view, what are some of the teaching points of this case? I think the MDS thing is really challenging. DR HOLSTEIN: Mm-hmm. Absolutely. So obviously when we think about len maintenance, we always worry about the development of MDS but really that MDS was actually diagnosed before the true len maintenance was even started. So clearly this was something brewing, that it was actually diagnosable post-transplant. But you always have to remember that just having myeloma predisposes one to myelodysplastic syndromes and leukemias. And, of course, high-dose melphalan predisposes patients to that as well. I think the point of being able to use doublets in today’s era is a good one. Obviously we know that in general triplets are better than doublets, but not every patient, I think, truly needs triplet therapy. And sometimes it’s just about what you can get into a patient safely and still achieve a good response. And in this particular case, low-dose pomalidomide and dexamethasone has really done what we wanted it to do. DR LOVE: Just as a side teaching point, because I find that not everybody is aware of this, which is the issue of using IMiDs in patients with renal dysfunction. And I don't know what this man’s renal function is, but I guess he’s healthy, presumably normal. But how do you approach the use of lenalidomide as opposed to pomalidomide in patients with renal dysfunction? DR HOLSTEIN: So with lenalidomide I do dose based on their clearance. With pomalidomide I really don’t worry about the renal function. There’s just not sufficient data out there to suggest that we need to be dose reducing based only on renal function. Case: A 52-year-old woman initially diagnosed with smoldering MM presents with widespread bone disease DR LOVE: So let’s finish out with your 52-year-old lady. It looks like a really interesting case. DR HOLSTEIN: Yes. So again, she’s somebody that I met when she was progressing fairly quickly after a transplant. But her story dates back to 2009, when just kind of on routine labs she was noted to have an elevated total protein, which then led to the appropriate workup for a plasma cell dyscrasia. So at the time of diagnosis, she actually had a relatively robust M spike of 2.5 grams, an IgG kappa paraprotein. The bone marrow done at diagnosis showed 10% to 15% plasma cells, so already she’s in the at least smoldering category. She had monosomy 13 and then a few trisomies on FISH, but nothing else bad. And then they did a skeletal survey, which was unremarkable, and then presumably diagnosed with smoldering myeloma. When I met her, she had gone through a couple of different oncologists, so I didn’t have all the records to kind of see how frequently she’d been followed after she was diagnosed with smoldering myeloma and whether any kind of routine surveillance imaging studies were done. But what I do know is that by March of 2015 — so about 6 years later — she developed knee pain. And workup at that time then showed that she had widespread bone disease, unfortunately. So clearly in the intervening 6 years, she had progressed to active myeloma. I think one of the points here is that if she had presented in 2017 with an M spike of 2.5 and bone marrow showing 10% to 15% plasma cells, we would not have stopped at the skeletal survey but instead, based on the newer IMWG criteria, we would have done PET-CT or whole body MRI and, in all likelihood, would have diagnosed her with active myeloma at that time. Updated IMWG (International Myeloma Working Group) criteria on risk stratification in MM DR LOVE: Before you go on, could you review the IMWG criteria and how they’ve changed? DR HOLSTEIN: Sure. So previously it was good enough to say if you had a negative skeletal survey, you didn’t need to do anything more. And that was all the proof you needed for not having any bone disease. The IMWG criteria really updated a couple of things. Importantly, with respect to the imaging studies, they have now said that in order to be diagnosed with smoldering, you need to have a negative whole body imaging. That could either be PET-CT or whole body MRI. But the important thing here is that we’re using much more sensitive techniques to assess for very subtle lytic disease. Of course, the problem with skeletal surveys is the lack of sensitivity. The other couple of things that have changed how we think about smoldering and how we classify it as smoldering versus active myeloma include the bone marrow percentage of plasma cells. So now if the bone marrow plasma cell percentage is above 60% at time of diagnosis, that automatically qualifies the patient as having active myeloma based on a lot of data showing that those patients are at very high risk for quickly progressing to active myeloma. And then the third thing really has been the inclusion of the free light chain ratio greater than 100. And so now if there’s a free light chain ratio greater than 100 at time of diagnosis, the patient now qualifies as having active myeloma and should be considered for up-front therapy. Management of high-risk R/R MM that progresses rapidly on triplet therapy DR LOVE: So what happened then with this patient? DR HOLSTEIN: So once she was diagnosed with active disease, she received cyclophosphamide/bortezomib/dexamethasone induction therapy. She achieved a VGPR after 5 cycles. And then she had a standard melphalan 200 transplant in October 2015, really appeared to be in a CR post-transplant. She was started on lenalidomide maintenance in February of 2016. And really by July of 2016, she had evidence of relapsed disease based on disease in her blood, with a positive SPEP. So again, a very short duration of disease control post-transplant, even in the presence of len maintenance. That’s when I met her. So she had kind of this new M spike in her blood. She had been on relatively low doses of lenalidomide because of some fluctuations in her liver function tests. And so her treating oncologist had been a little bit nervous about trying to push the dose. So she had been on only 5 mg. We did a bone marrow, of course, before making any treatment decisions. And the bone marrow when she met me showed about 10% to 20% plasma cells, but, importantly, the FISH showed that she had now picked up a deletion 17p in her myeloma cells. So we had the discussion that this now meant that she had high-risk disease. Of course already her disease behavior was telling us that she had high-risk disease in terms of relapsing so quickly. But we kind of had concrete proof of high-risk disease features with the new deletion 17p. Here again, the decision for me was whether or not I try to kind of maximize lenalidomide before moving on to something else, since she had been on low-dose lenalidomide. I kind of took the risk and put her on treatment dose of lenalidomide, but in combination with carfilzomib and dexamethasone, which we know from Phase III data is a very potent triplet therapy. And she initially responded but then very quickly lost that response. So after 2 cycles, she’d had a partial response, I think, and then after the third cycle really had stable disease and after the fourth cycle had clearly started progressing again. So I had to have the unfortunate discussion about the fact that she had just been on a very active triplet regimen and relapsed/progressed very quickly on it. The next therapy that I chose was pomalidomide/daratumumab/dexamethasone. Again, we have excellent Phase II data in this case suggesting that this is a very active regimen. We know from some of the daratumumab studies that daratumumab appears to be somewhat agnostic with respect to high-risk cytogenetics, so I had hoped that this would be a beneficial triplet for her. But again, a very similar story. She achieved a partial response after 2 cycles and then started having just a little hint of progressive disease, not meeting criteria for progressive disease but kind of numbers going in the wrong direction after cycle 3. With cycle 4 went back to weekly daratumumab just hoping perhaps I could achieve disease control again with that approach, but it did not work. And she actually on PET-CT had new extramedullary disease and also just in talking with her, she was like, “Oh, by the way, I have these new bumps on my head” that were clearly plasmacytomas. So again, unfortunately, a very aggressive disease that’s progressing very quickly through one of the most active triplet regimens we have. At this point we talked about clinical trials. We talked about the likelihood that any additional therapies that are out there are probably not going to be able to control her disease for very long. She really wanted to keep working for as long as possible and didn’t want to travel for a clinical trial. And we unfortunately didn’t have anything that would be of benefit for her at our institution. So I offered her carfilzomib/panobinostat/dexamethasone, discussing in great honesty the fact that she had already progressed on a carfilzomib-containing regimen but discussing the fact that at least with respect to bortezomib, there’s data out there suggesting that you can regain sensitivity to your proteasome inhibitor by adding in the HDAC inhibitor. So so far she is responding to therapy. She achieved a PR after cycle 2 but, importantly, is still continuing to respond. So with her 2 previous triplet regimens, once we got to cycle 3 that’s where things went wrong. We just started cycle 4 a couple of weeks ago, and her markers are continuing to respond. She’s also had a complete resolution of the soft tissue lesions on her skull as well. DR LOVE: That’s really interesting. Activity and tolerability of panobinostat in combination with carfilzomib/dexamethasone DR LOVE: I was curious about why you chose carfilzomib in this situation to pair up with panobinostat, as opposed to bortezomib. DR HOLSTEIN: Oh, so namely because of side-effect profile. So although, of course, bortezomib/panobinostat/dexamethasone is FDA approved and we have a Phase III study supporting that therapy, that Phase III study also demonstrated a high number of patients with significant toxicity, particularly GI toxicity. And I have been impressed with the Phase II study — again, recognizing it’s a Phase II and not Phase III — but with the Phase II study of carfilzomib/panobinostat/dexamethasone, where the GI profile is much better. Now that’s probably due, in part, due to the fact that carfilzomib itself isn’t as GI toxic as bortezomib is, but also due to the fact that they switched up the dosing of panobinostat so that it’s every other week instead of 2 weeks on, 1 week off. And so again, I was honest in saying that, “Look. This really just has Phase II data behind it, but from a preclinical perspective, I think there’s rationale for combining an HDAC inhibitor with a proteasome inhibitor.” And again, trying to keep her working for as long as possible meant that I didn’t want to give her a therapy where she was running to the bathroom all the time. DR LOVE: And what actually happened? Did she have GI problems? DR HOLSTEIN: So it’s interesting. She has diarrhea on the weeks that she has panobinostat. She does fine on the weeks that she does not take panobinostat. But it really has been manageable. She manages it with some loperamide. And we have not had to go to extraordinary measures to deal with the diarrhea. We also have not had to dose reduce for any reason. We do see the cyclical thrombocytopenia, but again, at least, with each cycle thus far, her platelet count always recovers by the time we’re ready to start another cycle. DR LOVE: I think that this is a really fascinating case. And when I saw the case, I was thinking to myself, “I don’t think too many people would have pulled out the panobinostat in this situation.” But it obviously worked. And it looks like she clearly was progressing on carfilzomib. So it’s almost like a 1-patient experiment. DR HOLSTEIN: Right. Right. The only difference is that the dose of carfilzomib is a little bit higher, but — so with this regimen, it’s at 45 mg/m2. I was using it at 36 mg/m2 when partnered with lenalidomide. But I honestly don’t think that that is enough to confer the results that we have seen. I really do think that what we’ve seen in the preclinical setting with combining HDAC inhibitors and proteasome inhibitors suggests that these HDAC inhibitors can overcome proteasome inhibitor resistance. So I think this is really interesting. Obviously it’s an N of 1. But I didn’t have a whole lot of options, because she really wanted to stay close to home. And at the time, we talked about perhaps trying off-label checkpoint inhibitor therapy with an IMiD. And we had kind of discussed the pros and cons of that. And then since then, of course, all the data have come out with respect to the pembrolizumab data and the FDA shutting down those studies. So I subsequently have told her that I would not offer her a checkpoint inhibitor therapy at this time. DR LOVE: So just getting back to the panobinostat, because it’s been kind of hard for me to get a feel. I ask people when they use it or what their experience is. I kind of get the feeling that it’s not on everybody’s radar that much, particularly in general oncology practice. When you look at the data and both the laboratory data as well as the clinical data, do you feel that — I mean, obviously it was helpful in this patient. But globally, what are kind of some of the situations where you think about this? And how helpful do you think it is? DR HOLSTEIN: I’ll be honest. This is the first time I’ve ever prescribed the drug. So I always feel kind of bad for the drug when I’m talking about it, because I just never have been willing to use it, just because I didn’t think that the side-effect profile is something that was worth the potential minimal efficacy for patients when combined with bortezomib. However, I have paid attention to, obviously, the carfilzomib data and also the lenalidomide data. And there have been a few occasions when community docs have called me up kind of at a loss for any other regimens. And I’ve said, “You could always try the carfilzomib/panobinostat/dex.” I don’t know if they, in fact, ever did. Oh, it is a drug, I think, that has been difficult to think about using, just because I don’t think the bortezomib partnership is the ideal one from a side-effect perspective. But I think from laboratory studies and, again, from resistance mechanisms’ perspective, we should be thinking about this drug a little bit more. And, certainly, based on this experience, I’m now going to have it a little bit more at the forefront of my thoughts when I’m looking at patients who are starting to run out of options. Status of the Phase III KEYNOTE-183 and 185 trials: Pembrolizumab in combination with an immunomodulatory drug (IMiD) and dexamethasone DR LOVE: So one final question: You referred to the issue of checkpoint inhibitors, particularly with IMiDs. Do you see that not really heading anywhere at this point? DR HOLSTEIN: I’m hopeful that there still is going to be a story there. I don't know whether it’s going to be drug-specific. Obviously there are some differences amongst the checkpoint inhibitors that are being tested as opposed to whether they’re PD-1 or PD-L1, kind of how modified they are. So I don't know whether this is going to be a global problem. Obviously the initial Phase I/Phase II data did not show a toxicity profile that was surprising. Certainly all the autoimmune-based things were expected based on what we’ve seen with checkpoint inhibitors in other settings. DR LOVE: What was the reason that the trial was — was it toxicity or lack of efficacy? DR HOLSTEIN: So the FDA first shut down 2 Phase III studies looking at IMiD plus pembrolizumab. And they were actually shut down for increased deaths. And so they recently released the Kaplan-Meier curves for 2 of these KEYNOTE studies. And the data are really striking. There is clearly an increased signal for increased death for the patients who were getting pembrolizumab. And this is unexpected. Again, I think everybody expected that we would be dealing with colitis and thyroid issues and all the typical autoimmune things that we’ve seen in other disease settings. But to have, actually, patients die has been very unexpected. And since then, the FDA — I think appropriately, at least until we understand this more — has really started shutting down all other checkpoint inhibitor therapy studies for myeloma right now. But I really do hope that we kind of work our way through this, and I do think that there’s potential for the use of checkpoint inhibitor therapy in myeloma. We just clearly don’t know yet what that niche is. DR LOVE: So — but was there any evidence of increased incidence of autoimmune toxicity, or it’s not clear at this point? DR HOLSTEIN: It’s not really clear. They focused more on the deaths. But what they also — I think in the initial data that’s been released thus far, it also doesn’t look like we’re seeing significantly improved response rates or anything like that. But what is clear is an impressive increase in deaths, unfortunately. Recent therapeutic advances in MM DR RICHARDSON: As you know, this has been such a dynamic field. We have no less than 21 FDA approvals in the last 14 years, which is unprecedented in any heme malignancy for sure, in fact possibly even across the board. But that being said, the advances have, of course, resulted in a wonderful array of therapeutic options for providers to offer to their patients. I think the important point is, though, to try and help frame that and understand how some of these new advances are going to impact on practice. So as a couple of background points, Neil, I think, as we all know, multiple myeloma is clearly not just one disease. There is dramatic heterogeneity across the spectrum of the illness. But what’s also very important to appreciate is that there is heterogeneity within the patient, not just between the patients. And in that context, there is this real need to risk stratify and understand, as we individualize therapy, with the array of new agents that we have, what we need to think about in terms of guiding principles. And on this slide, I’m just simply trying to illustrate the point that we have, on the left, of course, metaphase cytogenetics and, of course, florescence in situ hybridization, or FISH, in the middle and, of course, gene expression profiling as a new wave of the future. But set into that is a real understanding of this entity of clonal heterogeneity. And I think what’s nice to show, or hopefully helpful to share with MDs is this, that essentially over time in the natural history of the disease in any one patient, the tempo of illness can change. So you have this clonal heterogeneity on the one hand but also this ability of the disease to ebb and flow. And that’s an incredibly important principle to understand as you manage your patient longitudinally with the illness. And our understanding of this biological process has become far more sophisticated over the last decade or so. And, I guess, from a practical point of view, what it tells us is that it’s important to throw a big net around this disease. And when treatment is appropriate, it needs to be principled on the idea that you have backbone drugs that constitute your framework. And then you rationally add to it with appropriate other drugs that may be specific in certain settings or advantageous in the sense that they are essentially mutationally or genetically agnostic. DR LOVE: Can I just clarify one point? I was interested by what you were saying about clonal heterogeneity. At any given point in time — let’s say the newly diagnosed patients — is there evidence that there’s different clones in the same patient? DR RICHARDSON: Absolutely. Yes, there is. And the evidence for that has emerged over the last 5 or 6 years or so with some really nice work from a variety of investigators illustrating this point. And I think, as you know, we sequence patients over time as patients are characterized when they participate in clinical trials, in initial treatment studies, followed by studies in the relapsed setting, Neil. We’ve been able to start to understand this better. I think what’s also very important is that as we know, myeloma is truly a malignancy that’s influenced by its microenvironment. And I think that’s both — the bone marrow milieu, but beyond that it’s cortical bone, the extramedullary compartment and very importantly is our understanding now of how the immune system really impacts upon this and that immunosuppression in myeloma patients is ubiquitous. We’ve understood this for years, because patients are so vulnerable to infection. But the implications in terms of tumor biology are huge. So it’s kind of that spectrum of illness that people need to understand. But yes, the level of evidence is high, I think, Neil. Changing landscape of smoldering MM DR RICHARDSON: So that really brings me nicely to the next slide, which is that treating myeloma truly is a marathon. It’s really not a sprint. One has to think about, obviously now, the asymptomatic space, which is becoming very exciting in terms of therapeutic opportunities. And clinical trials are really now very much an important aspect of the management of patients with smoldering myeloma. I think what’s very critical to understand in the smoldering disease is that essentially this is an area that’s relatively dynamic in terms of definition. And what we’re beginning to increasingly see is that the so-called high-risk smoldering patient really now constitutes an active disease process, which warrants therapy. And so some of the recent guidelines that have changed to reflect that, I think, are important in practice. However, I would stress these are guidelines. And every clinician should use their clinical judgment in assessing a patient whether or not they have active disease versus a more indolent process. And there’s nothing better than careful follow-up to ensure that process can be as accurate as possible. Now, when we think about this issue of heterogeneity, I do want to share that with you in a bit more detail, Neil. And this next slide actually addresses your question, I think, very nicely, with appropriate references on the slide. But, essentially, what we’ve come to appreciate, that these evolve over time. There are selection pressures both from actually the biology of the illness and, indeed, from therapy. And this clonal evolution can indeed result not only in progression, but it also explains the complexity of the resistance mechanisms that exist. So I think that this is an important concept to grasp, because it provides a very strong rationale to this idea of a series of backbone drugs to which you then rationally add and build appropriate other agents in combination to improve outcome. Impact of cytogenetics on treatment choice DR LOVE: I was thinking about this project we’re doing in CLL looking at the issue of 17p deletion and how a lot of patients acquire that with time. It made me think a little bit about what you are talking about here with myeloma. You talked about kind of what the pressures are that change on this. From a clinical point of view, do you think that we’re going to move into a situation where maybe, for example, at first relapse we’re going to be looking as closely at the tumor, even genomically, as we do up front and that as you move down the line you’ll continue to be taking new looks at the tumor? DR RICHARDSON: Neil, you’re spot on, as always. That’s exactly right. In fact, I would argue it’s more relevant to know where you are down the line than it is initially, if you’re kind of thinking about things across the spectrum, because at the end of the day, where your patient is right now may be radically different from where they were 3 years ago at diagnosis. So this concept of assessing patients with cytogenetics and FISH at each restaging point is a very valid and a very important one. And I’m glad you raise it. DR LOVE: Do you do that clinically? DR RICHARDSON: Oh, absolutely. Absolutely. So in other words, we assess patients at diagnosis, then at first relapse, second relapse and beyond. And cytogenetics can seriously influence therapeutic choices now, because we know, for example, in the proteasome inhibitor space that a PI is essential if you’re dealing with 17p deletion. We know that that really matters. And some of the most exciting data, we’ll come to in a moment, which is around the use of ixazomib in this setting, because it gives you the ability to longitudinally control those clones. But I think it’s one example, Neil. Obviously the monoclonal antibodies are another one, and carfilzomib and so on. And we’ll come to all of that in a moment. But I think it brings this beautifully to the construct that multimodality targeting of myeloma in the context of the bone marrow microenvironment is essential. And this is a slide from my colleague, Giada Bianchi. And it’s a super pictorial, I think, and hopefully to the audience gives you a really nice view of how we must think of integrating our treatments. You can see, obviously, we need a target, the cortical bone. We have the excitement not only with the well-established bisphosphonates in the aminobisphosphonate compartment, such as zoledronic acid and pamidronic acid, but now, of course, we have the really provocative data of denosumab in this setting, showing even clinical benefit in a randomized Phase III trial in favor of denosumab over the standard, which is zoledronic acid. Certainly in practice terms, the use of denosumab in renal disease seems to be very important. And my colleague Noopur Raje has led that work. And really, it’s fascinating to see how denosumab, I think, will impact on practice going forward, recognizing, of course, that zoledronic acid is the gold standard with pamidronate as an important other option as well. Bisphosphonate therapy in MM DR LOVE: Just out of curiosity, when you look at this complex diagram, can you tease out, either through the diagram or in your own vision, of how bone-targeted agents might — exactly what they’re doing? And does it go beyond our classic concept of what we think it’s doing? Does it interfere with the myeloma process itself? DR RICHARDSON: Yes. That’s a great question, Neil. I think what’s so exciting about the bisphosphonate space has been recent data from a variety of laboratories, including our own, showing that zoledronic acid influences, actually, the immune milieu. There’s clear evidence from a variety of labs now that gamma delta T cells are stimulated by bisphosphonates. And this is dynamic. It’s not a static process, which is another very important argument for caregivers to understand that, whilst we recommend bisphosphonates monthly for the first 2 years and then kind of a wait and see afterwards. Certainly in my practice, I’m a firm believer in every 3 months even in patients in complete remission, because not only is the bone, in my view, a barrier to long-term disease control, I think it’s a sanctuary site for disease, in my own view. But also with that immunological story, it helps us understand why, for example, in the UK Myeloma IX trial Gareth Morgan and colleagues were able to actually demonstrate a survival benefit to zoledronic acid over a less potent bisphosphonate, which was unexpected in that study. DR LOVE: In terms of the immune effect, do you see the same immune effect with denosumab? DR RICHARDSON: That’s a great question. And I think at this juncture, I’m not sure that we entirely know. I would argue that it’s possible. But given the biology, one might argue that it is something we need to better understand before we make that leap of faith. Role of histone deacetylase inhibitors in the treatment of MM DR LOVE: Just a quick follow-up question about HDAC inhibitors, because you’ve been very involved with that research. And I don't know. To me, it’s kind of like clinically — I mean, yes, panobinostat’s approved, but it hasn’t really been kind of like the kind of hit that some of these other types of agents have done, monoclonal antibodies, et cetera. Do you think that maybe there’s more — so potential in that mechanism that in the future it’ll be a more important part of myeloma therapy, or is it — DR RICHARDSON: Yes, Neil, I firmly believe it. I mean, I think panobinostat was the proof of principle. I also happen to feel that vorinostat was also a promising agent. But panobinostat obviously achieved FDA approval. And if you think back to the PANORAMA study, the progression-free survival benefit to those patients in the 3-drug platform compared to the 2-drug control in whom prior bortezomib and IMiD exposure had resulted in therapeutic failure, the PFS benefit in those patients was almost 8 months. So when you have that kind of PFS difference, you — and that’s in the Phase III randomized placebo-controlled trial. So you really have a level of evidence that’s strong that something’s going on. The challenge with panobinostat, of course, has been better understanding how to manage some of the toxicities. And I think we’ve got there. We know that you can go to lower doses, for example. We know that if you administer bortezomib weekly, subcutaneously with appropriate hydration, a lot of the toxicity, particularly the GI side effects, are much, much less. But I think what’s really exciting, Neil, is the new next-generation HDACs and, of course, the AC241 compound, I think, is a very, very important new advance. And it’s an exciting new advance because it’s very well tolerated, in my experience. And I participate in the studies with other investigators and, having been working with pano and now working with 241 extensively, I’m very impressed that it’s a step in the right direction. So I’m very hopeful that that agent will fulfill its potential as well. What’s exciting about them as a whole class, Neil, is several things: one that they’re not only epigenetically critical, ie, stabilizing this highly unstable genome that is the hallmark of myeloma, but they’re also very important in terms of things that you might not expect. Obviously there’s this aggresome target, which is important, and bortezomib in proteasome-mediated resistance, but beyond that there’s an immunological effect that may be less appreciated. There’s the upregulation of CD38 expression by this class of drug. And that makes it obviously a very attractive partner with some of our most important antibodies. So I think that, frankly, the opportunity for the HDAC class to do more for myeloma patients is very real. Correlation between CD38 expression levels and response to daratumumab DR LOVE: I keep thinking of all these questions I want to ask you, but I didn’t know about the upregulation of CD38. Is there a correlation between the amount of CD38 expression and benefit from daratumumab? And are you thinking that maybe there’s a synergy between, say, HDAC inhibitors and something like daratumumab? DR RICHARDSON: Absolutely, Neil. Yes, I do believe that. I think that there’s clear evidence with the daratumumab therapy that you can run out of clinical benefit over time if you reduce schedule. You go to a situation where you’re infusing less frequently. You go from weekly to 2-weekly to monthly. And there is evidence that lower levels of CD38 expression are associated with lower degrees of response. But strategies that upregulate CD38 aren’t just, however, limited to HDAC inhibition. They include simple maneuvers such as — a cyclophosphamide, for example, can do that. So there are a number of ways you can think about optimizing responsiveness to CD38 targeting. And I think for our folks on the call, the important message is, frequency of administration matters. Be careful about becoming too infrequent. Two, that in the efforts to improve responsiveness to CD38 targeting, the use of other drugs rationally — obviously the IMiDs are a knockout. Bortezomib has been very helpful. Clearly carfilzomib shows similar promise. There are studies now looking at ixazomib in combination with daratumumab in press or in process even, and at the same time, of course, the HDAC idea, I think, is very compelling, as is the use of conventional chemotherapies like cyclophosphamide. Optimizing the frequency and convenience of daratumumab administration DR LOVE: I guess the other thing is — I don’t want to get too far off track, but I have to ask you in terms of other things that might contribute to, say, the effectiveness of daratumumab — I am curious about your thoughts about subcutaneous daratumumab, because — I don't know — it seems like that has the potential to change — I don't know — kind of when the patient’s exposed to the drug and how high levels, et cetera. It’s just a completely different approach. DR RICHARDSON: Yes, it’s exciting. I think it’s very important for patients to improve the convenience of administration and so optimize frequency of administration and so forth. And I think it’s promising. I think there are a couple of things one just has to be a little bit careful about. It has a hyaluronidase vehicle built into it to allow breakdown of tissue so that there’s absorption of the antibody. Patients, in my experience, have reported that it’s generally very well tolerated, surprisingly so because it’s a fairly substantial volume of antibody injected under the skin. I think one just has to be a little careful as we go forward with combinations, because — realizing that you’ve got steroids in the mix. You’ve got, obviously, proteasome inhibitors. You’ve got immunomodulatory agents that could stimulate the immune system. We just have to be careful, I think, about as we go into combinations with the subQ approach what kind of local reactions we see. Having said that, I’m very hopeful that it’ll pan out, because certainly data so far suggests that it’s working very well. Clinical experience with the investigational anti-CD38 monoclonal antibody isatuximab DR RICHARDSON: I think it’s important, though, Neil, to note that we’ve got other antibodies in the same space targeting the same antigen. And, of course, isatuximab is a very promising antibody, shorter infusion time, has different characteristics in terms of some of the pathways it’s activating and, in my experience, has been both well tolerated and is exquisitely active. And it’s basically a 2-hour infusion every couple of weeks. So there’s a lot of work going on to help us better understand really what we have to offer our patients. And I think, Neil — this would be very familiar to you — it’ll be analogous to the CD20 space. We’ll have a variety of antibodies we can choose from in the long term. DR LOVE: And, surprisingly, it looks like maybe obinutuzumab, in some situations, might be more effective than rituximab, which I think people thought never was going to happen. DR RICHARDSON: Right. DR LOVE: What about this new agent? Is it the main one? Is this what you think is going to be next up? And how long do you think it’ll be before it might become available? What’s it called again? DR RICHARDSON: It’s isatuximab. DR LOVE: Isatuximab. DR RICHARDSON: Isatuximab. ICARIA-MM: An ongoing Phase III trial of pomalidomide and dexamethasone with or without isatuximab for R/R MM DR RICHARDSON: We’re currently conducting a Phase III trial — DR LOVE: Wow! DR RICHARDSON: — of isatuximab/pom/dex versus pom/dex in relapsed/refractory patients and, at the same time, our initial data with isatuximab/pom/dex in a multicenter trial. My co-principal investigator is Dr Joe Mikhael from the Mayo. Basically we’ve seen wonderful results in this setting so far. And I think that it’s again showing great promise. DR LOVE: What about single-agent activity? DR RICHARDSON: Yes, it’s real. Tom Martin from UCSF has led that work. And there’s clearly monotherapy activity that’s equivalent to daratumumab. I think what we all feel — because I’m a huge fan of dara — it’s never, of course, a zero-sum game. And the more, the better, basically. But I think for us who’ve worked with both antibodies, both dara and isatuximab, I think we’ve both been — I’ve certainly been impressed that isatuximab has this advantage of an infusional time that’s much shorter, actually, and also from the nursing perspective and patient perspective. Certainly I’ve been impressed that it’s a well-tolerated antibody and the infusional reactional rate is really very favorable. DR LOVE: That’s really fascinating. Any projections or guesses when we might see the data from the Phase III trial? DR RICHARDSON: Oh, yes. It’s moving along quickly, as you can imagine. It’s in a high-risk space, because it’s for relapsed/refractory disease. And so as a result of that, I think we’ll get a signal relatively quickly in the next couple of years from it, because it’s enrolling robustly. It’s a big international trial. But I have to say that I think that again, if we get a signal from that, it is, as I understand it, a SPA, so it will lead to an FDA approval. But I’m very impressed, for example, that daratumumab plus pom/dex was approved by the FDA off of a single-arm Phase II. And I do applaud the FDA for that, because they obviously felt comfortable that this robustness of response signal they saw, as well as the PFS from the single-arm trial, warranted approval. And that’s great for patients, because it means there’s real access to daratumumab/pomalidomide and dex. And as you know, Neil, these approvals are so vital, because at the end of the day, especially in the current healthcare environment, insurance companies and payers are, I think, quite entitled to say, “Where’s the evidence?” And when you have an FDA approval, there’s no better evidence than that. So I particularly applaud the FDA for their proactive approach, because it really does improve access for our patients to really important combinations. Sequencing of therapies to achieve optimal outcomes in MM DR LOVE: Anything else you want to say about novel agents? I mean, I guess we can go on for the next couple of hours, but — DR RICHARDSON: We could. I was actually going to say, “When do the bars open,” Neil. DR LOVE: Okay. DR RICHARDSON: No. DR LOVE: All right. Let’s keep moving then. DR RICHARDSON: No, no. I mean, I’d love to say simply that the good news for providers is lots of things going on. But you’re right, Neil. That generates the problem of, “Goodness, me. What do we do?” And so this is a slide I want you to share with our audience, because it says, multiple options are now available to treat both newly diagnosed and relapsed/refractory myeloma. And how do we sequence therapies to ensure the best outcomes for our patients? And this is adapted from a paper that my colleague and partner Dr Jacob Laubach and others published just last year. But the important point is, in Jacob’s paper, what he was really trying to drive at was, how do we make sense of all the options that we have? And you’ve got first-, second- and third-line choices. And I think again, as I said earlier, the important message for providers is, it’s not a zero-sum game. It’s not one versus the other. I think one really can make choices and that you can revisit drug classes repeatedly. You can revisit the same drug as long as you bring it together with a rational combination. And I want to make here a very clear emphasis on the other most important approved antibody in our space, which is elotuzumab, a very important partner drug with IMiDs and, indeed, also proteasome inhibitors and certainly a very well-tolerated antibody. You just have to be a little careful about this infection signal, but I do think, in our experience certainly, it’s been very manageable. Recognition and management of immune paresis DR LOVE: Hold on. Infection signal? What’s that? DR RICHARDSON: Yes. Yes. Good question, Neil. What we saw in the ELOQUENT studies was, there was slightly higher incidences of infection with elotuzumab, chest infections and so forth. And in a recent up-front study that Jacob led of RVd plus elo, robust responses but a couple of septic episodes, which may reflect — and including some mortality in association with these, unfortunately and very sadly. But an important message for providers is that be careful about steroid premedication, infectious risk in our patients, especially in newly diagnosed patients where, actually, the immune paresis can be profound. DR LOVE: Are these neutropenic infections? DR RICHARDSON: No. Interestingly enough, not necessarily, Neil, no. I mean, again, immune paresis is profound in myeloma. And so you can have an absolute neutrophil count that seems more reassuring, but in reality, because you don’t have competent immunoglobulin, these patients are basically as vulnerable as your classical neutropenic. So important message. Be careful and, if in doubt, treat. And I think the important point is that the use of immunoglobulin supplementation to augment uninvolved immunoglobulin levels is clearly valid for any patient who has recurrent infections, for sure. But I think elo really has promise. I mean, I firmly believe that. We use it in the maintenance setting now. We use it earlier. And we have lovely data from the smoldering space with it. And it’s truly an immuno adjuvant, as you know, Neil, through its effect on SLAMF7 and its stimulation of natural killer cells. Potential utility of elotuzumab in combination with lenalidomide in the maintenance setting DR LOVE: So — hold on a second. You said in the maintenance setting? Are you talking about outside a trial? DR RICHARDSON: I think we sometimes do this. And I’ll be perfectly candid, if I may. I think it’s not an inappropriate use of the drug at all. DR LOVE: I mean, it makes a lot of sense, for sure. DR RICHARDSON: Yes. There are maintenance trials ongoing. But what we typically will do is, if you’ve got a patient now on the gold standard, which is lenalidomide maintenance until progression in whichever setting, be it transplant or not, if you see biochemical progression and, for whatever reason, a proteasome inhibitor might not be an ideal choice, elotuzumab integrated with IMiD for biochemical progression, we’ve seen, (A), is well tolerated, and (B), frankly, is, it makes great sense. You’re essentially augmenting the immune system to improve further immune surveillance in the maintenance setting, because you’re synergizing with your IMiD to provide that extra level of cellular immune activity that you need. And because it’s very well tolerated, in my experience, it’s a very reasonable thing to do, I think, especially if, for example, a patient has neurotoxicity or some vascular risk that might make either bortezomib or carfilzomib a less attractive add-on. Obviously when you’ve got lenalidomide as the backbone, Neil, you can always think about moving to pomalidomide, I should say, to be more complete. But at the end of the day, sometimes it’s very nice to have pom in reserve for the next step. So adding elo at that point may make sense. DR LOVE: That's interesting, though, that when you brought up that term, it kind of caught my attention, of elo as maintenance. And, I mean, technically what you’re saying is kind of early progression, being very aggressive. DR RICHARDSON: Yes. Toxicities associated with long-term single-agent lenalidomide maintenance therapy; management of lenalidomide-associated diarrhea DR LOVE: And, of course, that has been a scenario that people have talked a lot about since elo was approved. But just to be clear, though, in those kinds of patients, you have them on len maintenance and you start to kind of see they’re progressing biochemically, do you also usually bump up the dose of len? DR RICHARDSON: That’s a great question, Neil, and some people do that. Some folks like to add steroid. I’m more cautious about adding steroid. I think that that, in a short term, may make sense, but long term, obviously, it becomes more of an issue. Bumping up the len dose is perfectly reasonable as long as the patient’s tolerated the len. But I think, as you think about the strategy, one has to just be aware of tolerability issues. And one constant challenge with len, especially as monotherapy, in the absence of steroid and over the long haul, is this so-called bile acid malabsorption diarrhea, which we actually first noticed back in 2009 or so — before that, actually — when we were doing monotherapy studies with lenalidomide in the relapsed/refractory space. And we saw this diarrhea emerge and, from some really nice input from our GI colleagues, basically treated it as if it’s something like a GVHD, give colestipol to bind bile acid and see what happens. And, sure enough, we saw responses. And, of course, there was a very elegant report from the Marsden group where they basically showed that this was, indeed, a bile acid malabsorption process. And whilst it was a small series of patients, it was a very nice proof of principle. DR LOVE: Did you say GVHD? DR RICHARDSON: Yes. To be clear in what I mean by that is that lenalidomide is clearly an immune stimulator. So basically what happens is, you get a degree of immune stimulation in the gut. So your gut immunity is enhanced. And so just to give you the reason why on earth did we start using colestipol, empirically, back in 2009? Because as a center, for example, we obviously have a very busy transplant program, and they have an allo component. And, basically, graft-versus-host disease of the gut can sometimes be helped with the use of colestipol or a bile acid binding agent. So our GI experts, who were giving us guidance on how to manage this lenalidomide-related diarrhea, suggested this might be a strategy. DR LOVE: And what’s the actual agent that you use? DR RICHARDSON: It’s colestipol, 1 to 2 grams. It’s given before meals. It’s a bile acid binding agent. It helps with cholesterol as well, interestingly enough. But it really works in about two thirds to three quarters of cases in whom you use it. And the classic clues for our providers to hear that someone’s getting what we call Revy belly for short, but basically lenalidomide-related diarrhea, is that they’ll report that their diarrhea occurs after eating, about half an hour later. It’s associated with gassiness. And it’s particularly exacerbated by the consumption of fatty food, which obviously triggers more bile acid release. DR LOVE: And I heard about this recently. And I’m dying to poll people about it, because I’m wondering if people have heard about this. I hadn’t heard about it. I think it’s fascinating. And this GVHD thing is really fascinating. DR RICHARDSON: Yes. I mean, and I don’t want to get ahead of myself there, but just so for folks to understand the principle, the principle is that you’re stimulating your gut immunity. DR LOVE: Right. DR RICHARDSON: Your gut’s tuned on. DR LOVE: So cool. DR RICHARDSON: And then, basically, the bile acid drops onto the intestinal mucosa and there’s a little diarrhea that follows. For patients, though, it can be an absolute devil. And it can be very, very challenging from a quality-of-life point of view. Recent FDA approval of ibrutinib for chronic graft-versus-host disease DR LOVE: I never thought I’d be asking you this question, but I was so curious, because I saw that ibrutinib was just approved for GVHD, right? DR RICHARDSON: Yes. DR LOVE: Which is like, “Where did that come from?” So where did that come from? I assume it’s some kind of immune effect of ibrutinib. And is this just in allo, or do you — for example, what about solid tumor transplants? DR RICHARDSON: I think probably both. I love the — that’s fascinating data. I agree with you. And just to give you a little clue, my colleague, Jacob Laubach, and the Alliance, which we’re part of, is leading a trial of ibrutinib/lenalidomide and dexamethasone in myeloma. And we’re hoping to open fairly soon. DR LOVE: Wow! DR RICHARDSON: His partner, Yvonne Efebera from OSU, is also part of that team. Potential of ibrutinib-based combinations for R/R MM DR LOVE: What do we know about ibrutinib in myeloma to start with? DR RICHARDSON: Oh. It’s positive. Basically, we’ve published our work there. DR LOVE: As a monotherapy? DR RICHARDSON: Yes. Yes. With dex. DR LOVE: You see responses to ibrutinib in myeloma? DR RICHARDSON: Yes. DR LOVE: Wow! DR RICHARDSON: It’s not a knock ‘em-sock ‘em signal, to be honest with you, Neil, but it’s a signal that’s real, and continuous therapy and disease control over the long haul. So we were quite pleased. And the combination strategies that are going forward are several. There’s ibrutinib plus len, which Jacob’s leading. And the idea is, just as you’ve touched on, we want to get some information that could then potentially inform maintenance strategies. And then at the same time there’s ibrutinib/pom, pomalidomide being pursued, as well as other studies looking at ibrutinib and a proteasome inhibitor. DR LOVE: And is this ibrutinib as a BTK inhibitor or as an immune agent? DR RICHARDSON: Essentially both. I mean, so BTK is the target in myeloma, obviously. But the fact is that some of its immune stabilization effects in the gut may become relevant to improving tolerability as an all-oral combination in patients over the long term. So with the immunomodulator backbone. So I think that, Neil, there’s real value to these interesting combinations of approved drugs, because they can give providers real options when you’re facing the continuum of challenges that we know. And that’s kind of actually what this next slide, I think, very nicely illustrates, which is that basically if you think about what targets in myeloma we’re after, there are genomic abnormalities, which I’ve framed with the red box, targeting overcoming mutations, the critical role of combination therapy very much, Neil, the evolving position and timing of transplant. And this is a very important area. And then, of course, an absolute fundamental in myeloma management now, the importance of continuous treatment. And then in terms of the research space, we’re looking, obviously, at next-generation agents that target protein degradation, not only proteasome inhibitors but also upstream and downstream of the proteasome. And then, of course, the real breakthrough of the last couple of years, which has been the realization that restoring antimyeloma immunity really matters and that the antibodies have led that charge. And now, of course, we have the checkpoint inhibitors and, potentially, also the therapeutic opportunity afforded by vaccines. Yes. Great. Thank you, Neil, for this next slide, because that, I think, helps us understand this. This is a fairly simple cartoon, but I think it illustrates the points nicely. Activity and side effects of CAR T-cell therapy in MM DR RICHARDSON: We have, obviously, the types of immunotherapy and immuno-oncologic agents that are emerging. And the antibodies are arguably passive. And I include here not only antibodies, but I should emphasize the role of checkpoint inhibitors in this space. And then the active ones, of course, include not just the vaccines I just touched on but the real excitement around chimeric antigen receptor T cells, CAR T-cell technology, which really, of course, is very exciting in heme malignancy broadly. But in myeloma now, we have some very provocative data with the BCMA target that is suggesting that this incredibly interesting and, I think, exciting approach can have great promise for patients. But I think we have to be a little cautious here. It’s very much what I would call an early phase process at this moment. We have early data, which is driven by, essentially, numerator experiences. And what I mean by that is, for every 50 or 60 patients potentially considered for a CAR T program, 10 to 20 will actually get through. And then in that context, you’ll see remarkable results. But that, of course, just have to bear in mind that this is not necessarily an off-the-shelf technology at this point, far from it. It’s also extremely expensive. So I think we have to just be a little bit careful about the enthusiasm for it, to simply say it’s a great new direction, very exciting. When one thinks of it in the big spectrum, I think it’s going to be incredibly exciting for patients to have more access to this approach, particularly as we realize some of the limitations of autologous transplant, so arguably, in my view, CAR T technology may replace autologous transplant in the long term. I may be wrong, but it seems like a reasonable hypothesis. But I think we also shouldn’t lose sight of the fact that off-the-shelf antibodies, be they biphenotypic or otherwise, really — and that’s an exciting area in itself — that may provide us with real promise going forward. DR LOVE: More from a pragmatic point of view, you mean? DR RICHARDSON: Yes, exactly, because, at the end of the day for your community practice patient who’s in the Midwest, who perhaps he’s a lovely person who would rather come to clinic once every 2 weeks or once a month and receive an immunotherapy, obviously the monoclonal antibodies lead the charge with an IMiD backbone, proteasome inhibitor, et cetera. And that’s the sort of person who might be a little older, too, in whom a CAR T technology may make very little sense. So I think that the important point is that there are numerous options. And I think the reality of CAR T is that it’s probably, in my view, been the most exciting step in transplantation-type biology for myeloma that we’ve seen, recognizing its uniqueness in that sense. DR LOVE: Just to clarify it, though, from a clinician’s point of view, from a practical point of view right now, although, of course, right now, this product’s not been approved, but who knows when that would happen? To me it kind of reminds me, like, for example, of the — what’s it called? Axi-cel, in — CD19 agent for diffuse large B-cell. And who was I interviewing from your place? Anyhow — where they’ve seen people with very advanced disease, no options, have tremendous clinical responses. Is that kind of where you think myeloma is going to start out, as a postapproved strategy that really ought to be considered by fairly good performance status patients? DR RICHARDSON: Right, exactly. And I think that that’s probably where the field is going pretty quickly, actually. But just an element of caution, though, because at the end of the day, what we’re seeing with this approach is that there are significant toxicities, the cytokine release syndrome being one. The responses are dramatic. And in our own practice, we’ve obviously got a very active CAR T program. That’s being led by my colleague Nikhil Munshi. And the studies that we’re working with Nikhil on we’re seeing patients have really dramatic responses. But they’re highly selected, Neil. For example, in my own practice I have a number of my patients who we’re lining up for CAR T therapy. And literally waiting lists can be as long as 6 months. You can imagine how that impacts on outcome, because obviously patients who have more challenging disease will obviously need to go on to other therapies in the interim and get cracking with better salvage strategies that are immediately available to them. So you can see, can’t you, Neil, how that could influence some of your data output, because, essentially, you’re selecting a very specific population. It doesn’t detract, though, from the fact that you’ve got pentarefractory patients whom other agents have failed them who clearly benefit. So I think real promise. But you’re right, Neil. Once it’s approved, it’ll give us another important string to the bow. But again, I personally am very struck that we also see dramatic responses for patients with daratumumab, the checkpoint inhibitors, some of the next-generation proteasome inhibitors. These agents really provide a fascinating platform going forward. DR LOVE: I think that’s a really good point. One other issue you mentioned in terms of toxicity, both the cytokine release as well as the neurologic toxicity — I’ve kind of heard that in the myeloma situation with the BCMA, there’s not as much of that. Is that the case? DR RICHARDSON: Yes, I think to some extent it’s not so severe, I guess is the point. What we’ve seen in our own BCMA experience is that it’s there, but it’s manageable. And, in fact, some of the data from the U Penn group support that. And this recent presentation at ASCO from the Chinese suggested the same signal. They definitely saw the toxicity. They had a fairly larger cohort of patients to report on. But again, if you look at the nitty-gritty of how they reported it, 35 patients in, actually 19 or so evaluable for a response, 100% response rate in those evaluable for response, but the remaining 11 were not evaluable. So when you look at data like that, again, I think the importance is tremendous promise, beautiful science that underpins it. But again, is it prime time? Not yet. Let’s see. Promising therapeutic vaccines and antibodies for MM DR LOVE: You also mentioned therapeutic vaccines on this slide. Where are we with that strategy? DR RICHARDSON: I think those show great promise, too. And I especially want to acknowledge my colleague David Avigan at the Beth Israel, who’s led lovely work with the dendritic cell fusion vaccine in this area as a post-transplant strategy. And there’s now a CTN randomized trial looking at this approach with an IMiD backbone, in this case lenalidomide, to better evaluate its impact post-transplant. And I think those data are really promising. There are also very exciting vaccines that we’re deploying earlier in the illness, in the smoldering space. And these are peptide-targeting vaccines, which are very, very promising, I think, combined with some of the newer immunotherapeutics, not least of which are checkpoint inhibitors and IMiDs. And these provide, I think, what I think is fascinating, actually, the ability for memory. In other words, that you can educate your T cells for long-term immune surveillance in smoldering patients or even, arguably, an MGUS, and then be able to go forward. DR LOVE: Do you want to talk about this slide? DR RICHARDSON: I’d be delighted, yes. I mean, basically this is just a summary slide, Neil, that I think for our audience might be helpful, because what it really does is summarize the critical points we’ve made on the therapeutic space. You’ve got great new PIs, like carfilzomib. You’ve obviously got ixazomib, which we’ll talk about a bit more in a moment, HDAC inhibition, which we’ve talked about at length, and monoclonal antibodies, which, obviously, are a huge game changer. The important point about the antibodies is that they’re agnostic to mutational thrust, it would seem. And obviously we have next-generation IMiDs that are very important to mention. These include not only pomalidomide but, just so you know, Neil, on the horizon, these new cell mods, which we’re studying now in Phase I and II. And they are really promising. They are oral agents. They’re on the IMiD platform, but they’re much more potent and they’re much more selective. DR LOVE: What are they again? DR RICHARDSON: They’re so-called cell mods. DR LOVE: Could you just clarify, though? I’m still not — this is a new IMiD, or a class, or what? DR RICHARDSON: Yes — no, no. It is. It’s in the IMiD class. And they’re so-called cell mods. They’re built on the IMiD platform, so — DR LOVE: Cell mods? DR RICHARDSON: Yes, cell mods, c-e-l-l m-o-d-s, cell mods. DR LOVE: And what are they? DR RICHARDSON: They’re again in the IMiD family. And they’re basically very specific and very potent. They build on the success of thalidomide, lenalidomide and pomalidomide. And there are a whole class of them that have been further refined, and they are really very, very, very promising, in my view. DR LOVE: Huh. And so are any of them specifically — have we seen Phase I or II data on? DR RICHARDSON: Yes. Yes. The data currently hasn’t been presented, but Sagar is leading one of the them, key compounds. And we will be spearheading another. So it’s kind of work in process. But it’s exciting. And I share it with you simply to say the future is looking very bright, particularly when you then think about you integrate it with immune function, as we’ve discussed. Effectiveness and tolerability of the investigational proteasome inhibitor marizomib for central nervous system MM and malignant glioblastoma DR LOVE: This is only like the tenth thing you’ve said that I never heard before. DR RICHARDSON: Neil, it’s my pleasure. But dropping down a little bit, obviously beyond the antibodies and the vaccines, I do want to emphasize that we also have new proteasome inhibitors. And one that perhaps has been under the radar screen for a while is marizomib. And that is a beta lactone that targets the beta5, beta1 and beta2 subunits all in one. It’s unique in that regard. And it’s very exciting. It’s being developed, actually, in brain tumors, because in the original Phase I we did with marizomib in myeloma, we noticed some CNS side effects that were manageable but real. And we therefore hypothesized that this must be crossing the blood-brain barrier, which the other proteasome inhibitors don’t. And sure enough, it does. And it went to modeling in GBM, and it’s very active. So now it’s in clinical trial. And those are going very well in glioblastoma. DR LOVE: It’s IV? DR RICHARDSON: It’s an IV, but it has an oral preparation as well. So it’s got the promise of oral bioavailability and activity as well. But in myeloma, frankly, Neil, it’s active when we combine it with pom. And it’s also very excitingly effective in CNS myeloma, which is obviously a rare bird, thank God, because it’s extremely difficult to treat. But it’s becoming more frequent as patients live longer. CNS involvement with myeloma is increasing. And so we actually published a case for a series in the British Journal of Hematology this year, where we showed that marizomib in combination with other drugs was effective in CNS myeloma. DR LOVE: What’s the usual — is it meningitis, or what — DR RICHARDSON: Yes. Yes. It’s typically leptomeningeal spread. Interesting enough, myeloma prefers that. It’s like lymphoma in that regard, to solid plasmacytoma within the parenchyma of the brain. That’s vanishingly rare. But leptomeningeal spread of disease is not. And that basically is uncommon, thank goodness, but to say that it is unseen is not correct. The frequency of CNS myeloma, I think, is clearly increasing as patients live longer with the illness. DR LOVE: Just out of curiosity, about how many people in your practice right now have meningeal myeloma? DR RICHARDSON: In our group, we have probably at any one time, we have 3 or 4 patients affected by it. Obviously their prognosis can be very challenging. We typically use craniospinal radiation. In terms of intrathecal therapy, the only effective agents really are intrathecal thiotepa, which is not easy to access. It’s an alkylator, obviously. But we do then use whatever you have. Could it be ara-C? Unfortunately, methotrexate you can use, but it’s not particularly active, in my experience, and obviously use dexamethasone. DR LOVE: Have you had any patients like that who you gave this other proteasome inhibitor to? DR RICHARDSON: Right. Exactly. This was the case series that we published in British Journal. And again, it’s just a couple of cases, but the principle was the point, that you could administer marizomib. It does cross the blood-brain barrier. And in these cases that we reported, there was activity seen. So it’s a future direction. DR LOVE: Do you see clinical improvement? DR RICHARDSON: Oh, absolutely, both clinical and radiological. DR LOVE: Radiologic also. Wow! DR RICHARDSON: Yes. DR LOVE: That’s fascinating. DR RICHARDSON: Yes, and also based on cell counts as well. DR LOVE: Do you think it’s possible or likely that there may be significant numbers — doesn’t sound like it, if you guys only have 3 or 4 patients, but what I was going to say is that people are missing it? DR RICHARDSON: Great question. I think we’ll see — I mean, again, fortunately, it’s rare, because it’s not easy to treat and it’s lethal. But the fact is that as patients live longer, this is going to be an increasing challenge, in my view, as a sanctuary site. But I think independent of the CNS indication — and I think, frankly, marizomib is probably going to be approved for glioblastoma actually — DR LOVE: Really?! DR RICHARDSON: — as a proteasome inhibitor in that space. Yes. I would speculate it is, because it’s going into Phase III studies. And in that context, it’s exquisitely active. DR LOVE: So you actually see objective responses with GBM? DR RICHARDSON: Yes. Absolutely. DR LOVE: Wow! DR RICHARDSON: The important point is that marizomib is also — and I think this is the important point in myeloma for folks to hear: Obviously it works in myeloma systemically. And in our trial that we published, we showed that even after bortezomib and carfilzomib failure, basically mariz could help patients and restore a response. So — and the science behind that is strong, because it affects beta5, beta1 and beta2. It covalently binds those subunits. Now, why that’s relevant, Neil, is this: Because when you inhibit beta5, which is what ixazomib, bortezomib and carfilzomib do, beta1 and beta2 get upregulated to compensate for the beta5 inhibition. Marizomib has the value of hitting all 3. DR LOVE: Wow! DR RICHARDSON: So there’s real science behind why — it may be, like, as it were, when lenalidomide fails a patient, when you use pomalidomide, for example, if, say, bortezomib failed a patient or carfilzomib failed a patient that marizomib would be your next go-to. DR LOVE: What are they thinking in terms of when it might get approved for GBM? DR RICHARDSON: Great question. I believe in the next few years we’ll see that. DR LOVE: Few years. DR RICHARDSON: Because — yes. I think so. Again, the idea for applying it in CNS tumors came from us, actually. But in terms of the actual clinical development, that’s in process. DR LOVE: That’s so fascinating. I’m so happy to hear that about GBM. What a tough situation right now. DR RICHARDSON: Neil, I completely agree with you. GBM is a hideous disease. And I think that they need a biological agent. And proteasome inhibition biologically makes great sense in GBM. So the fact we’ve got one that can punch into the disease is critical. So I agree with you. I think it’s very promising. Activity of melflufen, a peptidase-activated derivative of melphalan DR LOVE: Do you want to talk about this patient, or you want to keep talking about the other stuff? DR RICHARDSON: If you don’t mind, if we can go back to that, because I just want to conclude a couple of points. I really wanted to make some points about, obviously, a variety of new targeted agents. We’ve got the targeting of the 11;14 translocation with venetoclax, which is very exciting. We’ll come to that in a moment in some closing comments. But I also want to make a comment about the nuclear transport inhibition, the SINE inhibitor, because basically that’s selinexor. And that’s showing great promise. And finally there’s a new chemotherapeutic, so-called melflufen, which is basically a peptidase-avid, next-generation form of melphalan, which basically spares some of the stem cell toxicity that you see with classical melphalan and also some of the classical toxicity of melphalan, be it mucositis and so on. What melflufen does — it’s a compound out of the Karolinska Institute in Sweden — is, it targets the myeloma more specifically through peptidase activation. And in that context, the melflufen data have been really, I would argue, surprisingly positive, because — and when I say “surprisingly,” that may sound a little bit, “Wow! Why?” Actually, it makes sense. In the myeloma space, when immunotherapies and proteasome inhibition and so on have failed our patients, there’s a subgroup of patients we’ve consistently seen have been responsive to chemotherapeutics. And perhaps the best clue came from when carfilzomib was put up against cyclophosphamide in the FOCUS trial. Remarkably, that was a negative study. I don’t think that was any ding against the carfilzomib, frankly, because I think using a single agent in the relapsed/refractory space is very hard. But I think what it showed is that there are a subgroup of patients who are chemotherapeutically responsive. And melflufen has filled that bill in a series of clinical trials that we’ve done now, where after IMiD failure, after proteasome inhibitor failure, melflufen has generated a solid response rate in combination with dexamethasone at around 35%. And that’s after — these are in double-, triple-, quadruple-refractory patients. So that’s a promising signal. So just to mention melflufen. And, obviously, in that same breath, selinexor, really interesting data, particularly in combination with bortezomib, where it does appear to be, again, active in patients with pentarefractory disease, which again shows the value of being very broad minded as we think about this disease. DR LOVE: Just to — could you just clarify that before you go on? I kind of like the name, melflufen. It kind of has a little bit of a maybe Scandinavian feel. But what exact — it’s a pill? What does it do? DR RICHARDSON: Oh, no. It’s intravenous. DR LOVE: Okay. DR RICHARDSON: And it’s called J1 by generic. It’s basically — that was the original number of it. And it became melflufen. It’s basically a next-generation melphalan. It’s built on the melphalan backbone. DR LOVE: Oh. Interesting. DR RICHARDSON: But what it essentially does is, it’s peptidase avid. So what happens is, in myeloma, the cells are packed with peptidases, stem cells, other tissues less so. So there’s an avidity that takes it up. So, in a sense, it’s a targeted therapeutic, because there’s preferential uptake into the myeloma. What’s really exciting about it, Neil, is it doesn’t seem to cause mucositis, doesn’t seem to — it does cause myelosuppression. I want to be very clear about that. DR LOVE: But it’s like a chemotherapeutic agent? DR RICHARDSON: Oh, yes. It’s a classic alkylator class of drug. Yes. DR LOVE: Wow! DR RICHARDSON: Yes. So — but the point is, and that was my posit, that you see patients be responsive to chemotherapeutics long into their illness. And this subgroup of patients seem to benefit from this approach. And melflufen may be an ideal choice for these types of patients, because this is where IMiDs, PIs, et cetera, have run out of steam. They can be salvaged with melflufen. The other obvious point is that melflufen may move into where melphalan is classically used now, in transplant and so on, because it could be that it’s better. DR LOVE: Wow! DR RICHARDSON: But we’ll have to see. DR LOVE: Fascinating. IFM/DFCI 2009 Phase III trial results: RVd with or without ASCT for newly diagnosed MM DR RICHARDSON: And then — oh yes, if I may, one thing, Neil, which is just to say that I want to make sure we emphasize the refinement of prognostics and MRD in guiding therapy, because prognostics are obviously accelerating. We’ve got some wonderful work by lots of investigators looking at better strategies to prognosticate. And MRD, of course, is emerging as an exciting new tool, primarily in the research arena, in other words, minimal residual disease negativity versus positivity. My only word of caution about MRD is that is it ready for prime time, clinical practice? I would be careful, because, for example, in our own work with our French partners, looking at the timing of stem cell transplant, MRD-negative patients still relapse at a rate of around 20% at 3 years. So is it an absolute flagpole for guiding treatment? In the research arena yes, it may well be. But in standard practice, I would say it may be helpful to know it sometimes or a patient may be reassured to know, but as a Holy Grail I think one has to be a little bit careful. I think we ought to let things evolve a little bit before we start recommending it for routine community practice. DR LOVE: Just to clarify that, though, the one practical potential use that you were referring to in terms of transplant, you would think — I mean, it seems like if somebody were on the fence about transplant, maybe there was going to be a problem being out of work, et cetera, that maybe if they knew they were MRD-negative, let’s say, from RVd or induction, they might be more comfortable holding off on it. DR RICHARDSON: Yes. I agree. I think the important point is, though, that we’re learning so much from the effort we’ve done with our French partners. As you know, the French arm of the study demonstrated no survival benefit to stem cell transplant early versus late but did show a PFS benefit that was impressive, 14 months. But, interestingly, no OS benefit, Neil. And I think that’s an incredibly important message, because it says several things to me. One is that you can successfully salvage people later. So to your point, your dad in a family who has a daughter’s wedding 6 months from now may say, “You know what? I’ll keep my transplant in reserve.” The second point is that if you have a big PFS difference and you successfully salvage, that may explain part of it, but it may not explain all of it, because as you know, in most of our studies, like, for example, Brian Durie’s Rd versus RVd, clearly a big PFS difference and boy, a big OS difference as well. If you look at the most successful platforms, PFS correlates with OS. So why is it in transplant that we don’t see an OS difference? I think salvage is important, but I don’t think it’s the whole story. And I think we have to recognize that, kind of, one size does not fit all. And what we do realize from our trial is that there are a couple of acute and late-onset toxicity signals that we need to be aware of. Transplant, generally speaking, is very safe. Mortality rates related to therapy are less than 5% for sure and typically less than 1% or 2%. But there is mortality associated with transplant. And we would be wrong not to be aware of it. I guess more worrying, though, Neil, to me personally is that as patients live longer with myeloma, 15 to 20 years, we’re seeing this real specter of MDS/AML secondary to therapy. And that is a signal we saw in our French trial, albeit at very low numbers but with relatively short follow-up. And I think we need to watch that carefully, Neil. DR LOVE: Could I just clarify one thing that you said that kind of surprised me a little bit, which is the thought that transplant doesn’t affect survival. I kind of had thought that the thinking was it’s too early, really, to look at survival. Do we really know that it doesn’t affect survival? DR RICHARDSON: I will tell you that from the French study, of course, which we’re an integral part, the follow-up at 4 years was very solid. And there’s no OS difference. Now, longer-term follow-up may show subsets of patients in whom OS is improved, but that will obviously require for subset analysis and OS difference that is real and achieves statistical significance. My only point about making that as a point to our audience is, clearly autologous stem cell transplant for the younger, transplant-eligible patient is a standard of care. No question about it. The point is, it’s not the one-size-fits-all. That’s the issue, that you can use transplant more judiciously, in my view, now, particularly given this signal that in the longer term you may have AML/MDS to worry about in a small number of patients. Second of all — and this is real, Neil — that the tolerance of lenalidomide maintenance post melphalan is not as good as if you don’t have it in the mix. That’s what we’re seeing from our trial in the US. DR LOVE: Tolerance in terms of counts? DR RICHARDSON: Counts, infectious complications, therapeutic — DR LOVE: Really? Wow! DR RICHARDSON: — dose reductions, et cetera. And when you remember that lenalidomide, post-transplant, generated 2 and a half years’ median overall survival benefit, len really does make a difference. So you can see where I’m going with this, Neil, that as you think about the therapeutic sandwich that you’re offering your patient, you may — if you’ll excuse the metaphor — if your transplant’s ham and cheese, you may want to move your ham and cheese back a little bit if you need to, because at the end of the day, you’re getting a big mileage from your lenalidomide. So you see what I’m thinking with this. It’s a concept that for patients is very attractive, because it gives them choice. But I think it’s not just choice based upon wishful thinking. I think it’s choice based upon data. DR LOVE: One more question related to MRD, just more of a global question. Maybe it’s just my ignorance, but when you think about the technology of next-generation sequencing in myeloma, like, where is it being applied, looking for mutations, prognosis or MRD, all the above? DR RICHARDSON: All the above. All the above. I think it’s a very exciting experimental tool. And I think that it continues to be in the research arena. But it, I think, again, shows great promise for our patients in the longer term. Case: A 70-year-old woman with high-risk MM and bone metastases receives daratumumab on a clinical trial after disease progression on multiple lines of therapy DR LOVE: So do you want to talk about your patient here? DR RICHARDSON: Yes. No. Lovely. This is one of a few cases I’d love to discuss with our audience, because they kind of, I think, exemplify where we’re going. This is a lovely lady who was originally diagnosed at the age of 62 in 2009. She had IgG kappa isotype. She had advanced bone disease, so she was a classic Durie-Salmon III. She had ISS2 disease at that time, but if you use the revised ISS, she was clearly ISS3, because not only did she have an elevated LDH, but she also had deletion 17 positivity by FISH. So she would fall into a high-risk category by any measure now. The important past medical history or concurrent medial history that’s relevant was she did have quite severe — she does have, I should say, quite severe hypertension, requiring triple therapy to control her blood pressure. She’s otherwise fit and well. And, basically, her initial treatment consisted, at her local doctor’s, of lenalidomide and dexamethasone with zoledronic acid. We saw her and recommended the addition of a proteasome inhibitor based upon her high-risk characteristics. And she achieved VGPR with very proactive approach to neuropathy, using intravenous normal saline, partnering the steroids, using emollient creams and supplements with her bortezomib. We were able to achieve minimal neuropathy, just Grade 1. She went on to autologous transplant. We mobilized her with high-dose cyclophosphamide, 3 gr/m2, and then took her to high-dose melphalan at 200 mg/m2. She achieved complete remission. She really didn’t want a proteasome inhibitor as part of her post-transplant mix, primarily because she didn’t want to do anything other than a pill. So we agreed to that, although I did caution her and said, “I’m very worried about your deletion 17. We’re not perhaps doing the best here,” but she said, “Paul, bear with me. Let’s give it a try.” DR LOVE: Just out of curiosity, if that happened today, would you have given her ixazomib? DR RICHARDSON: Without a doubt. Without a doubt. Yep. DR LOVE: What will prompt you to switch to ixazomib or utilize ixazomib earlier, maintenance, for example, or even up front? DR RICHARDSON: Here because she wanted a pill. DR LOVE: Right. I mean, everybody would want a pill, don’t you think? DR RICHARDSON: Yes, but I think there’s even a more compelling reason for it as well. DR LOVE: Okay. DR RICHARDSON: Ixazomib really does give us the biggest delta we’ve seen in terms of benefit to deletion 17 positivity in randomized trials. The advantage in the TOURMALINE trial for ixazomib/Rd, or ixazomib/lenalidomide/dexamethasone, compared to len/dex alone was staggering. It was 10 months, which is a big PFS by any measure, Neil. DR LOVE: Could I just ask you a practical point? I think you mentioned Joe Mikhael a little while ago. I was talking to him, and I was asking about the GI toxicity. And, of course, you’ve had a lot of experience with ixazomib. And what he told me was that in his experience, it’s not uncommon and that it usually is only in the first month. I hadn’t heard that before. DR RICHARDSON: Yes. It’s typically — I agree with Joe. It’s early and manageable quickly. You can dose reduce, obviously, 4 mg — DR LOVE: But, I mean, is it common? DR RICHARDSON: It’s low-grade, but I would say it’s an important side effect, because it’s an oral proteasome inhibitor. But it’s manageable. And you start at 4 mg weekly, Neil, and you can easily drop to 3. And a little bit of low-dose steroid goes a long way with the GI side effects and also, frankly, appropriate supportive care. So in my experience, it’s very manageable. I was particularly impressed by oprozomib, which was an epoxy ketone oral inhibitor. It was very active, but unfortunately the GI side effects were prohibitive. You had people on 3 or 4 antiemetics and really getting sick. DR LOVE: That’s the carfilzomib oral? DR RICHARDSON: Exactly. But that’s not currently being taken forward. It’s still back to the drawing board to kind of figure out how to better give it. DR LOVE: Joe told me that when he starts patients on ixazomib, he gives them antidiarrheals and antiemetics and tells them about it, et cetera, et cetera. Do you do that? DR RICHARDSON: Yes, you can. Exactly. You absolutely can. DR LOVE: Hmm. Interesting. DR RICHARDSON: Yes. DR LOVE: So this lady — let’s see. Where did we leave off here? She got transplanted. And what kind of maintenance did she get? DR RICHARDSON: She got lenalidomide maintenance, 3 weeks on, one week off with zoledronic acid. DR LOVE: But you would have given her, what, RVd? DR RICHARDSON: Yes. I mean, if she had allowed me to, I would have given her bortezomib every 2 weeks. But she chose not to. And that’s fine, completely understood. Nowadays I would offer her ixazomib, which would have met her need, which would have been all oral. So nowadays I’d have given her ixazomib. In the context of what happened to her, though, Neil, it’s very instructive. Her progression-free interval was only 1 year, and she progressed, which is a very bad sign in any setting, but it’s a particularly difficult sign when someone progresses within a year on maintenance. As a practice point for our audience, someone who progresses within 1 to 2 years and isn’t on maintenance, that’s not the same biology as someone who is on maintenance who progresses within 1 year. But for either group, you worry about these patients. DR LOVE: So did she progress biochemically, or also clinically? DR RICHARDSON: Biochemically and clinically. She reported increasing bony discomfort and fatigue, so we added bortezomib. And she did actually respond to that, but obviously it was aggressive bortezomib dosing. It was not every 2 weeks. We went in weekly, and then occasionally I had to dial her up even more. But she had a nice response to the RVd platform again, but unfortunately, again, a short progression-free interval. Now, in 2012, I frankly wanted to give carfilzomib its due and try carfilzomib for her, ideally in a combo. The problem was her bad hypertension. And I was worried about that, because obviously we have the vascular signal from carfilzomib. So we had a prospective clinical trial looking at pomalidomide/bortezomib and dex. And, actually, she chose that, because her neuropathy was minimal. DR LOVE: How much hypertension did she have? DR RICHARDSON: Oh. She was on 3 drugs. DR LOVE: Oh, really? DR RICHARDSON: And basically her baseline was 130, 140/80. And you basically worry about that, because carfilzomib, as you know, can be associated with significant rates of hypertension. So we believe that’s because of endothelial actions that it has, which may also explain the DVT risk, the other things that we see with carfilzomib. So basically — and also may explain, obviously, the cardiotoxicity. So we believe in her that that was perhaps a choice we would have but perhaps be kept in reserve. In any event, she went onto pom/bortezomib/dex on protocol, had a very good partial response, which was great, but again, classic for deletion 17 positivity, she was short just 1 year. She progressed in 2013 with an aggressive relapse. And this was not biochemical. This was clinical. She had extramedullary disease. She really didn’t feel well. She was really sick, and I was very worried about her. DR LOVE: Just out of curiosity, getting back to your earlier point about retesting patients, as she had these relapses, did you go back and see if she was still 17p or any — DR RICHARDSON: Yes. Yes. On the protocol, for the 2011 progression, she asked us not to poke her too much, so leave her in peace a little bit and see what happened. So we did. But for the 2012 relapse, we absolutely remarrowed her and did all the cytogenetics and FLOW. And, sure enough, she had plenty of 17p. I think her percentage, if my memory serves me rightly, was around 40%, which no one would argue with — that’s enriched for 17p. DR LOVE: And just out of curiosity, what percentage do you need to consider it 17p? DR RICHARDSON: I completely agree with Sagar here. Any 17p is bad. I think there is a quantitative effect. At 60%, I think you’re in trouble. But I think anywhere in between also reflects that. I will share with you that in the TOURMALINE study, we did look at various cutoffs. And we showed that it mattered, no matter whether you were at 5%, 20% or 60%. Having said that, clearly the worst was 60%. DR LOVE: Huh. Interesting. So what happened at that point? DR RICHARDSON: Again, we thought carfilzomib, because I thought, “I’m running out of options here. And we just have to bite the bullet with regard to any vascular toxicity,” perhaps put her on low-molecular-weight heparin, something like that, and hold our breath with the blood pressure. But actually at that time, we had the 501 study open and running in the Phase II dosing with daratumumab at 16 mg/kg. And we had data. I mean, I basically had seen patients have dramatic responses with the antibody. And they could have horrible genetics and extramedullary disease. And so we basically went ahead and enrolled her. And she was on 16 mg/kg in the expansion cohort of that study and, bingo, she achieved complete remission. And she’s been on it as monotherapy for over 4 years. And her quote to me this year, “Best I’ve ever felt since diagnosis.” DR LOVE: At this point, how long do her infusions take? What happened with her first infusion? DR RICHARDSON: Long infusion with the first. She tolerated it beautifully. She’s now on basically 4 hours, I think, around 3 to 4 hours. She’s at the shortest length you can give, and she’s doing just fine. DR LOVE: Would you consider switching her to subQ, or you don’t think it would make that much difference if it became available? DR RICHARDSON: I think she’s very comfortable with the routine. And I’m just — again, I’m very cognizant of her extramedullary disease. And I think that as she and I said to each other in jest, “We’re not going to mess with success.” DR LOVE: Right. You mentioned before, incidentally, the high volume of subQ. Do you know what the volume is? DR RICHARDSON: Yes, it’s several hundred ccs. DR LOVE: Several hundred? Wow! DR RICHARDSON: Yes. DR LOVE: That’s a lot. DR RICHARDSON: Yes. DR LOVE: Wow! DR RICHARDSON: Yes, exactly. DR LOVE: Huh. So let me ask you: If you were to encounter a patient like this again, same exact clinical situation, you were about to treat the patient, symptomatic, 2, 3 relapses in, what do you think the likelihood is that a patient — I mean, nowadays probably they wouldn’t even get single agent. But just in terms of your global take on the data, the likelihood that a patient would get a response like this to single-agent dara. DR RICHARDSON: Yes. I think single-agent dara is very active, particularly if you use it earlier. I do this frequently, where I’ll start with dara/dex alone and then add drugs to it as needed. DR LOVE: Interesting. DR RICHARDSON: But if I have someone I’m very worried about, Neil, I’ll go straight in with the triplet. Yes. DR LOVE: Fascinating. Case: A 61-year-old man with R/R MM receives ixazomib/lenalidomide/dexamethasone on a clinical trial DR LOVE: So I think you have a couple of more cases. I don't know if you want to maybe pick one. I don't know how much time you have, but — DR RICHARDSON: Sure. I mean, I think I could be very quick about this case. This is a lovely gentleman with early relapse who basically got the combination of ixazomib and lenalidomide and dex. And just to show the next slide, if we can, Neil — because it walks us very quickly through him. Basically, he had a classic induction strategy with VTd. Long history: He was successfully transplanted. He had thalidomide maintenance back in the day, did very well, actually. And then when he progressed on thal, we thought it very reasonable to offer him ixazomib/len/dex in the protocol-directed setting. His best response was a PR. Interesting, when we did his marrow testing, just real world, we had insufficient plasma cells. But having said that, his response was very durable. And I just show this case because it shows the value of stable disease. He literally had stable disease for almost 2 years, but then he went to partial response. And he has no complaints and working full time. So he’s an interesting case, because what he illustrates to you, Neil, we’re 4 years in now, that basically he’s MRD-positive by anybody’s measure, but look how well he’s doing. And he is working full time and he has a normal quality — and I say “normal” — an excellent quality of life. DR LOVE: Getting back to what I was asking you about ixazomib, how did he do when he started out with it? DR RICHARDSON: Very well tolerated, no major issues. Case: A 64-year-old man with R/R MM and bone metastases harbors a 13q deletion abnormality DR RICHARDSON: Now, this next gentleman is more remarkable. And he’s another ixazomib case that I think is worth sharing, because he actually received a twice-a-week schedule of monotherapy. But this was his background: Very nice man. He’s actually British but lives here. Basically a very nice man, had some interesting cytogenetic abnormalities at diagnosis. Did have 13 deletion by FISH, lots of bone disease. And what he basically had in terms of therapeutic opportunity was, he got bortezomib and dex to start with, which he did unfortunately develop significant neuropathy. This was where he was treated at U Mass Worcester, where he got aggressive combination chemotherapy with platinum as well as bortezomib. Unfortunately, he did very poorly with that regimen. He perforated his gut and actually was in the ICU. And had to have a defunctioning colostomy. DR LOVE: What do you think the perforation was from? DR RICHARDSON: Platinum/etoposide/doxorubicin. Yes. Yes, it’s very mucosally toxic as a combination. So he came through to transplantation in June and — amazingly enough and very brave but did it. And he did it with his defunctioning colostomy. And then he had that all reanastomosed post-transplant. He went on to classic maintenance with lenalidomide/dexamethasone and concurrent zoledronic acid. He really couldn’t tolerate more melphalan. And another thought might have been carfilzomib, potentially. But at that time, he really was very sick. I mean, he was exhausted. He was burnt out. His docs in Worcester were thinking about a second transplant. And he said, “Absolutely not.” I should mention that with his transplant, despite having the defunctioning colostomy, he was in hospital for 40 days. So it was a long haul. So basically, the maintenance then followed — I apologize. His hospitalization was a little bit less than that. Not 40 days. It was a good 30 days, though. My point is, it wasn’t a traditional transplant where you’re in for 3 weeks, basically. It was a bit longer. Anyway, he went on to maintenance thereafter and essentially then progressed on maintenance within a year. So he was enrolled in a single-agent ixazomib study. And what was really interesting was that, in essence, he came through with a twice-a-week drug orally. And again, this is a guy who’d been a sitting duck for GI toxicity, Neil, but he wasn’t, interestingly enough. And then he came forward. This is his initial course. He started in 2010 on ixazomib, 3 mg twice a week. He achieved a minimal response by December — over time, over 3 to 4 years but did really well. He then went into PR January 2014. We’ve dose reduced him to optimize tolerance, and he’s down at 2.3 twice a week. And he’s in sustained PR. DR LOVE: What were the tolerance issues that caused you to dose reduce? DR RICHARDSON: Just a little bit of skin rash, actually, and some arthralgia. Some GI toxicity, but minimal. And then basically where we have ended up is, this is a quote from him: “Feeling great and looking forward to driving across the USA in a Land Rover” with his wife, because he’s British, you see, hence the Land Rover as opposed to a Jeep. But isn’t that a lovely story? So 2 examples of how these new approaches can make a difference. And these are take-home messages around ixazomib. This would be my closing comments, that there’s a continuing evolution of multiple myeloma treatment, selected new classes and targets. And, as you can see, we have got a wealth of exciting options ahead of us with the vaccines, marizomib, the third-generation IMiDs, the cell mods that I talked about, obviously the promise of melflufen, the excitement around selinexor, the real excitement around venetoclax and then the obviously other drugs, the checkpoint inhibitors and more. And I just include nelfinavir, because that is not produced by any company now, unfortunately, but it’s protease inhibitor that may have an effect on MEK, and in combination with bortezomib, it’s very active. I just give it as an interesting example. DR LOVE: Oh, yes. I see it at the bottom. DR RICHARDSON: It’s an old HIV drug. DR LOVE: Got it. DR RICHARDSON: Yes. DR LOVE: Got it. You’re right. HIV drug. That’s wild. DR RICHARDSON: Yes. And it was combined with bortezomib by some very innovative thinking from our Swiss colleagues. And in a relapsed/refractory population, they were able to show great responses. Venetoclax for MM with or without t(11;14) DR LOVE: So just one final question down to the very lower right — and I think you mentioned it before, but I wonder if you could elaborate a little bit more about what we know about venetoclax in myeloma. DR RICHARDSON: Yes. Obviously targeting 11;14, but maybe doing more than that, and very synergistic with bortezomib. Just to especially acknowledge Shaji Kumar and his team at the Mayo, who have really spearheaded the development of venetoclax. I think it’s exciting stuff. It certainly seems to be active and well tolerated. And it provides this targeted approach. So I think it adds to the armamentarium in a very appropriate and in a promising way. DR LOVE: Can you describe a situation — or maybe you already have tried to access venetoclax and give it to a patient outside a trial setting. DR RICHARDSON: Yes. I know community colleagues who have done that. I personally have not, because we have a very strict policy in our pharmacy. But essentially it’s not impossible, because, of course, there’s Phase II information now. So it would be possible if needed. But essentially it’s being used in patients with 11;14. But it also should be mentioned that it’s active in non-11;14s as well, if they’ve got any evidence of Bcl-2 mutations. So that’s a reasonable thing to remember. DR LOVE: So actually I was interviewing Dr Kumar. And he kind of mentioned something about — I think it was a Bcl-2 assay or something. And you just said Bcl-2 mutation. What is that? DR RICHARDSON: The idea would be simply that if you’ve got abnormal — Bcl-2 is targetable in your disease, then if your levels are increased such that it may be an appropriate target — DR LOVE: But I always thought it was an overexpression. Is it a mutation? DR RICHARDSON: When I say “an overexpression,” I mean in the sense that exactly, it’s increased. And what I mean by “mutation” is that, in other words, there’s an abnormality of it. Perhaps “mutation” is the wrong term. I would just say Bcl-2 overexpression is probably correct. DR LOVE: Right. And are there clinical assays right now that do that? DR RICHARDSON: I would defer to Shaji on this one. So but I think that again, not something I’ve done myself. We are entering clinical studies with venetoclax. My partner Dr Jacob Laubach is leading those in our own group and taking those forward. Comparison of proteasome inhibitors for MM DR RICHARDSON: Yes. And this could segue very nicely after what we just talked about. I think there are certain take-home messages that we can talk about with ixazomib as a focus. First of all, that proteasome inhibition is a standard of therapy for myeloma treatment, and I think that’s exemplified by the survival benefit seen in pretty much every setting with the use of bortezomib. And the real excitement around carfilzomib, where we’re seeing it provide clinical benefit of an order of magnitude greater than is seen with bortezomib certainly is illustrated by the ENDEAVOR study. Ixazomib is the next step in this, in my view, because it’s effective, it’s safe, above all it’s convenient. And it seems to be an ideal partner in a combination approach with oral treatments like lenalidomide. And there are studies now with pomalidomide that are very promising as well. It’s given weekly, but obviously there are now efforts to look at twice a week, which was one of the take-aways from the patient. He’s on the twice-a-week schedule with very resistant, biologically resistant, clinically resistant disease. And so he has done very well for a long period. And the twice-a-week schedule, therefore, in my view, is definitely worth thinking about. I think what’s exciting about it is this concept of continuous therapy, which is, continuous therapy really matters. And this might explain, Neil, why you see the biggest delta in 17p-deleted patients with ixazomib, compared to, say, bortezomib and even compared to carfilzomib, recognizing how potent carfilzomib is. The delta is almost 10 months. And that’s the biggest seen in any randomized trial, to my knowledge. So that may be because you’re able to dose it continuously. And we know that duration of exposure to proteasome inhibitor matters. For example, if you dose bortezomib to 64 doses, you see 17p overdriven. If you only give, basically, for argument’s sake, 16 doses, as the French did with the bortezomib/dex induction, 17p is not overdriven. So that’s where this principle may be so vital. DR LOVE: So just out of curiosity, if we were going to do a curve — and maybe there’s a curve like this that exists — where you look at, say, drug levels over time, if you were to compare ixazomib to IV bortezomib to subQ bortezomib, kind of what would those curves look like? DR RICHARDSON: I think you could see there, really, an interesting difference, because essentially we have derivative slides that we show this, where you look at number of clinic visits and so on. And the convenience of ixazomib exposure over time is huge, because obviously patients stay on it. It’s oral. It’s easy. But in terms of actual curves related to dose and exposure, I can’t recall those, Neil. I think in some ways we may be able to still look at them in a way of comparative trials. For example, in the ASPIRE trial, carfilzomib was given for 18 months and then had to stop, because there are no safety data beyond 18 months. And there you see the curves start to close again, suggesting that once you take away your proteasome inhibitor, things go south. DR LOVE: I mean, obviously that the duration of exposure, for practical reasons, if you can treat for a longer period of time. But I was wondering, also within the treatment period, I mean, when you give, for example, IV bortezomib, obviously it peaks and comes down. DR RICHARDSON: Yes. DR LOVE: Does it come down lower than the steady state of ixazomib? DR RICHARDSON: That’s a great question. There’s a very interesting piece of pharmacology to ixazomib. It’s got rapid on/rapid off pharmacodynamics and kinetics. So it means that its half-life actually is reasonable, hence the weekly dosing. But the on-off effect is incredibly interesting, because what it means is that you get this — and you also see effects on the subunits, which are different to bortezomib. So it’s not bortezomib. People say, “Ixazomib’s oral bortezomib.” That’s actually not true. They are both boronate peptides, but they are actually quite distinct, whereas, for example, carfilzomib and oprozomib are probably closer to each other. Bortezomib and ixazomib are distinct. But I would say that ixa has this advantage of this rapid on/rapid off pharmacology, which makes it less toxic in what it does. But I think you’ve got an excellent point there, Neil, that the half-life probably confers benefit. Interestingly, it’s worth mentioning that bortezomib also has this Cmax effect, which may contribute to its toxicity. But interestingly, it also may be relevant therapeutically, particularly in extramedullary disease, because there have been some papers showing that when subcutaneous bortezomib may fail in an extramedullary patient, remember to try IV, because responses have been seen IV versus not seen with subQ, which are quite interesting. Improving outcomes for newly diagnosed amyloid light chain (AL) amyloidosis DR KUMAR: It’s a very fascinating disease in a way, because it’s, again, a myriad of different presentations and this often goes undiagnosed for a long period of time because of the nonspecific nature of symptoms. But I think we have made big strides in terms of understanding the biology of the disease. It’s interesting that when we looked at this question back in 2010, trying to see if the outcomes have improved, what we saw was that the early mortality in this disease really hadn’t changed. So what we continued to see was about 40% of these patients dying during the first year after diagnosis. Now, with this new publication, where we looked up until 2015/2016, now we are starting to see a real improvement in that early mortality. And the reason behind that is, I think, (1), we’re probably diagnosing the disease a little earlier. The awareness of the condition has certainly improved, especially amongst the nephrologists and the cardiologists who often get to see these patients first. Now, the most of those patients who died early on, they used to be the patients with cardiac involvement. Now, with better use of the cardiac biomarkers, we can identify these patients earlier. We can probably stratify the treatment better, so that we can probably treat them with less toxic or less intense therapies up front, so decreases the risk of treatment-related mortality. So what I think the 2 critical things that we have, I think, has changed the field in a way, so to speak, is this whole concept of early mortality, knowing how to risk-stratify these patients. And treating them according to that has made a big difference. We know transplant works well for these patients, but we also know that the vast majority of the patients cannot tolerate a transplant. So just taking those patients who are best adapted or suited for transplant and transplanting just those patients decreased the treatment-related mortality. In the remaining group of patients using treatments either with melphalan/dexamethasone or bortezomib-based therapy, we can actually get a good hematologic response. And understanding that getting a good hematologic response is kind of the foundation of a better outcome for these patients has also made a difference for them. Investigational strategies for the treatment of AL amyloidosis; factors predicting organ response DR KUMAR: Now, I think one of the most exciting things about amyloid right now are these new-generational drugs, which seem to be able to dissolve the fibrils. So the NEOD001 is a new antibody that actually attacks the amyloid fibrils themselves. And the early results from single-arm trials seems to be quite promising. So there have been 2 Phase III trials that are either completed enrollment or enrolling right now, which hopefully we get to hear from in the next year or so, which will prove that this particular antibody can actually improve the organ function. So by using treatments like bortezomib or stem cell transplant to shut down the light chain production on one side and using drugs like NEOD001 to dissolve the existing amyloid fibrils will probably make a big impact on this disease. DR LOVE: What about other proteasome inhibitors, specifically carfilzomib and ixazomib? DR KUMAR: So there’s very limited data, mostly case reports at this point, in terms of using ixazomib or carfilzomib in this setting. There’s actually a Phase III trial of ixazomib that is currently ongoing in patients with amyloidosis, trying to see if that would actually improve the hematologic response rates and the outcomes. But there have been some interesting reports of daratumumab being used. And there have been very interesting and very deep responses of daratumumab in terms of hematologic response. And based on that data, in fact, there’s a Phase III trial that is currently being planned. DR LOVE: When you said about daratumumab, it reminded me of something I’ve got to ask you. When I was at ASCO, somebody came up to me and handed me an abstract and said, “Why don’t you ask the myeloma people about it?” And it was a paper on daratumumab in lung cancer. So do you know anything about what daratumumab would be doing in lung cancer? DR KUMAR: That’s an interesting question, because when they did all these myeloma trials, one thing they noticed was that actually it does change the T-cell immunity and the repertoire of T cells in these patients. So the suppressive T cells tend to be much more highly expressing CD38. So what the daratumumab seems to be doing is kind of eliminating some of the suppressive T-cell clones and kind of changing that balance. Again, we don’t know how much that particular aspect plays a role in terms of controlling the disease, but I wouldn’t be shocked to hear that maybe it does have effect in other cancers because of this immunomodulatory effect that it has. DR LOVE: So getting back to AL amyloidosis, maybe you can comment a little bit about a poster that you presented, Factors Predicting Organ Response in Light Chain AL Amyloidosis. DR KUMAR: Right. So the problem with the AL amyloidosis right now is, the hematologic response comes early. It could come in 3, 4, 5 months. But the organ response could be a year or year and a half from there. So we want to make an early call whether the treatment is effective or not. So what we have typically been using is the hematologic response. If we get a good hematologic response, we hope that will translate to an organ response, and which it does in the vast majority of the patients. So what we’ve been trying to do is to identify factors which tell you that this patient is going to benefit eventually. So some of the initial work was looking at how much does the initial organ response look like in terms of how much is the hematologic response. Now, the current work that we are doing is to try and find out a composite endpoint, so to speak, which would be a surrogate for the eventual better outcome. DR LOVE: In your mind globally, what is the chance that you see response in organ response? DR KUMAR: So depending upon the therapies, if you look at a stem cell transplant, again, you would see an organ response in nearly 60% of those patients and a hematologic response in upwards of 80% to 90% of those patients. Now, with melphalan/dexamethasone or bortezomib/cyclophosphamide/dexamethasone, we still see hematologic response in the 60% to 70% range and organ response in the 50% to 60% range. DR LOVE: I see you had another paper in Blood looking at the multiparametric flow cytometry in AL amyloidosis. What did you report there? DR KUMAR: So the flow cytometry is increasingly being used in all plasma cell diseases, especially with myeloma. But in the amyloid too what we have seen is, again, suppression of the normal clones or the normal plasma cells. The proliferation rate of the plasma cells, presence of circulating plasma cells, all these tend to identify patients with a much poorer risk or high risk in terms of outcomes. Essentially what it’s telling us is that it’s probably a much more evolved clone that is probably is harder to control in the long run. Presentation and treatment of localized AL amyloidosis DR LOVE: So the one final paper I wanted to ask you about, which is really interesting — I know nothing about localized AL amyloidosis. DR KUMAR: Right. DR LOVE: How often do you see it, and what do we know about it? DR KUMAR: It’s not very common. But what can happen is, sometimes patients most commonly come with skin lesions, or sometimes they can have lesions on the tracheobronchial tree, sinuses, and they tend to be just one area of amyloid deposit. And you biopsy it, and you know that it’s coming from the light chain. There may be some local plasma cell infiltration. But the vast majority of these patients don’t go on to develop systemic multiorgan amyloid. So these patients can be managed very conservatively. Especially if it’s causing obstructive symptoms, we may do surgery. Sometimes we just watch them. Certainly an uncommon phenomenon, but it’s something we don’t want to be overtreating. Advances in the treatment of WM DR LOVE: So let’s move on now, talk a little bit about Waldenström’s macroglobulinemia. Maybe you can just provide a little bit of an overview of some of the major developments in this field over the past couple of years. DR KUMAR: So again, this is another area that is quite — there have been dramatic advances both in terms of understanding the biology of disease as well as in terms of developing the therapy. So again, going from something that was purely morphologic diagnosis to, again, looking for the MYD88 mutation and using that for diagnosing these patients, I think, has really changed. Now you know that we have a much more homogeneous group of patients we are looking at. Now, in terms of therapy, obviously rituximab was a major role. And the combination of the cyclophosphamide/dexamethasone/rituximab has been used for a while. We still continue to use that regimen. But again, the new drugs that have come along — again, ibrutinib is something that is quite active in this disease and has a broad approval at this point for use, though we often tend to use that more in the relapsed setting rather than in the up-front setting right now. The other part, too, is, we are starting to understand the role of the CXCR4 mutations. And maybe some newer therapies targeting that abnormality could, again, make a difference in terms of outcomes for this high-risk disease. Incorporation of ibrutinib into the treatment of WM DR LOVE: Could you talk a little bit about what we know about ibrutinib in Waldenström’s and also about the iNNOVATE study that was published in Lancet Oncology? DR KUMAR: So we know that ibrutinib is active in this disease, both in the relapsed setting and the up-front setting. And the clinical trial clearly showed a benefit. I think what we are struggling with is, should we be using ibrutinib in everybody in the up-front setting, even though it’s approved? I think the data is rather limited in that up-front setting. The clinical trial was mostly focused on the relapsed setting. So I think most of us tend to not use that in the up-front setting and use that later on. DR LOVE: What about in the older, frail patient? DR KUMAR: Again, it’s a balance. Again, the risk of bleeding and so forth with these patients, ibrutinib can be a challenge, especially in the older patients who may have other comorbidities. Some of those patients may be on anticoagulation, per se, and that can be a challenge. So I think it’s important still to try and use — maybe some of the really old frail patients, maybe even using single-agent rituximab may be a reasonable choice in these patients. DR LOVE: Of course, we’ve been hearing about ibrutinib, particularly in CLL, for a while in terms of some of the tolerability issues, atrial fibrillation and bleeding. What have you, yourself, observed in these patients Waldenström? DR KUMAR: Again, the older patients especially, we worry about the complications, such as atrial fibrillation, the bleeding issues. I haven’t had too much of a challenge. Again, it’s a limited number of patients where I have used ibrutinib. I haven’t really encountered too much of these problems. So again, I think there’s probably a selection bias in terms of the types of patients we see in our referral center compared to out in the community. Guiding principles in the treatment of WM DR LOVE: Any myths or misperceptions that you think are out there about Waldenström? You see second opinions. Do you see people doing things that maybe you don’t agree with? DR KUMAR: Obviously when you have more choices, there’s going to be more different therapies that are being chosen. But the problem is, there are not comparative studies really for between these multiple approaches. So I think you really have to look at the patient and see what can this patient tolerate. And again, considering that we’re not going to cure this, and especially in an older patient, I think the key parameter should be to keep that patient asymptomatic for as long as you can. DR LOVE: What fraction of patients with Waldenström’s nowadays die from the disease? DR KUMAR: We still see patients who become refractory to all these therapies. So clearly those patients are out there. We always worry about some of these patients who develop second malignancies, too, so we do see some of those patients developing leukemias. Whether it’s related to previous therapy or otherwise, that can be a challenge, too. DR LOVE: What are some of the clinical research concepts right now in the disease that you think are most promising and exciting? DR KUMAR: From a Waldenström’s standpoint? So I think just understanding some of the additional mutations that happen in these patients, the CXCR4 is particularly of great interest right now, since we have drugs that could kind of affect that pathway. But I think just understanding what makes these cells tick, so to speak, I guess, so that we can really get to the most critical pathways. DR LOVE: There are other BTK inhibitors out there. One I’ve heard about is acalabrutinib. Any reason to think they might pose any advantage over ibrutinib? DR KUMAR: So far, what we have heard is maybe some of these new-generation BTK inhibitors could be a lot better tolerated compared to ibrutinib. I think the key differentiating factor is probably going to be, (1), the tolerance factor. And second is, we know that there can be mutations in that pathway and whether some of these newer BTK inhibitors can do something that ibrutinib cannot in that particular setting. Diagnosis and management of smoldering MM DR LOVE: So I want to touch a little bit on smoldering myeloma. And I see you had a paper with your colleagues, Morie Gertz, a bunch of other people, “Diagnosis and Management of Smoldering Myeloma, the Razor’s Edge Between Clonality and Cancer.” This was in Leukemia and Lymphoma. Again, can you talk about what you were trying to get into with that paper and what some of the key issues are right now in terms of smoldering disease? DR KUMAR: No. I think this is probably one of the most exciting areas of research right now in myeloma. I mean, we have known for years that patients with myeloma always have MUGAs. Many of them may go through a smoldering phase before they become active disease. Now, the problem had been that we did not have very good predictors as to who would actually go on to develop active myeloma. And the concern always was we might overtreat these patients with therapies that could have potentially long-term consequences, like alkylating drugs. Now, I think the field is — 10 years, it’s changed dramatically. Now we have better markers to identify patients who can progress, and we have drugs which are safer for long-term therapy. So I think now we are starting to look at, okay, do we really wait for the other shoe to drop, so to speak, before we do something about these patients, or can we predict that this patient is going to get the CRAB features in the next year or the year after that? And if that’s going to happen with a very good certainty, then you might as well start treating them now before something bad happens. So understanding that this is a spectrum, I think increasingly what we are trying to do is, is there a point where we can intervene much earlier in the spectrum before anything bad happens? And that way, we prevent the progression to myeloma. But I think even more provocative is the fact that if we intervene early enough, is there a possibility we can cure this disease? So I think that is an area of exciting and a lot of research. ASCENT Phase II study of carfilzomib/lenalidomide/dexamethasone and daratumumab with or without ASCT for patients with high-risk smoldering MM DR KUMAR: There is a clinical trial called the ASCENT trial that we’re going to be starting soon, which actually uses a combination of carfilzomib/lenalidomide/dexamethasone and daratumumab in patients with high-risk smoldering myeloma, with or without transplant. But the goal is to give therapy only for 2 years and you stop. And then you see if you can get these patients to an MRD-negative status and keep them MRD-negative for the next 2 to 5 years, essentially meaning, could be that these patients are cured now. DR LOVE: Wow! That’s an interesting trial. It’s a randomized trial? DR KUMAR: No. It’s a single-arm trial at this point. DR LOVE: Wow! DR KUMAR: But there’s plenty of historical comparisons. And what we’re looking for is MRD negativity. So we know that very few cells, if any, left behind, and it stays that way for a prolonged period of time. DR LOVE: That’s really fascinating. MRD testing in MM and its application in clinical trials and practice DR LOVE: Speaking of MRD, I see in Clinical Cancer Research, again, just a couple of months ago, you and Ken Anderson had a paper, “The Role of Minimal Residual Disease Testing in Myeloma and Drug Development, Current Value and Future Applications.” Can you go through, again, where we are today with MRD testing in myeloma? DR KUMAR: Right. I think MRD testing is kind of the other frontier, I think. So one end, you have the smoldering. Can we cure? Can we intervene early and cure the disease? On the other end of the spectrum is the patients who have active myeloma. Can we get them to a deep enough response that maybe this would maybe mean cure in a small proportion of patients and also could be a surrogate endpoint for clinical trials? So the way I look at MRD testing, it’s become mainstream in myeloma for 2 reasons. One, the techniques have really evolved, so we have flow cytometric assays that can detect one in a million cells. We have next-generation sequencing approach, which can detect one in a million cells. So clearly we have reached an area where the sensitivity is no longer a big issue. And we also know that imaging studies can complement these bone marrow examinations. Now, when you look at the minimal residual disease testing, I look at it from a standpoint — or 2 major benefits for doing that testing. One is, can we use it as a surrogate endpoint in clinical trials? Now, the progression-free survival and overall survival in myeloma, it’s 5 to 6 years and counting. So we cannot do clinical trials in a fast manner like what we used to do before. So if we can show that the MRD-negative status is a surrogate for better outcome, we could call the results of these clinical trials much earlier, and we can get drugs approved much faster. But the more important thing in the clinic is, what do we do with the testing? Are we going to act upon it? If somebody’s MRD-positive, are you going to change therapy? If somebody’s MRD-negative, are we going to stop therapy? So that is what we don’t have information on currently. So we are now designing clinical trials where we would take patients after a defined duration of therapy, do MRD testing and, if they are negative, maybe consider stopping them or, if they are positive, maybe intensifying the therapy in a randomized fashion so that we know exactly what to do with that test result. DR LOVE: So question that we asked investigators all the time is, Part A: Are you using MRD testing kind of to manage patients outside a trial setting? And Part B is, do you think general oncologists ought to be using MRD testing outside a trial setting? DR KUMAR: So at this point, I don’t use the MRD test outside of the clinical setting. And I would not recommend anybody for doing MRD testing routinely in everyone but maybe use it more in the context of clinical trials. Now, the only area where I would actually have maybe a caveat to this whole concept are the people with high-risk disease. Now, what we know from multiple trials, especially the Spanish trial, people who have high-risk disease who are not MRD-negative, their outcomes tend to be very bad. So that may be a setting where I might even think about doing MRD testing outside of a clinical trial, purely from, again, knowing what is the prognosis of this patient with high-risk disease after therapy. Somebody who’s gotten induction therapy and transplant, now they are still MRD-positive, then we have to be very carefully watching these patients or maybe even continuing the maintenance or triplet therapy maintenance for a longer period of time. DR LOVE: Your hesitation about using MRD testing outside a trial setting right now, is that mainly because we don’t know what it means in terms of what to do, or are you concerned about the assays themselves in terms of delivering accurate information? DR KUMAR: I’m not that concerned about the assay itself. I think the assays are reproducible and they’re fairly robust. The issue is, there are patients who actually get a partial response and then go for 10 years without any problems. So we don’t know, necessarily, that every patient with MRD-positive result needs to be acted upon. Now, we know that all these patients had MUGAs before, so maybe all we have done with treatment is get them back to the MUGAs phase. So they may still have clonal cells, but they are not really malignant in the true sense that these patients might go for years without anything happening. MRD negativity after induction therapy and prediction of benefit from transplant DR LOVE: So there is one situation which kind of from the outside seems like maybe, to me, maybe you could consider it. And it ties into this question we ask people a lot, which is, if a patient achieves MRD negativity with induction triple therapy, do they benefit from transplant? DR KUMAR: That’s a great question. And I think that is, again, part of the same question asked: Do you do anything about the result? Right? I think in the absence of that knowledge, I would extrapolate the Phase III trials and say, “Everybody benefits from a transplant.” The closest we have is that we know that patients who get a complete response or don’t get a complete response with induction therapy, they both benefit from a transplant. And again, post-transplant, if you have a complete response or don’t have a complete response, both patients do benefit from maintenance therapy. So if you were to extrapolate that, I would say we want to deliver the best package of treatment in the up-front setting. And that best package for somebody who’s transplant eligible would be the induction therapy, a transplant and maintenance therapy. DR LOVE: So if you had a patient who was kind of on the fence about transplant, they didn’t want to miss work, et cetera, would you feel better about it if they were MRD-negative? DR KUMAR: Yes. I would feel better if they’re MRD-negative. Because we know that those patients will do better whether you do transplant or not. They’re going to do better. I think about it as a prognostic factor in that particular situation. Importance of risk stratification in the selection of initial therapy for MM DR LOVE: You had a slide deck on initial therapy of myeloma. And again, without going through all the slides, I wonder if you could just summarize some of the key points you were trying to get across there. DR KUMAR: Right. So I think the key point with the initial therapy of myeloma is the importance of risk stratification. So I think doing a FISH-based assay, understanding who have high-risk disease, I think we can use the revised ISS staging system, which incorporates LDH, ISS and the FISH testing. I think that’s very important, because it gives you a sense of both the patient and for years what to expect. Once you do that, I think the current standard of care for a patient should be a combination of a proteasome inhibitor and an immunomodulatory drug, so a bortezomib/lenalidomide/dexamethasone should be the standard, unless that patient cannot tolerate 3 drugs for whatever reason, whether it’s a frail, very old patient. So that would be the ideal initial therapy, understanding that every part of the world you may not be able to do that. Now, once you get that initial therapy with bortezomib/lenalidomide/dexamethasone, in somebody who’s transplant eligible, they should go to a transplant. If they’re ineligible, they should continue with the same therapy. If they can go to a transplant, then, based on some of the trials, I don’t feel very strongly about a tandem transplant or consolidation therapy. But after transplant, I think everybody should be on maintenance. If they have high-risk disease, I would use a bortezomib-based maintenance. If they have standard-risk disease, I would use a lenalidomide-based maintenance. If somebody has a 17p deletion, I often tend to put them on both bortezomib and lenalidomide, because the outcomes of these patients are very poor. DR LOVE: When you do use a proteasome inhibitor as part of maintenance in this high-risk situation, for how long? DR KUMAR: I would keep them on it until progression. DR LOVE: Any thoughts about ixazomib in this setting? Certainly it seems like it’d be a lot more convenient. DR KUMAR: Absolutely. So the only data we have right now is from the Phase II study of IRd used for newly diagnosed myeloma, where we have had patients stay on ixazomib for 4 to 5 years now. So it’s safe. No question about it. It’s convenient, because it’s a pill every other week or every week, depending on the schedule. But again, I think we just need to wait and see what the Phase III trial shows. We should get some data in the next year. DR LOVE: So you referred to the ongoing ECOG trial comparing KRd to RVd. I’m curious right now how you indirectly compare these two regimens, ie, what do you think the trial is going to show? DR KUMAR: So we have equipoise at this point, right, because we know Phase II studies, KRd, the results look outstanding. The depth of response is higher than what we have seen with VRd. So that supports the hypothesis that this is a better regimen. On the other side, we have the CLARION study showing KMP versus VMP is no different, suggesting that there might be elements in terms of toxicity and being able to stay on that dose for long periods of time. So I think the key thing is the Phase III trial in a community setting, where all types of patients are coming in. Is that the best approach? Maybe at the end of the day we might find that there’s a subgroup of patients who are younger, better tolerating drugs, can do this better than patients — may benefit from KRd more than VRd. I think that’s what the trial will show us. Carfilzomib-associated cardiac dysfunction and dyspnea DR LOVE: I think certainly the tolerability/toxicity findings of that study are going to be fascinating. And again, ever since we first heard about carfilzomib, we’ve heard about dyspnea. We had cardiac dysfunction. I still am trying to clarify in my mind what really is going on and how that even compares to bortezomib. Right now, how do you see that? DR KUMAR: So I think it’s quite possible that it’s gotten maybe more press than it deserves. That’s quite possible. Especially the cardiac toxicities is something that sticks to your mind, right? You see one, and you’ll remember that. And especially in the general community oncology practice, cardiac toxicity is something that everybody dreads. So you see one, and then you fear about using the drug again. If you look at these randomized trials, in the ASPIRE trial there was no real difference between KRd and Rd arms. The ENDEAVOR trial there was clearly hypertension. There was some renal signal. So it seems like there is some vascular toxicity or endothelial toxicity that happens with this drug. I don't know if it is necessarily a very common phenomenon. And I think it can be very easily managed by being careful about what kind of patients you put on the trial, how closely you monitor the blood pressure, the fluid status and so forth. The Italians actually showed that when you monitor the patients very carefully and control their blood pressure before going on the treatment, your risk of cardiac toxicity is actually much lower. DR LOVE: That's interesting, so just controlling their baseline hypertension. Do you see hypertension because of carfilzomib? DR KUMAR: We do see that hypertension secondary to carfilzomib. So we do see a transient increase in the creatinine in some of these patients, some elevation of blood pressure and cardiac toxicity in a small number of patients. This feeling of shortness of breath is something that patients commonly talk about. The concern always had been that originally when we started using carfilzomib, there was concern about the tumor lysis/renal toxicity. And we all recommended that you use a lot of fluids before and after. I have a feeling that we may have pushed that a little too much. And I think being more judicious about the fluid use, maybe less is better in this particular setting. I think that really helps, maybe using only for the initial infusions and not using it subsequently can make a difference. DR LOVE: Another issue with carfilzomib has been the schedule, which is pretty inconvenient, but we’ve also — starting to see some data using it weekly. What do you think about that, and do you use that strategy? DR KUMAR: So the weekly, it certainly seems to be effective. The concern I have is when you go up to 70 mg/m2 dose on a weekly basis, you do see a toxicity signal I worry about, especially in the older patients. I don’t have any problems using maybe up to 56 mg/m2 on the weekly schedule, but the weekly schedule is what is going to make the drug more convenient for the patients. Advances in the treatment of R/R MM DR LOVE: So let’s talk about relapsed/refractory disease. Could you discuss your approach to sequencing systemic agents and regimens for patients in this setting? DR KUMAR: So obviously patients with myeloma are living a lot longer than before. So the number of patients in the general practice of patients living with myeloma are continuing to increase and will continue to increase as we have more and more new therapies. So it’s going to be a bigger and bigger problem for people in the community oncology practice, as many of these patients are going to get the majority or the major chunk of their treatment under their own care. So to identify how we approach disease relapse and particularly how we sequence therapy is going to be very important as we have more and more choices available with the new drugs coming online. Now, the patients, once they relapse, their outcomes after the first relapse also continue to improve. So when you look — on the left-hand side is actually a study that was done looking at patients when they relapse the very first time. You can see that the median overall survival is about 3 years from the time of first relapse. And even when you look at patients who relapse after becoming refractory to an immunomodulatory drug and a proteasome inhibitor, their median overall survival is still substantial, over a year. So what we are seeing is patients, when they continue the use of the therapies, but they still continue to maintain a good performance status and get additional therapies. So I think what we are seeing is, starting all the way from the first relapse to the subsequent relapses, there is still a considerable time period when they have to get additional therapies. And this particularly makes the whole sequencing question even more important. Principles guiding the sequencing of therapies for R/R MM DR KUMAR: So why do we care about sequencing? So as we already talked about patients living longer, they will have multiple relapses during the course of the disease. And we need to do this with a better understanding of the biology of the disease as well as risk. And we have increasing drug combinations and choices with multiple Phase III trials showing a variety of different triplets that can be used in patients with disease relapse. And, obviously, the disease is very heterogeneous. No two patients are alike. So as we sequence therapies, we need to figure out how we can adapt the treatment to the individual patient. And we need to do it in such a fashion that we optimize the efficacy and maximize the benefit of each of these regimens while still maintaining very limited toxicity for these drugs. So when we talk about the biology of the disease, what we know is that when patients get sequential therapies, their duration of response and the depth of response continue to decrease with each subsequent therapy. And part of this is explained by the clonal evolution that we see. As this particular slide shows on the right bottom, you can see that there are clones that are present in very small numbers at the time of diagnosis, which, under the pressure of therapy, grow. And some of the original clones disappear. And the clone that finally leads to the patient’s death may have been a very minor clone at the beginning, again highlighting the importance of clonal evolution, which may, in fact, impact how we select therapy and the combinations particularly. DR LOVE: From a macro perspective, when I talk to myeloma investigators, there’s obviously a very strong feeling in terms of up-front treatment to drive the tumor burden down as low as possible. There’s a belief, I think fueled by a lot of data, that in the long run, that really impacts survival. What about in the relapsed setting, particularly early versus late relapse? Same concept, maximal driving down tumor burden, is that more important, like, in first relapse, than, say, fourth relapse? DR KUMAR: Yes. I think it’s important, especially in the first relapse, because the outcome from the first relapse right now is probably better than the outcome from the newly diagnosed myeloma 10 years ago. So the way I would look at the first relapse or the second relapse is your second and third chance at trying to maximize the benefit of the therapies that you have. Now, once you get down to the fourth/fifth line of therapy, especially in somebody who has gone through a lot of drugs in a very short period of time, indicating that they have a high-risk disease, then I might start thinking more in terms of maintaining — more importance to the quality of life and potential toxicities of these therapies. But early on, I really want to try and maximize the benefit, especially by using combinations. So clearly we have a lot of new treatment options. So we have the old drugs that we still can use. We have novel drugs belonging to the newer classes of drugs, like the IMiDs and the proteasome inhibitors. They are among the same classes now — carfilzomib, ixazomib and pomalidomide. And then finally we have totally new classes of drug, like the monoclonal antibodies, the HDAC inhibitor and also some of the newer drugs like venetoclax that is coming through our clinical trials. DR LOVE: I guess you’d want to add CAR T therapy to that list. DR KUMAR: Absolutely. Yes. The immune therapy arena is exploding as we speak. And we have the CAR T cells, which seem to be very promising based on some of the recent data. We also have some of the BiTE platforms, which also kind of makes use of the patient’s immune system. So one of the things that we know about myeloma even from the diagnosis, but even particularly at the time of relapse, is that the disease can be very heterogeneous. We know there are some patients where the biochemical relapse may be very slow and does not always warrant start of the new therapy. Patients who may have standard-risk disease at the time of diagnosis may evolve to have high-risk disease at the time of relapse. Obviously we need to take into account residual toxicity from prior therapies, the performance status and also patients’ goals and preferences when we decide what particular therapy we’re going to use for the patients with relapsed myeloma. And the way I look at it, there are some broad principles I think we want to always employ. One key thing about myeloma is the fact that duration of initial response essentially defines the biology of the disease. So we have a lot of high-risk markers, but sometimes patients with high-risk markers also do very well. And patients sometimes without any high-risk markers don’t do well at all. Almost like the best litmus test we have is the depth of response to that initial therapy. So somebody who relapses very early or does not respond to primary therapy usually have high-risk biology. The second part, I think, that we want to keep in mind is that we always want to use combinations, preferably a triplet, based on all the data from the Phase III trials we have seen over the past few years. And at least what I try to do is, I should include at least 1 drug from a class that the patient is nonrefractory to into this combination. And obviously we have to take into account the performance status. These are older patients, often have comorbidities. So even though we want to use a triplet, we may not always be able to use a triplet in a given patient. And sometimes it’s a matter of giving a doublet and getting the performance status better so you can actually change over to a triplet. And I think most of these patients, especially in the earlier relapses, we want to treat them to the maximum response and we want to keep them on at least one of the drugs for long term, as long as they can tolerate it well. So again, when you want to visualize — let’s talk about the patient in the first relapse, right? How do the patients reach that first relapse? Either they can be on an induction therapy with a triplet, and they may continue on that therapy until the disease progresses, or they may be on a doublet, especially if the patient’s older, and they may or may not continue on maintenance at the time of relapse. And then there’s about 30% to 40% of the patients who are transplant eligible who would get a triplet induction, get a transplant and often are placed on maintenance therapy and then they relapse. Now, depending upon which path a given patient has taken getting to that first relapse, we can decide how to choose the given therapy for that patient. Treatment approach for lenalidomide-refractory relapsed MM DR LOVE: I’m kind of curious, before we go on, right now you would think that — I mean, in your own practice in patients that you’re taking care of from the beginning, is the most common scenario that you yourself face a patient who relapses on lenalidomide either as maintenance after transplant or as maintenance after a nontransplant? DR KUMAR: Right. That would definitely be the most common patient profile. And I think increasingly we’re going to start seeing that as the major group of patients. Now, obviously, before the maintenance after stem cell transplant became the norm, there are still patients who have had a transplant 4 to 5 years ago and has been doing well without any maintenance, and now they’re relapsing. Obviously they are the better-risk patients, and those patients actually have pretty much all the choices that newly diagnosed patients have today. DR LOVE: So when you look at this, how do you globally break down, if you had to pick 3, 4 or 5 categories that you talk to your fellows about in terms of the major categories of patients presenting with first relapse? DR KUMAR: I would actually group them based on what drug they’re refractory to. So you have patients who are refractory to lenalidomide or patients who are refractory to bortezomib, or they’re refractory to both of them or refractory to neither of those. So that would be the first starting point. DR LOVE: So maybe we can start out with a patient who’s not refractory to bortezomib. So, for example, this would be a patient, for example, on len maintenance. DR KUMAR: Correct. So this would be the patients who’d end up going onto some of the recent clinical trials, like the CASTOR trial or the ENDEAVOR trial, where patients were not refractory when they went onto the Phase III trial, or the PANORAMA trial, which used the combination of panobinostat with bortezomib/dex. So if you look at the results across these Phase III trials, it’s pretty clear that you have several choices you can use. Obviously it’s hard to compare the results across the trials, but let’s say a combination like daratumumab/bortezomib/dexamethasone is very active in this particular group of patients who are not refractory to bortezomib. But you also have other choices, like carfilzomib and dexamethasone, as used in the ENDEAVOR trial. Obviously the caveat here is a higher dose of carfilzomib for these patients. And there has been some side effects that were noted in that particular trial. So if I have a patient today in the clinic, let’s say, who got VRd induction therapy and a stem cell transplant and got lenalidomide maintenance and they’re relapsing on lenalidomide maintenance, my first choice would be to use a proteasome inhibitor-based combination, so a bortezomib-based combination which would add bortezomib to one of these new classes of drugs. Or the alternate choice would be — let’s say this patient had significant peripheral neuropathy with the 4 cycles of bortezomib that they got at the time of induction therapy. Then it would be a slightly different story. Then I would like to use either maybe a carfilzomib-based combination or I could think about using daratumumab or elotuzumab in combination with pomalidomide, so now going to a next-generation immunomodulatory drug, which we know would work even in patients who are refractory to lenalidomide. DR LOVE: But globally, are you basically trying to come up with a therapy that’s most likely to cause the response, most likely to drive the tumor down? Are you trying to, quote, use your best guns up front? I mean, oncologists sometimes think about, “Maybe we should save stuff.” From that perspective, how do you decide? DR KUMAR: My view would be that you want to use the best therapy that you have available at any given point. And this is particularly relevant, I think, for the newly diagnosed myeloma patient. What we have seen, as we showed in the previous slide, there’s a lot of clonal evolution that happens. So I think — again, a lot of it is hypothetical at this point, not necessarily proven through clinical trials, but based on everything we know about the disease and how it evolves, I would try to use the best combination up front. And then the next time we need some therapy, which hopefully would be several years later because we used the best treatment we have, then you go to something else which is totally nonoverlapping, essentially giving us another shot at keeping the disease under control for a long period of time. Incorporating ixazomib into the treatment algorithm for R/R MM DR LOVE: So finishing out with the patients who are not refractory to proteasome inhibitors, what about ixazomib? How does that fit in? DR KUMAR: So the ixazomib, again, the TOURMALINE trial looked at ixazomib/lenalidomide/dexamethasone combination. So that, again, would be an option for somebody who is not refractory to bortezomib, absolutely. DR LOVE: And what about the issue of the patient with the neuropathy from prior bortezomib? How often do you see it, and what about ixazomib in that situation? DR KUMAR: So I think that would be particularly beneficial for patients who have preexisting neuropathy, because ixazomib causes very little neuropathy compared to bortezomib. And obviously one thing that’s — advantages compared to any of these other regimens, is the fact that it’s going to be totally oral. So if somebody is refractory to lenalidomide, I would put somebody on a combination of ixazomib. Pomalidomide/dexamethasone would be a reasonable combination, too. DR LOVE: As long as we’re talking about ixazomib, I’m curious about your experience with it from a tolerability profile. And specifically, have you observed GI toxicity? DR KUMAR: Right. So the GI toxicity generally tends to be mostly in the initial cycles and can be very easily controlled with antinausea medications. And not every patient gets it, either. So generally what I have done is maybe the first couple of cycles, I would have them take either one of the antinausea medications ahead of time. If they have no problem, I usually stop it and see how they do without it. And most patients can do just fine. In fact, the initial Phase II trials we did, we have patients that are 4 and 5 years out, continuing on maintenance ixazomib. ELOQUENT-2 Phase III trial of elotuzumab/lenalidomide and dexamethasone for R/R MM DR LOVE: So one other question about this situation of patients who are not refractory to proteasome inhibitors is the potential strategy in a patient who has relapsed on, for example, len maintenance of increasing the dose of lenalidomide and adding in elotuzumab. Can you talk about what we know about elotuzumab with lenalidomide in general and about that specific strategy? DR KUMAR: Yes. So what we know about elotuzumab is, obviously, it’s an effective drug but doesn’t work well by its own. So the single-agent activity is almost not there. All the activity that we have seen with elotuzumab is either in combination with lenalidomide or with pomalidomide or with bortezomib, so it clearly has to be used in combination. So specifically in terms of when you look at the data with elotuzumab/lenalidomide/dexamethasone from the ELOQUENT study, almost a 6-, 7-month improvement in the progression-free survival compared to lenalidomide/dexamethasone, it’s a very well-tolerated drug. Infusion reactions can happen, but mostly in the initial dose or two. Specifically speaking to the strategy of increasing lenalidomide and adding elotuzumab, again, the data is limited to a small fraction of patients who went on the ELOQUENT trials with prior exposure to lenalidomide. I think it’s certainly a viable strategy. The catch there is why the patients went on a lower dose of lenalidomide. What happens with the lenalidomide, again, if they went down on the dose because of hematological toxicity, then going up on the dose sometimes is not feasible. But if they can tolerate a higher dose, I certainly would consider doing that, especially in patients with indolent relapse, where we might be able to get a considerable amount of time by using this combination. And then we can use other drugs that are still out there. DR LOVE: We’ll hear more about elotuzumab in your algorithm as we go along, but I am curious what your thoughts are about how elotuzumab actually works, specifically. DR KUMAR: So again, like all the monoclonal antibodies, I think they have shown multiple mechanisms. Clearly there’s activation of the NK cells. It seems to enhance the antimyeloma immunity. There are other, obviously — antibody-dependent cellular cytotoxicity seems to play a role. The typical combination of immune effects, like you see from many of the monoclonal antibodies, they all seem to play a role. What is the major component of that antimyeloma activity? Again, it’s hard to know. In that milieu, obviously, multiple mechanisms are in action, especially since it’s being used in combination with an immunomodulatory drug. Evaluation of elotuzumab as part of induction and/or maintenance therapy DR LOVE: Any thoughts about trials looking at moving elotuzumab up earlier? I mean, certainly one obvious place would be with lenalidomide in maintenance therapy, but also as part of up-front regimens. What are your thoughts about that strategy? DR KUMAR: Right. So the Phase III trial actually finished accrual about a couple of years ago. So there is a Phase III trial of elotuzumab/lenalidomide and dexamethasone compared to lenalidomide/dexamethasone in the transplant-ineligible patient population. So hopefully we should hear from that study fairly soon here. I think that would give us a better sense of how durable those responses are, especially from an immuno-oncology platform standpoint. DR LOVE: What about as maintenance therapy after transplant? DR KUMAR: Again, I think the data is mostly from the Phase II setting. So I think the question is, how much more does it contribute to lenalidomide in the maintenance setting? In the post-transplant maintenance with lenalidomide alone, we are looking at a PFS of about 4 years. So it has to be a significant improvement, especially considering that patients now have to come back and get the infusions every 2 weeks. DR LOVE: Good thought. Therapeutic options for patients with disease that is not refractory to lenalidomide or bortezomib or both DR LOVE: What about the patient who’s not refractory to lenalidomide? DR KUMAR: So the patients who are not refractory to lenalidomide, I think we have, again, 4 large Phase III trials that kind of inform us to what are the potential combinations we can use. The ASPIRE trial shows both an overall survival and a progression-free survival improvement. ELOQUENT trial also shows us an overall and progression-free survival improvement. TOURMALINE trial, the follow-up is shorter, only shows a PFS improvement, but of a similar magnitude as the elotuzumab. But I think the maximum benefit we have seen — again, without comparing the trials, necessarily — has been the combination of daratumumab/lenalidomide/dexamethasone. The difference between the 2 arms was considerable — again, very short follow-up. But we saw some dramatic effect by using that monoclonal antibody, which I think again speaks to the fact that when you use a drug or a class of drug that the patient has never seen, you’re going to see the maximum benefit in terms of the depth of response and the progression-free survival. DR LOVE: What typically, outside of a clinical trial setting, is the strategy that you use in this situation? DR KUMAR: So in somebody who is not refractory to lenalidomide, I think right now — again, all of these are choices, good choices. So if somebody — the advantage of the ixazomib/lenalidomide/dexamethasone, again, as we talked about before, it’s a completely oral regimen, very convenient, needs to come back only once a month, and eventually maybe even less often. But at the same time, if you have a combination, daratumumab/lenalidomide/dexamethasone, the progression-free survival is outstanding with that combination. So if somebody can come in once a week and get the infusion, that certainly would be an option. The combination of carfilzomib/len/dex, too, is very effective but again requires people to come back in twice a week to get the infusion. So a lot of it depends on what the patient wants from the logistics of who can bring them back every week. A young patient where I am not that concerned about side effects, such as cardiac toxicity, I would have no hesitation using carfilzomib. On the contrary, maybe an older patient with significant cardiovascular comorbidities, maybe I would lean more towards something that is more gentle, either elotuzumab/len/dex or ixazomib/len/dex. DR LOVE: How about the patient who’s not refractory to lenalidomide or a proteasome inhibitor? DR KUMAR: So I think these are the patients who I’m thinking this is almost like a newly diagnosed multiple myeloma. The fact that they are not refractory to either means they have been off therapy for a period of time, which usually speaks to the fact they have a good biology. So these patients, I actually think about, “Okay. Brand-new myeloma, maybe we could even use a combination like bortezomib/len/dex.” So a good example would be somebody who got 4 cycles of bortezomib/len/dex, had a stem cell transplant, went 3 or 4 or 5 years without any disease relapsing. Now, I might even consider going back to the bortezomib/len/dex in those patients and maybe even consider talking about a salvage autologous stem cell transplant, since the original transplant effect lasted for quite a period of time. So for these patients, I think the field is pretty wide open. Any of the triplets we talked about can be used here. So a PI/IMiD combination, a monoclonal antibody/IMiD combination, both of them can be used. Choice of proteasome inhibitor in the relapsed setting DR LOVE: And what about choice of proteasome inhibitors? You mentioned ixazomib, but what about carfilzomib? Do you believe it has greater efficacy in the relapsed setting? What do we know about that compared to bortezomib? DR KUMAR: So we have the ASPIRE trial, which clearly showed a good efficacy in the combination. We have the ENDEAVOR trial, which is a head-to-head trial, doubled the PFS. However, it was at a much higher dose of carfilzomib, with more toxicity than what we saw in the ASPIRE trial. So in the older patients, I would be hesitant in using the very high doses of carfilzomib, so those patients I would probably use a monoclonal antibody or an ixazomib-based combination. Or if they are not refractory to bortezomib, clearly a bortezomib/len/dex combination would be reasonable too, since we all feel very comfortable using that regimen. But in the younger patients, carfilzomib is a very good choice as well, if they don’t have any comorbidities. It’s really hard to know, since we only have 1 head-to-head trial of carfilzomib versus bortezomib. And that is the CLARION study, which actually did not show any difference in terms of the carfilzomib and bortezomib. So I think we really need to wait for other Phase III trials, like the ECOG trial that we are currently doing, which is comparing carfilzomib/len/dex versus bortezomib/len/dex in the newly diagnosed patients. So I think we need to wait for those trials before we can say with absolute certainty that carfilzomib is better than bortezomib. So maybe very context dependent. Options for patients with “double-refractory” MM DR LOVE: What about the patient who’s double refractory? I don't know. Maybe, what’s the situation you see that? Here, for example, a patient who’s getting len and bortezomib maintenance? DR KUMAR: Right. So there are clearly patients who either didn’t go to transplant and continued on bortezomib/lenalidomide/dexamethasone. And I think this is one place where we clearly — again, this is a part of a study that we did at the International Myeloma Working Group. And what we found was that when patients switched the class of therapy or used a different drug, they got a much better response depth, as well as the duration of response. So clearly I think it speaks to the fact that we really need to change the drug and the drug class, if we can. This is, again, part of the same study where we compared patients who were getting daratumumab versus standard-of-care regimens. And obviously when you give daratumumab, you have a much better outcome. So when you didn’t have a monoclonal antibody and you only had a proteasome inhibitor and immunomodulatory drug, you really didn’t have that option of changing the class of drug. Now that we have 2 monoclonal antibodies, we can certainly change the class of drug. And so, for example, if you look at the daratumumab as a single agent or the carfilzomib in combination with pomalidomide/dexamethasone — more recently, daratumumab has been approved in combination with pomalidomide/dexamethasone very recently. And this combination, too, is very effective. So somebody is refractory to bortezomib/lenalidomide/dexamethasone, I would go to a daratumumab/pomalidomide/dexamethasone combination in that patient. Venetoclax for patients with heavily pretreated t(11;14) MM DR LOVE: So I’m just kind of curious. There are a couple other modalities that are out there that I wanted to ask you about and maybe try to figure out where they might fit in. Maybe you can comment a little bit on it. First venetoclax, and the other, BCMA-based CAR T therapy, what do we know about those strategies? And how does that fit into this whole matrix that’s you’ve kind of been talking about? DR KUMAR: Right. So venetoclax is a small molecule inhibitor of Bcl-2 protein. And we know the Bcl-2 expression in myeloma cells are relatively high. And what we found in the preclinical studies is, when you use venetoclax, especially from patients’ cells in the patients with myeloma who have 11;14 translocation, those cells tend to be very sensitive to venetoclax. And that fits into the biology that we have seen. So what we found with venetoclax in the single-agent trial is that if you take patients with 11;14 translocation, 40% of those patients will actually get a partial response or better, with almost two thirds of the patients getting a VGPR or better. So this is with single-agent venetoclax. And considering that these patients had a median of 5 prior lines of therapy, those results were quite outstanding and totally unexpected. We kind of beat the expectation when we went into the clinical trial. So I think venetoclax actually offers the first possibility that we could do a biomarker-driven strategy in myeloma. Now, obviously, 11;14 is more of an enrichment, because only half of those patients respond. So there are biomarkers that are looking at a high Bcl-2 expression, low MCL-1 expression, which is the profile that best fits with a venetoclax-based therapy. So I think we are going to see that happening with a single agent in a subgroup of patients. The question that needs to be asked is, can the venetoclax have a much broader applicability? So there’s a Phase III trial that is looking at a combination of venetoclax with bortezomib based on, again, studies showing that the bortezomib can actually make cells more sensitive to the venetoclax, or vice versa, essentially making it the synergistic combination. Now, the other intriguing question is, can we actually use venetoclax in combination with, let’s say, bortezomib/lenalidomide/dexamethasone in newly diagnosed patients with 11;14 translocation? Maybe we can really drive those patients into a minimal residual disease-negative state and give them a much better outcome than what we have right now. But there’s also very interesting areas that need to be explored. One is plasma cell leukemia. Half of those patients have 11;14 translocation, so there could be a role for venetoclax in that group of patients. Amyloidosis, half of the patients have 11;14 translocation. So there could be a role for venetoclax there, too. PCR-based assay for Bcl-2 and association with response to venetoclax DR LOVE: You mentioned, which I’ve never heard about before, some type of assay for Bcl-2. What kind of assays are out there? And how well does that correlate with t(11;14)? Do you see high levels in non-t(11;14)? DR KUMAR: Absolutely. So the assay essentially is a PCR-based assay. So you look at the Bcl-2 expression as well as the BCL-XL expression and MCL-1. So essentially what we see is the profile of a high Bcl-2, low BCL-XL is typically seen in the patients with 11;14 translocation, or at least it tends to be much more commonly seen in that group of patients. Now, when we identify patients with that particular profile, it’s a very small number. But in the Phase I study, 8 out of the 9 patients with that profile had a partial response to venetoclax as a single agent. So I think that there’s promise, but obviously we need to have an assay that can be employed in the clinic to choose these patients. DR LOVE: Getting back to this double-refractory situation, where would venetoclax fit in? After daratumumab, way after or kind of how are you using it outside a trial setting? DR KUMAR: So right now for the 11;14 patients who are refractory to many of the standard therapies, many of us have been using venetoclax off label. But I think there are clinical trials we want to try and put those patients on. But I think if the whole thing pans out, based on what we have seen so far, that venetoclax is very effective in single agent in the 11;14 patient population, then I suspect it’s going to initially be used in patients who are refractory to the currently available agents but rapidly moving to the front-line setting, where it’ll be used in combination with other triplets. But in the non-11;14 translocation patients, too, it probably has a major role but will be used in combination with a proteasome inhibitor. But there are studies ongoing adding that to the monoclonal antibodies like daratumumab. So based on those results, we probably will see that moving to earlier lines of therapy. DR LOVE: So I was just interviewing Ann LaCasce this morning. I wish I had known about this Bcl-2 assay, because I would have asked her. But I’ll ask you. Has that been looked at in CLL? DR KUMAR: So this assay is not used in CLL, primarily because the CLL cells always have very high expression of Bcl-2. So I don’t think you really need that assay to pick out the patients. Here we are looking at only about 15% to 20% of patients having 11;14 and only half of them maybe having that assay that fits the profile of somebody who is exquisitely sensitive to venetoclax. DR LOVE: And then in terms of the levels that you see in this assay, is it much lower in myeloma than it is in CLL? DR KUMAR: Yes. In general, the Bcl-2 expression tends to be lower in myeloma. And some of the resistance factors, especially the MCL-1, tends to be much higher in myeloma compared to other cancers. DR LOVE: And then I guess from the same point of view, I have heard that tumor lysis syndrome is very uncommon with myeloma. Is that your experience? DR KUMAR: That is true. So initially when we did the trials, we were very cautious in ramping up the dose. But out of the 66 patients whom we put on the Phase I study of the single-agent venetoclax, we actually did not see any clinical TLS. Maybe there was 1 patient who had labs which may be suggestive of TLS. BCMA CAR T-cell therapy in MM DR LOVE: So the other thing I’ve been hearing about a lot of excitement — matter of fact, I’m interviewing your colleague, Vincent Rajkumar, tomorrow — was really — I saw him at ASCO — superexcited about this BCMA CAR T strategy. Can you talk a little bit about what we know about that and again where you think this might be fitting into the relapsed scenario? DR KUMAR: So the CAR T cell — and obviously as we have seen with leukemia, it’s an exciting modality. Now, the issue with myeloma is, the same antigens that they use for the ALL is probably not applicable. That is, the CD19 CAR T cell, even though the first report of the CAR T cell working in myeloma was actually based on a CD19 CAR T cell, even though we don’t fully understand why that would work in myeloma. But the BCMA is an antigen that is present on most of the myeloma cells. And a subgroup of myeloma patients have very high expression of the B-cell maturation antigen. Now based on that, the BCMA has been thought to be a very attractive target for the CAR T-cell strategy. And the results we have seen so far seem to bear that out. So one of my colleagues, Dr Yi Lin, actually presented data from the CAR T-cell platform. That one, actually, the initial, very early on only 18 patients were treated, but all the patients who were treated with what we consider as an effective dose actually had a response. And a couple of patients are close to a year now with durable response after a single dose of those CAR T cells. So it’s certainly a very exciting platform. Now, obviously, there are issues with the CAR T cell, because it requires the T cells to be apheresed. The particular chimeric T-cell receptor has to be inserted into those cells. So there’s an ex vivo manipulation that happens. And then the patients have to be infused, and there’s a lot of cytokine release syndrome that can happen in these patients, which can sometimes be life threatening, though with this particular CAR T cell, we did not really see a lot of that happening. Now, there are other exciting, again, platforms that could obviate this need for this ex vivo manipulation of the T cells, especially the BiTE platform. We know that blinatumomab has been effective in leukemia. So there are BiTE platforms based on the BCMA targeting that are entering clinical trials. So I think what the CAR T cells tell us is that BCMA is a valid target. Now, we need to find out maybe a better way of attacking that target or utilizing that target to enhance the immunity, whether it be CAR T cell or a BiTE platform. DR LOVE: Yes. It’ll be interesting to see how things play out in terms of toxicity. And I’m curious — I don't know if you’ve had patients yourself who have gotten this therapy — what you’ve seen not just in terms of cytokine release but also this neurologic syndrome that’s seen. DR KUMAR: Yes. So fortunately, we have really not seen much of this neurological syndrome among the few patients that we have put on the CAR T-cell trial. But it’s been very well described. And I think it’s something that we are starting to see not just in the context of CAR T cell. There seems to be a more broad phenomenon that happens with the whole immune manipulation that happens, whether it be checkpoint inhibitors or CAR T cells. We are starting to see some previously not well-described neurological phenomena. DR LOVE: That's interesting, because I don’t recall anybody mentioning that as it relates to checkpoint inhibitors, where you usually hear about in solid tumors, melanoma, Hodgkin lymphoma. DR KUMAR: Right. DR LOVE: What do we know — I wasn’t aware that you see neurologic problems with checkpoint inhibitors. DR KUMAR: So I think in the hematological malignancies especially, it’s hard to know whether it’s related to the long-term use. Or is it something that’s very idiosyncratic at this point? But we have seen — in fact, there are a couple of neurologists in our group who are very interested in trying to explore these very uncommon phenomena that they are seeing in these patients. So I think there’s a lot more that needs to be learned about this whole area. Combining immune checkpoint inhibitors with IMiDs DR LOVE: What about checkpoint inhibitors, particularly with IMiDs, in myeloma? DR KUMAR: So the data that we have seen so far, obviously it’s very exciting data, both in combination with lenalidomide and pomalidomide. So the initial trial looked at patients in combination with lenalidomide. And the responses were quite striking even in patients who were refractory to lenalidomide. And Dr Badros and colleagues looked at pomalidomide combination, and that also had a very high response rate. So clearly there is something there, especially when you consider that the checkpoint inhibitor by itself did not have any activity in myeloma. So, I mean, the data was interesting enough that there were 2 Phase III trials that are currently enrolling, 1 in relapsed myeloma in combination with pomalidomide and 1 in newly diagnosed myeloma in combination with lenalidomide. Now, there has been some recent press about some of those studies being put on hold because of some unanticipated deaths, but I think it’s still too early to really say much about it, because we don’t have much clarity on what exactly has been happening. ASCT for relapsed MM DR LOVE: So the last slide I want to ask you about is this one here in terms of transplant for relapse. DR KUMAR: So again, stem cell transplant is a very effective option for these patients. High-dose melphalan still can be used to play a major role for early treatment, no question about it. Now, the question that we are increasingly facing is, can we actually use it again? And given that the new therapies are so much more tolerable, patients actually are in a much better shape when they relapse the first and the second time that we can actually think about using stem cell transplant again. And this is particularly relevant because many of these patients collect stem cells and don’t go to an early stem cell transplant. So at the time of first relapse, they may have never seen a transplant. And those patients, there’s no question they should certainly be considered for stem cell transplant. Now, among those patients who have previously been transplanted, if they actually have 2 or 3 or 4 years without disease relapse, then I think stem cell transplant should again be brought up as a viable strategy. |