Optimizing Induction Therapy for Transplant-Eligible and Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (MM) — Robert Z Orlowski, MD, PhD

DR ORLOWSKI: Well Neil, thanks very much for the introduction and for the invitation to be part of this always wonderful program that RTP puts on, and it’s a pleasure to be here to talk with you about ways to optimize induction therapy. And this will cover both transplant eligible, as well as transplant ineligible patients who have newly diagnosed symptomatic multiple myeloma and need therapy.

Let’s start off with smoldering myeloma and how to differentiate it from symptomatic multiple myeloma because this is still an important area. In general, for symptomatic myeloma, you have to have 10% or more bone marrow plasmacytosis or an extramedullary plasmacytoma and 1 or more of the CRAB features or myeloma-defining events that are present here. The CRAB, of course, as you well know, stands for hypercalcemia is the C, R is for renal insufficiency, A is for anemia, and B is for bone lesions.

And then relatively recently there were new criteria that were added because these also represented patients at high risk of progression. And those included folks who had at least 60% involvement of the bone marrow or if their involved to uninvolved free light chain ratio was 100 or more or if they had more than 1 focal lesion on MRI. And we usually include PET/CT in that as well. If they don’t have any of those features, then they’re probably smoldering myeloma. But if they have 1 or more, they have symptomatic disease, and those are people that you definitely need to treat.

For transplant eligible patients, and this would typically be your folks who are more robust and possibly a little bit younger, with good organ function and good performance status. These are the current NCCN Guidelines for up-front therapy. And really the top choice is bortezomib with lenalidomide and dexamethasone, although bortezomib with cyclophosphamide and dexamethasone is also an option to consider.

The sorts of things that you take into consideration when making these decisions are in part briefly outlined here. On the clinical side, you want to know a little bit about disease burden. We in general prefer triplets, but if the disease burden is very low, and let’s say you have maybe a more frail patient, a doublet could still be reasonable. If you have very aggressive, rapidly growing disease, then you would definitely want to go with a triplet. Whereas if there are a lot of comorbid medical problems, a doublet may still be okay. And of course, as always, you think about eligibility for high-dose therapy and the patient and their family’s preferences.

On the biological side, you want to take into account ISS and preferably revised ISS stage. The higher the stage the more aggressive you want to be. You want to look at molecular risk. Do they have deletion 17p? Do they have t(4;14)? Do they have 1q21 amplification? These are associated with a shorter progression-free survival, and you may want to be more aggressive with them. Extramedullary disease is also something to keep in mind because that is a higher-risk feature.

And I’ve put a couple things here in question marks because we don’t use these yet routinely, but we may in the very near future, which include potentially studies of drug sensitivity and resistance to predict which regimen would be the best. And because immunotherapy is being used more and more often, I think some kind of measure of the immune effector cell health would be important moving forward as well.

In terms of using bortezomib, lenalidomide, and dexamethasone, which is the most popular choice right now, this was validated by the SWOG-S0777 study. And there was just an update published earlier this year which gave us additional information. You may remember that this was a trial that compared Rd to VRd and showed a higher complete response rate. You can see a doubling of that with VRd, and also a 50% improvement in the VGPR or better, where VGPR means very good partial response or at least a 90% reduction in disease burden.

These are the updated curves that show you that progression-free survival was better for the triplet, which is in red, than the doublet, which was in blue. And then these are the overall survival data which also show a nice separation. And this study, by the way, included patients who were transplant ineligible, as well as people who were transplant eligible but were willing to delay transplant until the time of first relapse.

High-risk patients sometimes have a shorter progression-free survival, and I did pull out this section of text from the updated manuscript, which did show that even for the high-risk patients there was a trend favoring VRd for PFS and OS, although the numbers were too small for those to be statistically significant. But it does support something we’ve been saying for many years, which is that proteasome inhibitors are important in high-risk patients, as well as in standard-risk patients.

One interesting study that was just recently published in Lancet Oncology, which was an intergroup trial led by ECOG, compared VRd to KRd, where K is carfilzomib. This was a 1:1 randomization, and then later on, we don’t have data about the second randomization, but there was a second one where people got 2 different durations of maintenance therapy.

I would have actually predicted that KRd would have been a little bit better, but as you can see from the left panel here, in terms of progression-free survival, there was no significant difference. Do keep in mind that this study was limited to patients who were standard risk, and the only high-risk group that was included were people with the t(4;14) translocation.

The other thing to keep in mind is that there was a trend for some adverse events to be increased with VRd and some to be increased with KRd. Here you can see heme and non-heme effects, which were a little bit higher with KRd. Part of that is because you’re giving the carfilzomib more frequently than you are the bortezomib. But there were more cardiac, pulmonary, and renal, whereas as you would imagine, there was less neuropathy with KRd because bortezomib, or V, does give you more neuropathy.

This plot shows you some of the subgroups, and although there are some differences that go one way or another in the hazard ratio, in general, for almost all of these groups, it did look like the VRd and KRd were equivalent.

High-risk patients were treated on a different study through the intergroup, and this was the SWOG-S1211 trial. And what we did here is we did VRd as the control for induction, and then VRd maintenance, and the experimental arm added elotuzumab with the hope that adding immunotherapy would result in an improvement in progression-free, as well as overall survival.

Here you can see the response rate and PFS data, and this, by the way, paper should be showing up soon in Lancet Hematology. You can see the overall response rate for the 2 arms was roughly similar, and the progression-free survival was roughly similar, as well. So unfortunately, adding elotuzumab in the high-risk setting does not seem to improve outcomes in newly diagnosed patients.

That doesn’t mean that other antibodies may not be of benefit though. Here is a meta-analysis that was done and presented at ASCO looking at daratumumab. And many of these studies included newly diagnosed patients, as you can see, almost 360. And in combining the dara-containing arms and comparing them with the combined non-dara-containing arms, it did look like the hazard ratio favored that adding dara did make a difference for high-risk patients. And I think this makes sense because dara improves the MRD negativity rate, and MRD negativity is important for all patients, but even more important in the high-risk setting.

Of course in the US VRd is, as we mentioned earlier, the standard of care, and we do now have some data about dara with VRd. And this is from the so-called GRIFFIN trial, led by Pete Vorhees, and here VRd, transplant, consolidation, and then maintenance was the control, and the experimental arm added dara as part of the induction, as well as consolidation and maintenance. This was a Phase II randomized trial. There is a Phase III ongoing. But you can see if you compare the left and the right sides that the dara/VRd group had a better complete and very good partial response rate or better compared with just VRd alone. And interestingly that depth improved as they went through induction, then transplant, then consolidation, and then eventually onto maintenance therapy.

I did include here the value of MRD negativity, and you can see that the folks who were MRD negative, which was more common on dara/VRd, did better in a couple of different important groups, including some of the patients with high-risk disease, although the error bars, you can see, are wide, and that’s because the number of high-risk patients was relatively small.

Let’s switch over now to transplant eligible patients, and here again are the NCCN Guidelines. VRd probably in a VRd lite with reduced dosing is the standard of care here as well. And of course we have dara with len/dex. And you can still consider things like bortezomib/dex, bortezomib/cyclophosphamide/dex or len/dex in the more mature, once again frail, patient population.

Just to remind you about the data for dara/len/dex. These were the published MAIA data, and they are going to be updated at this year’s ASH. And you can see that adding dara had a large benefit in terms of progression-free survival.

However, even though we always say the triplets are going to be better than doublets, it turns out that that isn’t always the case. And we know that from 2 press releases about 2 different studies. Showed you earlier the SWOG data of elo in the front-line high-risk setting. There also was the so-called ELOQUENT-1 study, which were all transplant ineligible patients, compared Rd to elotuzumab with Rd. And unfortunately there was no statistically significant improvement in progression-free survival.

And then we also heard about the TOURMALINE-MM2 trial, and this was in a similar patient population and compared len/dex with ixazomib/len/dex. As you know, IRd is approved in the relapsed or refractory setting, but this looked at it in newly diagnosed patients. There was a difference, with the IRd patients having a longer progression-free survival, but it did not meet the statistical endpoint that was set for the trial. So we’ll have to get more updates about subgroup analyses, but not all, unfortunately, triplets for newly diagnosed patients appear to be better.

So here’s a case that I pulled out just as an example from my practice. This was a 65-year-old patient who presented with fatigue, as well as pelvic pain. And if you look at CT on the right, you can see that they have a fairly large lytic lesion in the ischial space in the bone there on the right. Initial laboratory studies did show anemia, which would account for the fatigue. You’ve got the pelvic lytic lesion, and the bone marrow showed 56% plasma cells, as well as deletion 17p.

So this is definitely somebody that you want to treat because they have a high level of disease involvement and they’ve got not 1, but 2 symptoms because they’re both anemic and they have lytic bony lesions. So as I mentioned bortezomib is an important drug in this setting, and we did treat the patient with VRd. That was then followed with transplant.

And actually at MD Anderson, especially for high-risk patients, we’ve been doing a combination of melphalan and busulfan as the preparative regimen because of data from a randomized study, which actually were just updated, which showed that bu/mel did improve outcomes in transplant patients, especially those with high-risk disease. And then after transplant, again because of the high-risk, we decided to go with an ixazomib and lenalidomide-based maintenance therapy. And this patient continues to do well.

It is still possible that KRd could be useful in this setting because if your plan is to do, let’s say 4 or 6 cycles and then stop, it’s possible that KRd could give you a deeper response over a shorter period. And there is another ongoing national study comparing VRd to KRd to KRd with daratumumab, and that may inform that question further.

The second case that I pulled out for you here is an 83-year-old female who presented with foamy urine, as well as bony aches. Consistent with the foamy urine she had quite a bit of proteinuria, 3.5 grams over a 24-hour collection. And you can see the PET scan on the right, which looks like not something you would want to have as a PET scan, with multiple areas of increased bony uptake. The bone marrow showed 44% plasma cells, and the FISH showed a translocation 11;14.

What we did for this patient is because she was a little bit older but still in excellent shape, we went with daratumumab, lenalidomide, and dexamethasone. And after the initial induction period she was able to achieve a VGPR, and therapy is ongoing.

I do mention the VGPR because I think the t(11;14) translocation, of course, is a group of patients that typically express high levels of BCL2, and I think we’re going to wind up being able to use venetoclax, definitely in the relapsed or refractory setting, for these patients. And maybe in the future even add it to front line therapy to try to improve the outcomes in these patients further. Because sometimes it’s a little tougher to get the 11;14 patients into a complete remission.

DR LOVE: That was awesome, really great. A couple of questions. Maybe just first to focus on your cases. So the first patient, when did the patient present? How long ago, roughly?

DR ORLOWSKI: This was about 3 years ago now, and we’ve had good success with the combination of ixazomib and lenalidomide in maintenance. There’s going to be an update of the data presented at ASH, and we’re getting a manuscript together. It’s a very well-tolerated maintenance and seems to give a prolonged progression-free survival. Now this was a single-arm study at MD Anderson, so we don’t have Phase III data, but definitely I would go with a PI and IMiD-based maintenance for any high-risk patient like that one.

DR LOVE: So what I was going to ask you is outside a clinical trial setting, if the patient were to present today with the exact same situation, would you manage it the same or differently?

DR ORLOWSKI: I do think that with the availability of daratumumab now one might consider adding dara to the induction therapy. I showed you the GRIFFIN data, which showed that the VRd/dara had a better stringent complete response rate and a higher MRD-negative rate than VRd. There is some debate about whether dara adds to benefit in high-risk patients or not, and we really would need a dedicated trial. I showed you the meta-analysis, which is not the same as a trial, but anything that improves MRD negativity will improve outcomes in high-risk patients. So I would try to do that, although it isn’t yet typically reimbursed, so it can still be a challenge to get approved.

DR LOVE: The other thing about the case was the ixazomib maintenance. And I’m just kind of curious. In a recent webinar we did a very prominent investigator was kind of a little bit dismissive, called ixazomib bortezomib lite or something, the thought that it really wasn’t as effective. Particularly in the age of COVID, the fact that it’s oral and for maintenance therapy seems really ideal. And your data that you just quoted I think supports that even more. But any thoughts, of course it’s indirect comparison, about ixazomib maintenance versus say bortezomib maintenance?

DR ORLOWSKI: Definitely. And unfortunately we don’t have an IRd versus VRd combination or comparison study. In laboratory, if you compare them head-to-head there are some differences, and maybe bortezomib is stronger in the laboratory, but that doesn’t necessarily mean that the same thing is true in patients. And the all oral is a definite advantage, as you mentioned, with regard to COVID.

There were 2 trials that looked at ixazomib as a maintenance. One was in a post-transplant setting, and that compared it to placebo. Ixa did better, although the absolute value of the improvement was modest, but it was statistically significant. So if you have a patient, for example, that would be IMiD intolerant, and this could be because of len causing rash or diarrhea or cytopenias, I think definitely ixa is an opportunity. And then more recently there was a study of ixa as a maintenance in transplant-ineligible patients who did not go on to transplant. And compared to placebo there, there was both a statistically and a clinically meaningful improvement.

So I do think using ixa as a maintenance, either alone in transplant-ineligible patients after induction or with lenalidomide is a very reasonable approach to therapy, and I feel comfortable doing it.

DR LOVE: We had a webinar the other day with Irene Ghobrial from Dana-Farber, and we had general medical oncologists presenting cases. And one person had a case of a younger patient who was going to go to transplant, collected cells, delayed transplant, just went on lenalidomide maintenance and had biochemical progression in a couple years, then got the transplant. And that was another situation where it’s what kind of maintenance are you going to do there? They had already gotten lenalidomide, and the issue of ixazomib came up there. Is that a situation where you’d be thinking about that?

DR ORLOWSKI: It’s definitely an option. We know from the IFM Dana-Farber study, at least the French side of things, that if you get into an MRD-negative status after just induction therapy alone, your outcome is about as good as if you get to MRD negativity after a transplant. So I do think that if you have a high-quality response to induction that collecting and delaying transplant is probably reasonable.

And I do think that in terms of maintenance afterwards sometimes a transplant, we think, can reset drug sensitivity because you may be able to eliminate some of the clones that didn’t respond. Plus, because len is a drug that works in part through the immune microenvironment, and you restore immune competence after transplant, I wouldn’t totally dismiss the notion of giving len as a maintenance, even if they progressed on len before transplant. But I would probably definitely think about using either len with dara or len with ixa in this setting as a combination maintenance.

DR LOVE: That’s really interesting. I didn’t know that. I want to ask you about your second case with the 11;14. And I’m just kind of curious, first of all, if this patient were to relapse, or when the patient relapses, would you use venetoclax at that point? When would you be thinking about venetoclax? And if you had a very knowledgeable patient, physician, oncologist, et cetera, who really was very concerned about what was going on, willing to take a little bit of a risk, and reimbursement wasn’t an issue, for the patient like your second patient is there any way you might want to consider bringing venetoclax in earlier, outside a trial at this point?

DR ORLOWSKI: I think it’s definitely a good option. Venetoclax, of course, is FDA approved in other hematologic malignancies, so it is possible for any hematologist/oncologist to write a prescription. And if the patient can pay for it out of pocket, they can pick it up. I do think that the earlier that you use it, as is the case for any drug in myeloma, the better the outcome.

We have now data from the BELLINI trial that Shaji Kumar led that looked at bortezomib/dex with or without venetoclax, and the addition of the venetoclax had a huge advantage for the patients with t(11;14). So there is even a very good clinical trial-based argument that you could make to the patients insurance company that this is the right way to go. That trial, I think, gets a little bit of a bum rap because the patients who were not t(11;14) did worse, but the difference between the 11;14 patients who got venetoclax and who didn’t is just the biggest difference in any myeloma trial, I think, that we’ve ever seen. So the data really need not be discounted. And I would definitely try to use venetoclax as early as possible in a t(11;14) patient.

DR LOVE: Yeah, again, in that same conference with Dr Ghobrial we had a patient who got venetoclax on a clinical trial, I think venetoclax/bortezomib, had a 2-year response, actually stopped because the trial stopped it. And the thing that was amazing was that the patient got treated in 2015, and venetoclax didn’t have a name.

DR ORLOWSKI: The other thing in that kind of patient is if they stopped the venetoclax and then they relapse later off of the drug, I would retest their bone marrow, look to see if 11;14 is still present, and consider trying venetoclax again because it may be that the patient’s myeloma would still be sensitive at that time.

DR LOVE: Another thing I want to ask you about is kind of what happened with elo? I mean it kind of seems like it’s not really playing out very well, and I’m just kind of wondering why. Any thoughts about that?

DR ORLOWSKI: I actually like elotuzumab. I think the reason there’s less enthusiasm in some circles is because the drug by itself does not work. Unlike dara, for example, which we usually use in combination, but it does have a single-agent response rate. Also, I mentioned some of the up-front trials, where for reasons we don’t really understand elo-based combinations did not improve outcomes.

But in the relapsed or refractory setting you can give it either with lenalidomide or with pomalidomide, and I think if you have a patient who’s progressing on len maintenance, definitely elo with pom is a great option, so is dara with pom or isatuximab with pom. But I wouldn’t forget about elo because we’re not at a point, of course, yet, unfortunately, where we’re curing people. And it is an active drug, so we can’t afford to discard active drugs quite yet.

DR LOVE: Another thing I was going to mention when we were talking about ixazomib maintenance is I remember when it came out, I was all excited about the quality of life, oral, in particularly maintenance. But the other thing I was kind of wondering about is you would imagine the pharmacology, the blood levels are going to be very different than when you use subq or IV bortezomib. And I was wondering whether or not maybe there could be actually a treatment advantage because of the different pharmacologic profile.

DR ORLOWSKI: Well you’re definitely right. The distribution of the drug is different, and it does have benefits from the oral setting. It was tried at a twice-weekly schedule in the early clinical trials, but that schedule was not followed further because it did have more in the way of rash. But it definitely has less neuropathy, it seems, than does bortezomib. And really although it has some GI effects, that happens usually just with the first or the second dose and not later on. So it’s definitely a good drug and something to keep in the back pocket for your patients.

DR LOVE: Another question, you mentioned that the VRd versus Rd study had some high-risk patients, which I didn’t realize. How many did it have? Was that known before or that’s in this new paper?

DR ORLOWSKI: It was known before. It was really an all-comers trial, unlike the later ECOG and SWOG studies, where 1 focused on standard risk and 1 was on high risk, the S0777 study really enrolled everybody. And so usually around 20% of patients in any of these studies wind up being high risk in the newly diagnosed setting. That’s why the p-value didn’t quite reach statistical significance because the number was relatively small. But it think it supports our general experience over many, many trials, the proteasome inhibitors should definitely be used for everyone, but particularly for high-risk patients.

DR LOVE: Another question about the ENDURANCE trial. Got a lot more input on tolerability issues there, of course. And I’m curious, now that it’s shook out a little bit more with that data, what your vision is about what’s going on when you give carfilzomib, and you see dyspnea? Is there a cardiac effect? What’s the pathophysiology?

DR ORLOWSKI: Yeah, it’s a great question. Part of the problem is that the standard way to give carfilzomib involves giving fluid, and sometimes that can mean both pre and post hydration. And when you consider that some of these patients have creatinine clearances that are on the borderline side, and some of them are a little bit more mature and maybe not quite as robust, it can be that that winds up being too much fluid. And I think we have to be careful in giving pre and post hydration.

That having been said, even without the fluid, there are some patients where there can be some congestive heart failure and cardiac effects, and people have speculated that this may have something to do with an endothelial damage mechanism, although frankly we don’t really know for sure.

Again, there is another study that’s comparing VRd to KRd and then KRd with dara. It’s a 3-arm study, and everybody is going on to stem cell transplant. So it will be a different design than the ENDURANCE trial asking the question of whether a short course of KRd can be better than a short course of VRd. And it’ll be interesting to see those results. It’s still enrolling, so it’ll be a few years.

DR LOVE: So one final question, and you’re going to be the first person I ask this question to because I’ve been kind of thinking about it.

DR ORLOWSKI: Okay.

DR LOVE: Which is I’m going to put together a slide, I put together a slide actually, that says “now or later issues in oncology.” So these are issues that are going on right now in general medical oncology that the general medical oncologist is being exposed to from different treatment groups that have a theme. So for example, at ASCO we saw the use of the EGFR-TKI in lung cancer, osimertinib, with a spectacular progression-free survival advantage, but no survival advantage yet. It’s kind of early. Do you treat or not?

Then at ESMO we had the adjuvant breast abemaciclib study. Same thing, disease-free survival benefit, but too early for survival. Before that we had ovary with PARP, again spectacular improvement in PFS, too early for survival.

And those kinds of questions that are simmering around in general medical oncology. And then you come to myeloma, and you all have kind of a different approach, which is I think it kind of goes back to that iceberg model that you see people showing there’s a lot of disease below the — and the idea is to drive it down as much as possible.

So I guess I’m wondering what your perspective is, not only on the myeloma, but these other things. It’s interesting to see how there’s almost a different culture about how different disease types approach this question of when you see a PFS benefit earlier on. Any thoughts?

DR ORLOWSKI: Yeah, it’s a great question, and of course we’ve been debating earlier versus later for decades, around the transplant setting in particular. And we have at least a few studies that have looked at that question and generally concluded that as long as you don’t wait until 5 lines of therapy, if you do up-front transplant versus transplant at first relapse, in general the PFS and OS data are roughly comparable.

The way that I practice, in particular for standard-risk patients, is that if they achieve a high-quality response, which I now define as CR, and MRD negativity, I give them the option of collect and hold versus collect and go forward with transplant. I think when you’re dealing with induction therapies, I am still a proponent of doing as much as we can up front because every drug in myeloma works better if you give it earlier. Once we get to the point that 100% of patients are in CR and MRD negative with whatever regimen, hopefully soon, we can use to get there, then I think we’ll be at a point where we can debate should we drop some drugs and keep others. But we’ve been kind of slowly inching towards that area, but not quite gotten there yet.

DR LOVE: That’s interesting, though. I didn’t realize that principle has been validated of earlier therapy being more effective in myeloma.

DR ORLOWSKI: In general, if you look at many of the front line, and especially the relapsed/refractory setting, if you look at any of the major Phase III papers, almost all of them, and I say almost because there are a few exceptions, but if you look at the outcomes for patients with second-line treatment, say with dara/len/dex, their outcome is better than if they’ve had third-line treatment with that regimen. And the same thing is if they have fourth-line treatment. So that does speak to the fact that either the myeloma cell becomes more drug resistant or the immune microenvironment becomes less favorable or some combination of the 2, now that we’re using a bunch of immunotherapies, including antibodies, bispecifics, and of course hopefully very soon as a standard of care, CAR T cells.

Consolidation and Maintenance Therapy in Newly Diagnosed MM — Role of MRD Testing — Rafael Fonseca, MD

DR FONSECA: Well thank you very much for the invitation, Neil. It’s always a pleasure to be with you here today. We will talk about induction therapy, and then what are the concepts that we’re discussing right now with maintenance and consolidation, with a very special emphasis on what minimal residual disease testing means for patients who are facing the first line of therapy for multiple myeloma.

Now I won’t go into all the details, but just for a general background, let’s talk for a few slides regarding MRD testing. And what I would tell you is there’s a number of publications, both individually at the institutional level, but also meta-analysis, that continue to show the very profound impact it has to achieve MRD negative as patients go through the various phases of treatment, particularly in the front line.

Now this is one study from the Spanish group, Juan Jose Lahuerta, presents this study that shows to you their progression-free survival and overall survival in what is very clearly across the various subgroups of patients. Achievement of an MRD-negative status becomes a very important feature of success in the long term. And again, you can look at the literature. There’s multiple studies, including 2 meta-analyses that have been published in this regard.

So the real question is where are we going with MRD testing and how will it impact clinical practice in the future for multiple myeloma? Now there’s several ways by which you can do this. There are mechanisms to do next-generation sequencing, and then we have flow cytometry-based assay. And it’s fair to say that the most sophisticated flow cytometry has come to us from the European groups, where they have the multicolor flow cytometry evaluation for residual cells, where under the best hands they can detect at the level of 10^-6, so that is 1 cell out of a million. And this would be just — just one of the examples. And many of the clinical trials that will be discussed and are presented relate to this particular technology.

And alternative is that we now have an FDA-approved assay that essentially does B-cell DNA fingerprinting, and that is the clonoSEQ^® assay where they actually take the sequence of the B-cell receptor, they take the original sequence in the sample that is usually at the time of diagnosis, and then in subsequent determinations they can measure the copy number that is present. So under the ideal state you can achieve no copies being detected. And this assay also, with the loading of the proper number of cells, achieves the 1 to the 10^-6 sensitivity for detection of residual cells.

Now there’s still quite a few controversies regarding application of — of MRD, and I think we will have them with us for the next several years. And of course this started basically with the technology of using flow cytometry versus next-generation sequencing and the type of samples that one could be testing against. Of course, the most important question is can we use the information that comes from the MRD assay to make clinical decisions.

And I should be very clear here as I present you some of the cases and some of the studies in how I am thinking about its use in the clinical field. But MRD will never be — should never be the single determinant of what to do with therapy. It is like any other biomarker and any other clinical test. It is an extra piece of information that better informs the clinician and the patient on what might be the proper next step for therapy.

So questions are arising. So for instance, can we start using MRD to stop treatment? And we have patients who are on chronic therapy who are, for instance on chronic maintenance, we’ll talk a little bit more about that, will achieve a CR, and then are experiencing some of the toxicity, sometimes even mild fatigue. “I just don’t have the same level of energy. I’m sleeping a little bit more.” And for clinical reasons alone we have historically stopped therapy. So the question is can we make an even more informed decision as we bring MRD into the decision-making point?

So if a patient is positive but is tolerating, perhaps that may be an incentive to continue further on treatment. But if a patient has some toxicity, and they know they’re negative, it is possible that they will have a greater level of comfort in thinking about discontinuation of therapy, which again, we do sometimes for clinical reasons alone without even the participation of information of a biomarker, such as could be MRD. And I always argue that we have to bring this into the context in patients who have residual proteins.

But this is simply like what we saw with the evolution of the free light chain. I know there’s a lot of debate in the myeloma field right now whether we should wait for the Phase III trials, and I always argue that we never waited for Phase III trials to be developed for the free light chain testing. And I cannot imagine my myeloma practice now without such a — such an important biomarker, that is the determination of those free light chains.

Now some of the studies have tested MRD also in large perspective Phase III studies, and this is a very important study. I would say it’s one of the most important papers, the paper presented by Dr Perrot, now 2 years ago, where they actually look at MRD outcomes and both risk stratification, as well as the therapy that is provided for the patients. And what you can see first on the left is that the best scenario, in their hands and in this particular data set, which was the IFM 2009 study, was achieving MRD status and also having done so in the context of stem cell transplantation. Now patients who had RVD treatment who were MRD negative seemed to have also a very good outcome. And then you look at the rest of the patients, those that are positive, you can still separate how they do based on the transplant versus not, but clearly have an inferior outcome versus those that are MRD negative, that are shown in the upper part of the curve.

More interestingly, on the right side of the slide, I show you the important of correlating MRD and risk stratification for myeloma. You’ve heard in sessions like this many times before the importance of genetic markers to determine outcomes for myeloma patients. And what Dr Perrot shows here is that the best outcomes are for those patients that are MRD negative and have standard risk. But importantly, the second-best category are patients who have high-risk disease who are able to achieve MRD negativity. And in fact, it’s better to be in that category to have standard risk factor and remain MRD positive, which is the third curve there that you see in the blue.

And lastly, and as anticipated, the worst outcomes are for patients who have MRD positivity and also have high-risk features. So I think this starts changing how we think about the measurement of the responses and how we integrate this with other clinical variables and genetic variables to determine the outcomes for myeloma patients.

Now an important point, and I’ll make reference to this as we talk about consolidation and maintenance, in that same paper, and this is hidden in the supplemental material part of the paper, they found out that the outcomes seem to be similar no matter when you achieved that MRD-negative status. So on the left side you see what happens when patients achieve the MRD negativity, those in the red curve, at the time of initiation of maintenance versus the outcomes that you can see on the right side for those that are MRD negative 12 months after the — the participation and determination of this MRD status.

So the reality seems to be that it doesn’t matter when you get to this MRD-negative status. In fact, there’s no reason to believe there’s a magical point where MRD negativity matters, but what really matters is to get to that point.

Now how are we doing with some of the modern induction therapies? This is the GRIFFIN trial that has been published by Dr Voorhees, and what you see on the left side is what we are reporting with the combination of 4 drugs. In this it’s daratumumab plus RVD versus RVD alone on — on the far-right bars. And on the left side you see the standard response criteria. And if you just look at it just quickly, you’ll see that the red are patients who are able to achieve a stringent complete response. So clearly, we see that 4 drugs are better than 3 drugs.

But if you now focus on the right side of the slide, and you look at MRD negativity status, and this is at the level of 10^-5, you see that the proportion of patients that are able to achieve this with the 4 drugs is significantly higher than that of patients who are in the 3-drug regimen.

Now these studies are reporting early data, and when they are being presented, they primarily are reporting response. Some of them are reporting early signs of PFS. And it is only in time that we will know completely if these results continue to show an improvement in survival, which I bet they will, but perhaps more importantly what fraction of these patients will remain without progression over the very long term. And I’m to venture to say that some of these patients that are achieving an MRD-negative status with the best induction treatments that we have, followed by transplant, and followed by treatment post-transplant, will ultimately represent the first wave, the first significant wave, of the cure of multiple myeloma.

Now here’s another study. This study has been presented by Dr Gay from Italy that looks at 3 regimens. The regimens are the KCd followed by transplant followed by more KCd in the form of consolidation. The second arm is KRd followed by transplant followed by more KRd. And the last arm was KRd continuous without stem cell transplant.

I would ask you to focus on the right side of the slide. What you can see there, now in the blue bars, are the proportion of patients that achieve an MRD-negative status, again in this case a 10^-5. Now there’s a few conclusions that have been reached by the presentation of the data for this study. The first one is that the 2 arms that contain lenalidomide are superior to the arm that contains cyclophosphamide. So I think this is further evidence that we need to move to IMiD-based combinations for the front-line therapy of multiple myeloma.

But when you look at the rate of MRD negativity between the last 2 columns, the differences are 54% versus 58%. And I always say this is a bit like a Rorschach test, when psychologists present an ink blot to patients — to people, and they say what do you see there? Well, if you’re a transplanter you’re going to point out, rightfully so, that there’s a 4% absolute-point difference between transplant and not. And if you don’t believe in transplant, they’re going to see they’re about the same.

Now subsequent reports have demonstrated that those patients that undergo transplant appear to have a lower risk of an early relapse. The data for this study is maturing, and again, only in time we will know the — the full results and outcomes as patients continue to be monitored. But now we’re seeing regimens that can induce an MRD-negative status in approximately 60% of patients.

And another clinical trial now tests the 4-drug combinations. This is the MASTER trial, but instead of using the VRd regimen, now the backbone is KRd. And Dr Costa presented this at the ASH Meeting, where we see that again with the 4-drug combination you can achieve very deep level of responses. And once more I would draw your attention to the right side of the slide, where you can see that as we start testing for MRD negativity, if you measure exclusively at the level of 10^-6 you see that 65% of patients are 10^-6 MRD negative.

My only hope is that with time we show (1) that this provides clinical benefit, but (2) and I’ll say it again, that a fraction of these patients potentially will be cured from their multiple myeloma.

Now we see similar results for patients who are treated on their nontransplant protocols. I won’t go into the details. This is the MAIA study. But you can see again you can breakdown outcomes based on the depth of the response, again by MRD determination. And in this case the best outcomes are for the triplet, so the dara/Rd is — has the best outcomes. Although you can see that there’s a lot of similarity with the outcomes of those patients treated with Rd that also achieve MRD negativity. Those are the top 2 curves.

The important part here, and this is a concept that is agnostic to drugs, it really happens with whatever your drug regimen is, if you look at the red box, the likelihood that a person will achieve this MRD-negative status increases substantially with better treatments. And it’s just obvious, we never achieved this level of MRD negativity when we were treating myeloma with MP, VAD, or other similar regimens.

And we have similar results, for instance, with the ALCYONE clinical trial, which tested the combination of dara/VMP as front-line therapy for newly diagnosed noneligible patients. This was a global study. So as you can see, with better induction therapy and some of those trials incorporating to the stem cell transplant, we have very deep responses.

In 2020 I think it should be considered the standard of care to offer maintenance for patients. And we don’t have a lot of new information in that regard since we saw the meta-analysis that was reported that showed a very significant improvement, with a progression-free survival of approximately 53 months, and also significant improvement in overall survival.

We have subsequently seen the report of 2 clinical trials that are testing ixazomib as the maintenance treatment for patients who have both completed stem cell transplant, and in a separate trial for patients who are not transplant eligible but who have completed their induction therapy.

Both of those trials were positive. However, the magnitude of the benefit was not as large as what we had seen previously with both IFM and the CALGB study.

But it’s important to note that many of the academic centers are using the combination of ixazomib plus lenalidomide as maintenance for those patients who are completing the first phase of treatment and may have some high-risk features, be that genetic, as well as evidence from clinical features that the patients will have high-risk categories. Now this is important too, as well, as we all know this year has been quite different, and we’re trying to prevent patients coming back from our clinic. So the convenience of just using an all-oral regimen for the treatment of patients who have completed that first phase of induction, and if you may, the emancipation we provide them from having to come to our clinics, will be a very important aspect of both safety, as well as their quality of life.

I always like to say that with the advent of MRD and with the data that I’m presenting, I am hoping that there is a future where very deep determinations of the level of response can determine the boundaries of what we’re seeing in multiple myeloma. And that is both the X axis and the Y axis on this slide. On the Y axis I show the depth of the response, so the deeper you are the more likely you are to be in that MRD-negative status. And on the X axis I report on the duration of treatment.

And in the ideal world we want to have the deepest response possible with a duration of therapy that is limited, that is not forever. And we are getting closer and closer to being able to achieve this because of the incorporation of MRD testing in our clinical practice. Now you see a darker orange boundary on the bottom part of that square, and that’s on purpose, and that is to remind myself, and we’ll talk a little bit more about this, that there are some patients that have residual disease that perhaps keep a small monoclonal spike but who can do well for many, many years, sometimes in the excess of decades without having clinical recurrence of the disease. So we still don’t understand that part, and I marked that with that particular thicker border.

Now I saw that as of now, in 2020, the best strategies for control of myeloma are similar to Pax Romana. You come, you dominant the cells, you dominant the clone, you do that right from the get-go with your best treatments, and you stay there for a while. And I hope that stay is going to be shorter and shorter as we can get deeper and deeper with the response levels we can achieve in our patients.

Now because of that orange border I want to manage an extra concept, and that is should we always pursue MRD negativity? I think from the get-go it makes sense, but it’s important to remember, again, that there are some patients that might revert to an MGUS-like situation. So perhaps there are some myeloma categories where we should be relentless in the pursuit of this MRD-negative status, and I put that in the left side of my graph. Patients who have high-risk multiple myeloma, maybe they should be considered like ALL, where we don’t really tolerate residual cells.

On the other hand, there might be some patients that are — patients where some of the cells can stay in the background, they can be MGUS like, perhaps some of the — this hyperdiploid patients, and we would think of them more like we think of follicular lymphoma.

The best explanation for this I heard from Dr Hari from Wisconsin, and he said, “Listen, you’re in the top floor of your house, and you hear sounds in the basement. And if you do that, then you go down, and you see there’s mice, well you might say it’s not optimal, but you can wait until Monday to call the company to get rid of the mice. On the other hand, if those noises come out from a tiger, then you’re in trouble, and then you have to deal with that. So it’s you or the tiger.” And that’s the approach that I think we need to start taking. That is the integration of genomics, clinical features, select the best treatment, bring the clinical variables that patients have otherwise, and based on that try to make the most personalized approach for the treatment strategy for any of our patients.

Now I’d like to share with you a couple of cases of my practice where I have tested for MRD and how I’m thinking about this as I go through the first phase of treatment. The first one is a 53-year-old male who is married to a primary care doctor, and he came to me right from the beginning. So we started treatment. And he had all the features of CRAB, so we started him on induction therapy, in this case with a combination of KRd.

The patient completed stem cell transplant and has recovered and came for the day 100 evaluation. And this is how the report reads, as you see there on the right side. Now this patient does not have high-risk features, but this report I got on this patient on that day 100 visit. And at that time we decided that he would still go onto maintenance therapy because we don’t know that withholding maintenance at this point is the proper thing to do. But I can tell you that few of my conversation and the level of hope that someone like this has when they know they’re in the best response category at this point immediately after stem cell transplant is something desirable, is something I wish I could have with every single one of my patients who completes this induction therapy.

Now there’s another patient here that I would show for discussion. This is a 58-year-old male who comes to see me. He was newly diagnosed, and he also received induction therapy with KRd. Very smart individual. He completes his stem cell transplant, and he comes back, and unfortunately post stem cell transplant, and even though he didn’t have any features of aggressiveness, his testing shows that he still is MRD positive. And he is very uncomfortable with that finding.

And based on some of his reading of the literature, we decided to proceed with additional consolidation treatment post stem cell transplant. So he was started with a combination of daratumumab/Rd post-transplant, and the patient had a further drop in the number of copies of the residual DNA that he had. So when we first started him on this consolidation treatment it was November of 2018. By August of ’19 he was still positive, but the copy number had gone down. He was doing well with treatment, and at his request we continued with additional therapy. By February of 2020, he had become MRD negative, and we switched him at that point to lenalidomide-based maintenance.

And again, I’m hoping that as we’re able to put more and more patients in this MRD-negative category, and I get it, doing it safely and doing it with full participation in the decision-making process with patients, that this will ultimately convert into long-term disease control. And again, a fraction of those patients potentially being cured from their multiple myeloma.

So with that, I’ll conclude. Again, Neil, thank you for the invitation, and I appreciate the time.

DR LOVE: Thanks, Rafael. That was really awesome. I just want to follow up with a few questions. One thing is you referred to looking at survival in the GRIFFIN study, and I’m just kind of wondering in general, because I’ve been just thinking about this in general in oncology, so many trials are out there right now where this is an issue. How many trials right now have shown survival benefit in up-front treatment of myeloma? Is that even a feasible outcome to look for?

DR FONSECA: It is very hard because it takes a very long duration of time before you can do that. So there’s very few randomized Phase III clinical trials that show an improvement in survival. We do have them. And some of them will report in time. But it’s literally going to take 10 years plus for some of them to be able to report this. So for the most part we have been using progression-free survival. An example of the one that shows an improvement in overall survival is the SWOG 0777 and others that are coming forward, but the reality is you need very long duration of follow up. And that’s good news. And the reason is because we have fewer events in myeloma clinical trials because patients are living for longer.

Now in my mind I would like to see that as we continue to demonstrate that — this — very profound responses, particularly with an MRD-negative status, correlate both with PFS and the OS, then we can get earlier readout for the clinical trials to know what is it that we need to do at the bedside.

DR LOVE: Another thing you refer to is the idea of cure. So what evidence right now do we have that any patients are getting cured?

DR FONSECA: So the best evidence comes, in my mind, from 2 data sets. One is the Spanish study that was published in 2011, also by Dr Lahuerta. So what they did is they looked at very long-term outcomes for myeloma patients who completed autologous stem cell transplant. Now they defined very long-term follow up as 20 years. So as you can imagine, the induction therapies that these patients were getting were in the range of VAD and BVMCP, very, very old regimens. And what they found is that if you look at their data sets 30% of their patients were able to achieve a complete response. Now for reference, now they — it should be closer to 90% plus.

So 30% of the patients were able to achieve a complete response. And of those patients, 30% of them remained without progression at 20 years. So in that older data set one could conclude that 30% of 30% is about 9% of patients. So a small fraction of patients. And we could argue for a long time whether that should be 5% of 15%, but we know there’s a small fraction of patients that remain disease-free. We all have them in our clinical practice. Now some of them can be called functional cure because some of them may have a small protein, but I have a few patients that have completed stem cell transplant, some even without maintenance, continue to do well.

So if the math holds, and that 30% of 30% remains, now what if that would be 30% of 90%. That might mean that we could be starting to see the cure of about 20% to 30% of myeloma patients.

The other data set is a data set from the University of Arkansas. Dr Barlogie put, in his mind, the best combination possible, and long-term follow up shows that patients enrolled in total therapy clinical trial remained without progression essentially decades after they were started on treatment.

DR LOVE: We actually had a case presented at one of our recent conferences of a woman who had relapse/progression 20 years later, was treated in 1997 originally. How often do you see that? And how do you explain it?

DR FONSECA: Well unfortunately, we do see that. And I think about this in a couple ways, and we’re trying to collect those samples because it could be re-emergence of the same clone or it could be that a person goes back to that MGUS-like state. And then with the passage of that much time, just by probability, stochastic if you may, there’s acquisition of secondary genetic changes that will give rise again to myeloma. It comes from the same clone, originally from the same MGUS clone, but perhaps even a different myeloma clone.

So people are trying to understand this. Some have said that in some instances myeloma could be a bit like breast cancer, that it could be many years later that you still see emergence of those cells. But again, as we measure and as we don’t give space to the cells, I’m hoping that we’re going to be seeing less of that.

DR LOVE: So can you talk about how you think, right now, MRD fits into the management of induction treatment in a patient who’s younger and considering transplant? And is it reasonable to present to the patient the alternative of delaying transplant in a patient who’s MRD negative after initial induction therapy?

DR FONSECA: Sure. That — that’s a very tough question. So first of all, I believe first and foremost in patients’ health determination, right? Then I have patients that have come to me and have said, “I’m on the fence as to whether I want to do a transplant or not.” And I would not be one that would force the patient to do something. So we have had that conversation, so I have had patients who have elected to delay transplant.

Now some of my colleagues might say well, we don’t know that. But the reality is that delayed transplant has been an option that has been practiced by many centers over the years. I personally don’t favor that. I favor that most of my patients should go to transplant. But there might be circumstances or no reason at all why someone may not want to do transplant up front. And I can think of various examples of patients who had a busy professional life and understanding some of the differences, elected not to have their transplant up front.

But the real question will be, hopefully some of the clinical trials that are going on are going to give us this answer, what happens if you go through an induction treatment, let’s say 4 to 6 cycles of an optimal regimen, let’s say a quad regimen with an antibody, and you were to do a bone marrow, and you’re MRD negative. The law of diminishing returns might tell you that the incremental benefit of doing a transplant at that point might not be that great. And perhaps it would be reasonable to consider maybe a little bit more treatment and then stopping altogether and monitoring the patient.

I don’t have the comfort level to recommend that per se at this moment to my patients as a path to follow, but I think that’s really the next question in how we’re going to employ MRD testing to make decisions with patients. And I should say that physicians, when they think about a test, they think what am I going to do different, right?

This conversation happened for many years with FISH testing. And what I’m going to do different, it doesn’t mean what I’m going to prescribe different, it means what are you going to do differently. And that has 2 sides of it. First of all, for some of us that might change how we think about the next steps of treatment. That is something evolving and a personal preference. But at the very least, how you talk to patients makes a big difference. If you have someone who’s MRD negative — and in our center we also do a PET scan post bone marrow transplant — if a patient is negative for those 2 markers, there’s a very low likelihood that they will experience a relapse in the next 5 years.

So that’s what I’m going to do different. I’m going to talk differently to patients about what I might expect. In fact, I’ve taken the practice that I get the MRD results usually via an email, and even if it’s a weekend, and we have those results, I share them with patients. I know they’re waiting for them and they’re very important, and patients are very well informed.

DR LOVE: What about the issue of consolidation and maintenance? How are you approaching that nowadays in general clinically? And where, if at all, does MRD fit in? We have seen data suggesting patients benefit if they’re in a clinical CR, I believe, but what about patients who have MRD negativity in terms of either starting maintenance or continuing it?

DR FONSECA: So that’s a second big question with MRD, of course. Now the trial, like the MASTER trial that I was mentioned from Dr Costa measuring, in a repetitive fashion, MRD, and what they’re doing, if you have 2 of them that are negative, they’re going to stop therapy.

Now the main thing this meta-analysis suggested is that everyone, including those in a CR, would benefit from maintenance. Unfortunately in those trials we were lacking 2 things. One was a detailed genetic profiling, and number 2 was MRD. Because one could ask the question, well if I am CR and MRD negative, again, what is the benefit of me being on chronic therapy with something like lenalidomide? And there is no question on expense for doing that, right? Both in the sense of not only the economic expense, but also the toxicity that comes with fatigue and some of the chronic symptoms that patients will have on maintenance therapy.

I don’t have the comfort yet to stand behind that as a recommendation, but I have a patient who had a serious family issue, and she told me I want to get my MRD testing, and I understand what you’re telling me. I understand the studies of maintenance. And I deeply believe she did have that understanding. But if I’m MRD negative, I think I’m going to stay off maintenance because I just cannot afford to have the side effects at the moment.

DR LOVE: So I’m curious about your current clinical approach to maintenance treatment. You showed some data with ixazomib, and I’ve been hearing a lot more about using proteasome inhibitors in the maintenance setting for higher-risk patients. How do you approach the choice of therapy and the duration of it?

DR FONSECA: So our approach for maintenance is as follows. First of all, we offer maintenance to all patients. There might be patients who elect not to do that or who may have, for instance, to lenalidomide, a serious reaction, a very serious reaction, who maintenance will not be prescribed. But we offer maintenance to all patients. And the way I do it, I put lenalidomide 10 mg just once a day continuously, no breaks, and I think that makes everyone’s life easier. So it’s kind of in the background there.

If, however, the patient has high-risk genetic features we add a proteasome inhibitor. There’s good data from multiple groups, one of the most notable data sets, I think, comes from Emory University, from Sagar Lonial and team, where they have shown that the addition of a proteasome inhibitor can significantly improve the control and outcomes for high-risk patients. And many centers are doing that through the subcutaneous bortezomib approach. I think fewer centers are doing carfilzomib because of the logistics. But I personally like to use ixazomib just because, again, we have the oral convenience. In my experience it has been actually very well tolerated, and patients don’t have to be coming back for their appointments.

Furthermore, we can actually start spacing out the patients’ visits even for monitoring, so I’m a little bit of an outlier. I actually love the medical records, so people are going to cancel me after I say that, but I love the medical record and how we have it because I can track the results of the labs of my patients. So I may have them have labs once a month and then be seen every 3 months, but with me knowing I’m going to see those results, and if something happens I don’t like, we can always bring them back. But otherwise, why bother, and some patients drive 2, 3 hours to come see us — to our centers.

DR LOVE: I have heard people say, Joseph Mikhael for example in a recent webinar we had, and his concerns that the — that ixazomib is not as effective as bortezomib. What data do we have on that, and particularly as it relates to the maintenance setting?

DR FONSECA: They really have not been tested head-to-head, so I think a lot of what we’re going by is impressions, and impressions can fool us. We just recently learned that with regards to the efficacy of carfilzomib versus bortezomib up front in the ENDURANCE trial that was reported at the ASCO Meeting, right?

But there’s something to be said about the real world. So if you were to ask me, I think that the power that is carried by ixazomib is not the same as the one of bortezomib. And I still think that bortezomib doesn’t have the punch that carfilzomib does. But we have never tested ixazomib head-to-head to bortezomib. But in the real world, the convenience of the oral medication is huge.

When ixazomib was first approved I really didn’t anticipate it would be such an important drug, but the fact that patients can take it, can stay on treatment, don’t stop because they have to be driving or logistic challenges, has made it be a very important drug. And actually I think that consistency, something that has an X% decrement in efficacy over the subcutaneous, however translates into efficacy because patients get the drug, and they stay on the drug. And so my experience has been actually quite positive with the use of ixazomib.

DR LOVE: So what do we know about CAR T and MRD?

DR FONSECA: We know a little. What we know is that CAR T-cell treatments and bispecific treatments can induce MRD-negative status. I think that it should be the bar by which we start gauging these treatments, as well, too. We have some trials that are like the CARTITUDE trial that achieves essentially a response rate in 100% of patients. And one often underappreciated factor is that MRD determination is not a binomial. It’s not a positive or negative. Actually, there’s an amplitude in measurement.

So if you take all your CRs, and you start doing MRD, and you have a standardized protocol, which we actually do at our center, you can start measuring the copy number of residual cells in the bone marrow, as I showed in my second case, that you can track that over time. And I think once you complement that, you realize that under the level of detection that we have with traditional analysis of proteins, you still get an amplitude by measuring things such as MRD.

DR LOVE: Interesting. For the community-based general medical oncologist, is there — what technique do you recommend? Is there a specific assay for MRD that you recommend?

DR FONSECA: This is something that you have to work with your pathologist. In our institution, being an academic center, we do both. We do flow cytometry, and we do the next-generation sequencing, clonoSEQ assay. Now, I would tell the community doctors the clonoSEQ does not — or the MRD by flow does not have to be done multiple times. So we do it, for instance, at day 100. We might do it once a year. So I would work on a system that you can do that with the referral centers with which you work for — perhaps for the transplant.

Now there are some patients that you’re going to be monitoring long term, and I think it would be worthwhile to have that communication with your pathologist. So when you get the samples and you want to ask the question, you’re ready to get those MRD results back to the bedside and discuss them with patients. So we have used mostly the next-generation sequencing assay for the long-term maintenance cases just because of the consistency of the sensitivity. But it’s a conversation that (A) I would encourage you to have that with your pathologist, and (B) the referral center where you might be working with transplant cases.

DR LOVE: So that’s interesting. In other words, maybe find out who your transplanter — what kind of MRD assay they’re using?

DR FONSECA: I think that would be a reasonable thing to do. Now, one of the things I would caution, if you’re going to go with flow cytometry it has to be the next-generation flow cytometry. Some people will refer to this as a EuroFlow. Flow cytometry is normally done in laboratories and it just goes 10^-4 and ^-5 if you’re lucky, so I don’t think that really reaches the threshold. Myeloma doctors, we can be in rooms and discussing for hours what the right threshold is, whether it’s ^-5 or ^-6, but I would say something that’s at the ^-4, that is really not sufficient to have these kind of conversations.

Selection and Sequencing of Available and Recently Approved Therapies for Patients with Relapsed/Refractory MM — Nikhil C Munshi, MD

DR MUNSHI: I’m going to discuss various aspects of selection and sequencing of available, as well as recently approved therapies for patients with relapsed and refractory multiple myeloma. Now the important principles to be kept in mind before we decide what treatment to give and how to take care of the patient when they relapse from their initial treatment of myeloma.

One of the reasons that we want to give the best treatment when patients relapses for the first time, what we would call the first relapse, is because there is a reasonable amount of attrition. The number of patients who are able to go to the second, third, and fourth line of treatment goes down. So we do not have, in all the patients, best chance to give a better treatment later on. So we want to give the best treatment available at that same timepoint.

And the second point, for the same reason, is there is a diminishing return. Patients’ response to the second-, third-, and fourth-line keeps on going down. So we should do the best treatment for the second, and then go down subsequently. And to get the best, longest survival outcomes.

Now there are issues that we need to keep in mind. One is when do we start the retreatment? If a patient is in CR, and he becomes immunofixation positive, that’s not the right time to immediately start the treatment. So there are certain criteria. If patient’s M-spike is increasing slowly, but is asymptomatic, we can still wait. That state may last for some time. However, if the patient has a clear clinical relapse, which means there is increase in paraproteins and also end-organ damage, anemia, renal failure, bone disease, that’s the time to start treatment.

Or alternatively if there is a significant and fast, accelerated increase in M-spike doubling time, within less than 2 months, that’s another indication. We have to keep in mind if the patient is high-risk disease, then I wouldn’t wait until the end-organ damage. I would intervene early. But these are some of the indications for retreatment, for starting treatment for the relapsed disease.

The next question is what is my goal for treating relapsed patients? In the past, whatever best we can get, we were taking it. But now there is emerging data that the deeper response, when in relapsed patients, we have a better outcome. And there was this large, 8,000 patient meta-analysis that we did and published very recently, which of course shows that in newly diagnosed patients MRD negativity is good. However, it shows that in 1,124 patients that if you get MRD negativity in relapsed patients you have a better PFS and also better overall survival. So now the emerging goal for relapsed patients is also to try and get MRD negativity for a longer-term, superior outcome in this patient population.

Not only that, but when we put all these goals on top of each other you could see that a MRD negative relapsed patient may have a very similar PFS as what you see in MRD negative but newly diagnosed patients. And that’s unbelievable. But that’s a very important point, that if we get them into MRD negativity in first relapse we may improve their outcomes similar to what we would observe in newly diagnosed patients. The problem sometimes is the frequency of MRD negativity in relapsed patients may be less, and we have to keep that in mind.

Now what are the factors we consider before we pick the next treatment? There are a number of factors, first is a disease-related factor. The type of relapse and whether the patient has high-risk disease or not, and the disease burden. The second one is treatment-related factors, what previously treatment the patient got, what were the toxicities, the depth and the duration of response, which can tell us can I use the same drug or not, or some other sequence I use.

And finally patient factors. Are there any side effects, very importantly, but also their renal dysfunction, blood counts problem, and sometimes patients’ preference about needing to come to the hospital for IV and other things. So we have to keep this in mind. And then we have to synthesize this data into this kind of a box, where we look at frailty, morbidity, risk assessment, et cetera. But the box in the green is probably the most important driving factor, what was the patient’s last treatment? That determines my starting point, and then the other factors can modify drug versus another drug, because we always have many choices these days. That’s the beauty of myeloma, we have so many treatments available.

But keeping the previous therapies as my starting block, the rest of the factors can decide what I may add or not add. Usually, proteasome inhibitor and immunomodulators and sometimes both still remain a component of the relapsed treatment. And nearly all Phase III studies have shown that even in relapsed patients triplets are better than doublets, and so we are to keep that principle in mind most of the time to decide on what triplet I will use.

And I would also caution that it’s not correct to do cross-trial comparison. If the patient has gotten daratumumab/pomalidomide/dex or the patient gotten daratumumab/bortezomib/dex, and you see 2 different results. One is less, one is high, it does not mean one combination is superior to the other, partly because they’re a different patient population, different starting points, et cetera. So do not compare cross trial. You use what is best based on the principles we just discussed.

And so based on that, now we can synthesize what data exists. So when a patient has the first relapse, and most of the time patients have received a proteasome inhibitor, immunomodulator, and steroid; transplant if younger, not transplant later on, and they had lenalidomide maintenance, in rare case they could have had bortezomib maintenance. Depending upon that there are a number of choices available to go to.

So if the patient’s last treatment was more like bortezomib based, then we are going to use combination that uses immunomodulator. And there are 4 very good studies that have combined lenalidomide/dex with each of the newer drugs, ixazomib, elotuzumab, carfilzomib, and daratumumab. There are 4 very good, large studies. Each of them shows that the overall response rate for this 3-drug regimen varies from 78% to 93%, very high response rate. It doesn’t matter what we use.

And we get very good CRs, from 12% to almost 50%, so we can get deeper responses, as well. And median PFS is also very high with this triplet, anywhere from 20 months to 25-plus months, so 2-plus years of median PFS. And overall survival is very long in each of them. Most of the studies have not reached their overall survival.

So this gives us options based on what patients got before to select one antibody versus another, or using carfilzomib versus ixazomib. And similarly, if patient’s last treatment did not include bortezomib-based regimen, then we may include bortezomib-containing regimen. There are very good III studies that can give us some idea. Bortezomib has been combined with pomalidomide, it has been combined with daratumumab, and it has been compared to head-to-head with carfilzomib. But carfilzomib at this stage was found to be superior, so we can use PVd, we can use DVd, or Kd, or a combination of carfilzomib with pom or daratumumab.

Each of them have, again, shown a very high response, rate, goes up to 80%-plus, with CR rate that ranges from 10% to 30%, and a median PFS of a year and a half to 2 years. And so either lenalidomide/dex combination or bortezomib/dex combination or, in many cases, instead of bortezomib you could use carfilzomib-based combination, depending upon the symptoms. So for example, with initial RVD the patient got neuropathy, then I’m not going to go back to bortezomib. I would go to carfilzomib. So just as an example how a toxicity can help us decide which drug to go to. Also, we know carfilzomib can work when bortezomib has not worked, so there is a superior profile there to be utilized. And so this leads to the decision of what we do.

So when patients relapse, we can use an antibody, whether it’s anti-CD38 antibody combination, which could be a combination like dara/Kd, dara/PVd, dara/Vd, and dara/Pd versus dara/Rd. And these are the combinations we can pick, depending upon patient’s convenience, toxicities, et cetera. And now that daratumumab is available subcutaneous, there is increased convenience with shorter infusion time.

On the other hand, one can select also non-anti-CD38-containing regimen, where you can pomalidomide combined with Vd or cyclophosphamide/dex or with carfilzomib. And some of newer combinations we will discuss in a minute. So this is our algorithm for what options we have, and we would pick those treatments.

Now if you put all the data together we have 11 new agents which were approved, and then there are few newer agents which have been approved very recently. There are proteasome inhibitors, 3 of them; immunomodulators, 3 of them. We have 1 HDAC inhibitor. We have now 4 antibodies which are commercially available. We have an exportin inhibitor that is a very interesting new molecule, and then we have a number of other older drugs. And we can synthesize them based on patients features that I just mentioned.

Also, you will hear a lot about it, but there are a number of other treatments which are near approval, and we can go into details of how they will be incorporated into this.

But the 3 new drugs, isatuximab, an anti-CD38 antibody, very effective; belantamab, that is BCMA ADC; and selinexor, the exportin inhibitor; are more recently approved drugs. And I’m going to talk a little bit more about the data focused on this and how we can incorporate this drug into our treatment algorithm. And important to keep in mind, 2-, 3-, and 4-drug regimens are still effective, or very effective, in this setting, and we can appropriately combine all these drugs.

So if we go to isatuximab, it’s an anti-CD38 antibody. It has a number of effects. The primary effect is ADCC by targeting NK cells and macrophages in their activation. It also leads to direct apoptosis, also leads to innate immune responses, and it may have effect on the not so good immune cells which help myeloma grow, the immune depletion. And that’s why it has very broad-spectrum activity.

Now this molecule can be combined with multiple agents, and there are 2 very good, large Phase III studies that have been presented and published. One is ICARIA, which is isa with pom/dex, and IKEMA with isatuximab with carfilzomib and dexamethasone. So if you go to the ICARIA study, it was a very straightforward study in patients who had more than 2 lines of prior treatment, with prior exposure to IMiD and proteasome inhibitor. Patients were randomized to isa/Pd versus Pd.

And if you look at the outcome in this study, very clearly the overall response rate was overwhelmingly better in patients who got isa/Pd, 60% versus 35% in Pd alone. And if you look at patients who got VGPR or better, more than 30% got it when isa was added, compared to only 8% in the other group. So very clear superiority there.

If you look at CR, again significantly more with isa/Pd, and MRD negativity was also observed in 5% of the patient population. So clearly the combination provides superior outcome and improvement in overall and the depth of response.

Now if you look at the survival outcome in this 300-plus patient study, where 95% of the patients were len refractory, that’s an important point. It tells us the patient population. And you could see that PFS was 11.5 months versus 6 months in favor of addition of isatuximab. And if you look at overall survival at 12 months, 72 versus 63%.

So a very significant improvement in PFS and what appears to be an improvement in overall survival, as well. And so I think this 3-drug regimen has a great potential to provide benefit in this patient population.

The second study is combining isatuximab with carfilzomib and dex. And the randomization was isa/Kd versus Kd alone. And you can see the overall response rate was very similar, in the 80-plus-percent range. The VGPR was significantly better, 72 versus 56%, when isatuximab was added, and CR rate was also higher at 39 versus 27%.

Very importantly, the MRD-negative rate was quite significantly high. It was almost 30% in the isa/Kd combination compared to Kd alone, which was 13%. And if you look at MRD negativity in patients who got VGPR or better, 41% versus 22%. And so our whole theme of getting MRD negativity in relapse can be achieved using combinations such as this, and I think we ought to keep that in mind as we select these things.

And then when we look at PFS there was close to 50% improvement, or reduction in risk, where isa/Kd had a significantly superior PFS compared to Kd alone, not reached in the top group versus 19.1 months with Kd alone. So I think improvement in PFS also need to be kept in mind.

And if you look at which patients benefit, the whole long list of groups of patients benefitted. Patients who had prior PI, prior IMiD, or had refractory disease, they all benefitted from getting the 3-drug regimen. And so this is a very potent combination for patients who are getting treatment.

Then the third drug is belantamab. This is an antibody-drug conjugate which is targeting BCMA. And BCMA, or B-cell maturation antigen, is a very important target in myeloma. The reason is their expression, as you see here, is specifically in plasma cells and also myeloma cells, but not on any other cells. And we know that even in the rest of the body BCMA expression is very restricted to this cell population.

Not only that, but BCMA also is a molecule that has signaling impact in myeloma, so it provides activation of important intermediate cascades, like PI3, AKT, and Elk kinase, and that leads to growth and survival in myeloma. So it is a localized expression on myeloma cells, and this molecule provides benefit to the cell growth, and that means cells cannot do without it. And so when we use this as a target we have less chance, a very small chance, of losing the target and the cells developing resistance. So we have to keep that in mind.

Now belantamab mafodotin is an anti-BCMA antibody, but it’s conjugated with an immunotoxin called auristatin. And so it leads to a localized delivery of auristatin to BCMA-expressing myeloma cells and kills those cells. So the mechanism of action is primarily direct apoptosis of the myeloma cells through delivery of the immunotoxin.

Secondarily, because it’s an antibody, it also helps by some immune mechanism, such as induction of ADCC or ADPC, leading to killing of the myeloma cells by the immune cells. So we can take a little bit of advantage of that type of mechanism of action.

Combined, this drug has been now evaluated in a larger study called the DREAMM-2 study, which was in patients refractory to an immunomodulatory drug, to proteasome inhibitor, and also refractory or intolerant to anti-CD38 monoclonal antibody. And in this study patients received 2 different dosages, 2.5 mg/kg or 3.4 mg/kg, to understand both the toxicity and efficacy. And as you see here, patients having more than 4 lines, significantly refractory patient population, one third of the patients responded to either of the doses. So 2.5 mg dose gave very similar results, with half of the patients or more had VGPR or better. So quite effective in this advanced patient population.

If you look at duration of response and overall survival, both of the doses provided very similar results. Overall survival was close to 15 months. Duration of response was close to 11 months on 2.5 mg, but it was lower on 3.4 mg, 6.2. And median PFS was in the range of 3 to 4 months. So this is the benefit of this drug, with good response rates.

The one important thing to keep in mind is the toxicity. There are 2 toxicities which we are to keep in mind. One is straightforward thrombocytopenia, observed in one third to one half of the patient population, and we can live with thrombocytopenia. But the toxicity we are to be careful with is the keratopathy. There are changes in the superficial corneal epithelium observed in close to 70% of the patient population, and in some of them, less than half, it can be higher grade, Grade 3.

Now let’s talk one minute for what this means. Importantly, all of them have this keratopathy detected by an ophthalmologist, but only a small proportion, one third or so, has symptomatic thing. Symptoms could be dry eye or blurred vision, and observed a little bit less at 2.5 mg dose, a little bit higher at 3.4 mg dose. Median time to onset is around 2 months, and median duration of this toxicity, when the drug is stopped and then subsequently restarted with reduced dose, is around 21 days. It is reversible, so one has to be very careful in utilizing this.

Very importantly, use of this drug requires that an ophthalmologist evaluates the patient every dose, which is every 3 weeks. So they need to see the ophthalmologist. If the keratopathy is observed in earlier stage, you’re to hold the drug, and there’s a clear direction about changing the doses and how you continue. But with that, you can achieve a good response rate.

Now there is a next study, which is in pipeline right now, called DREAMM^-6 study. It uses belantamab with bortezomib and dexamethasone. There’s also another arm which we don’t have the data yet, on belantamab with lenalidomide and dex. But the main issue here is that belantamab with bortezomib can be given in this patient population, and what you see is that the overall response rate now is 78%, which is superior to what we will see with bortezomib and dexamethasone alone.

And in this small study, a number of patients, 50% get VGPR or better. So we can get deeper response with this combination. We are to stay tuned for its toxicity and tolerability, especially looking at the eye and other features that we are not concerned about, but we are very cautious about. And we are to keep that in mind. But I think this combination is going to be an important one for utilizing this drug.

And the last drug is selinexor, which is targeting a unique molecule called exportin, or XPO1. Now exportin plays a critical role in transport of many nuclear materials in and out of the nucleus, and that is by its inhibition, the number of tumor suppressor genes, et cetera, their activation is inhibited, and the levels are decreased, and then that leads to cell death. We tried in our group earlier on, described this quite a few years ago, but now this drug has been validated to be effective in myeloma.

In the initial STORM study, 122 patients were treated, median lines of treatment 7, and in that group of patient population a significant, one third of the patients, responded with a median duration of response of around 4.4 months. These were patients who were triple- and penta-class refractory, and even in those one could see the response with an FDA approval then in July of ’19 in patients who had 4 or more cycles.

Now more recently, selinexor in combination with bortezomib/dex has been compared with bortezomib/dex.

And in that combination, you could see that SVd provides PFS of close to 14 months, compared to Vd that provides a PFS of around 9 months, so significant superiority of SVd in this patient population. And this is one of the important combinations that one can use in appropriate line of treatment.

Selinexor is also being evaluated in combination with lenalidomide and dexamethasone, and you can see that we observed, in this particular smaller study, the pilot study, 60% overall response rate, but in patients who were len naïve the response rate was 92%. Patient who had len before the response rate goes down significantly lower. But the clinical benefit was still observed in 34% of the patient population. So that’s another combination to keep in mind for future utilization.

So if you put all this data together, we can select an antibody, whether it’s daratumumab, elotuzumab, or isatuximab, and use triplets based on this antibody. There is not clear, solid data to suggest a specific sequence, whether one is better than another. So our clinical judgment and all the factors I mentioned are to be utilized in this setting, which combination I use first versus second.

Data from high-risk groups suggest that utilization of, for example, proteasome inhibitor in the triplet may provide better benefit. But in standard risk any of these combinations would have very similar outcome.

And then if you look at what’s coming in the pipeline, there are very significant newer molecules are coming up, and you will hear in a very short time the SINEs, BCL2 inhibitors, venetoclax, MCL1 inhibitors, BiTEs, and very importantly CAR T-cell, which has impressive results. We will discuss it very shortly, but I would have you stay tuned for that appropriate utilization in this algorithm of treating relapsed/refractory disease.

Because of all these treatments we do, when patients go to sixth and seventh line of treatment, the treatment in later line is becoming challenging. Patients have a shorter PFS or duration of response, more resistance, and some cumulative toxicity. So to summarize, I think we have a number of novel drugs available, the clinical studies are ongoing, and the outcome is becoming significantly better. So that’s what I would say.

Now let’s go through some cases very quickly, and that will give you an idea how do I pick? What do I pick? So this is a young patient, 61-year-old, active legal practice. He presented with back pain and anemia. And you can see that he has significantly increased IgG kappa protein, M-spike of 5460, increased kappa light chain, bone marrow 70%, and FISH showing amplification 1q, which is what one of our newer high-risk features. The patient has anemia and very importantly multiple bone lesions.

So this patient got RVD times 5, but just got a minimal response, 45% reduction, changed to CyBorD, got a PR, got a transplant. In 4 months the patient relapsed. Then, he received treatment with carfilzomib/cyclophosphamide/dex, responded, but 3 months. Then he got daratumumab/pomalidomide/dexamethasone. He responded, 4 months.

So now what would be our next line of treatment? And this is where what I would do is would synthesize what drugs he has received, and then look at what he has not received. So he had received daratumumab with pomalidomide and dexamethasone, but has not received it with proteasome inhibitor. So that one option is available. He has not been on one of the newer drugs isatuximab, so he can still go to isatuximab. We do not know if patients who are relapsed with daratumumab are they going to respond to isatuximab or not? We have to keep that in mind. And then we can go for selinexor and/or belantamab. So combination of any of these drugs regimens would be good.

One thing you observe here is that the patient is responding to cytotoxic drugs. He responded to CyBorD, but not RVD. And one thing I would point out, that somebody who does not respond to RVD, it doesn’t matter what the cytogenetics are, that will be a high-risk patient, because normally 99% of patients respond to RVD. So this patient starting out expressed as a high-risk disease, and you can see how the follow up was. So now consideration of a drug like bendamustine in combination with proteasome inhibitor would be also an important combination to keep in mind.

So I think these are some of the points. The patient can also now get carfilzomib with pomalidomide. He hasn’t received that; carfilzomib with cyclophosphamide, but now with pom. So a combination like that would be important. But this is the patient where I would also think some of the newer drugs, if available, such as the BiTEs, or very likely a CAR T-cell would be a good option for this patient because no matter what. A patient like this may respond, but he’s going to relapse very quickly, so we need more deeper response in this patient to have a lasting effect for a long period of time.

This patient can also be considered for allogeneic transplant if that option is available at this point, partly because he has a very high-risk disease that is not going to have responses last for a very long period of time.

So this is how the complexity comes into our decision. We look at what is left and then try and decide what combination might give me the best response. One combination not listed here, and we haven’t talked about is a combination called DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin). It’s a Card-carrying combination. It’s old-fashioned chemotherapy. But if this patient has a fulminant relapse, a combination like that can slow down the disease, and then we can go to one of our newer treatments. So that’s one of the things you are to keep in mind.

Then we go to a very different case, in the first relapse. A young patient, 62-year-old, I think is young in my book, in good physical condition, presented for evaluation of fatigue and shortness of breath. And when you look at the lab, he had an IgG kappa M-spike of 6.1, high beta2 microglobulin, 9.8, 90% bone marrow, FISH showing 11;14 translocation. Hemoglobin 7.8, probably partly the genesis of shortness of breath. Mild renal dysfunction, 1.5, and of course diffuse bone lesions.

The patient had RVD, transplant, len maintenance for 2 years, and then he progressed. And the question is what do I do now? He only had 1 line of treatment. The good news for this patient is he has many, many options available, the whole list we went through. But we are to pick something. And the reason this is interesting is that patient is 11;14, and you will hear that one of the drugs, venetoclax, can have a good impact in this patient.

And the question comes should I use venetoclax or not? Now venetoclax currently not approved for use in myeloma. It’s available commercially for CLL and others, but not for myeloma. But the study shows that very high, 90-plus-percent of patients with venetoclax would respond. However, I would in this patient utilize the drug which is commercially available, approved for myeloma, and also very likely to provide 90% response rate. So a combination of anti-CD38 antibody with, most likely in this case, I would utilize with a proteasome inhibitor, partly because the patient was on immunomodulatory when he relapsed. It’s better to switch the class, utilize the proteasome inhibitor, and then, as a third line I can use pomalidomide with carfilzomib or with something else.  

And so that would be the plan. However, if the patient gets second-line daratumumab combination, responds, eventually when he relapses, that’s the time when I would consider venetoclax, which again has a 90-plus-percent response rate. So second combination gives 90% response, third would give us the same, and then we have many other things to do. This patient still has a decent prognosis because he had a reasonable duration of response and remission, and he has 11;14, which is standard risk. However, he was ISS 3 with beta2 microglobulin very high. So these are the things that we have to synthesize in deciding the treatment.

And the last patient is an older gentleman, 75 years old. He had coronary artery disease, 2-vessels, diabetes, hypertension, and he presented with rib pain, fatigue, and anemia. And if you look at his evaluation, he had 8.1 hemoglobin, mild creatinine 1.5, PET/CT showing compression fractures and rib lesions, bone marrow 80%, with 4;14 translocation, deletion 17p. Very high M-spike, 4.9, IgA kappa. IgA over 5 can even have a hyperviscosity. That’s one thing to keep in mind. And then if you look at beta2 microglobulin is ISS 3, very high beta2 microglobulin, although LDH is not elevated.

The patient got RVD lite times 8, very appropriate for the age, achieved a PR, but did get neuropathy, so we had to keep that in mind. He got only lenalidomide maintenance, although knowing that the patient had high-risk disease, if he did not have a neuropathy, I would have probably given him maintenance with both bortezomib and lenalidomide.

So I think we have to keep that in mind in the future. But neuropathy would prevent us from giving bortezomib to this patient.

He had a remission for 1.5 years, and then relapsed while being on lenalidomide at 10 mg dose. The next line given was daratumumab/pomalidomide/dexamethasone, very appropriate combination, antibody with a different class of immunomodulator. Got a PR and remission for 14 months, but he progressed.

What is the next treatment? One point to clarify here is during the past 3 years the patient has been closely followed for cardiac function, and ejection fraction is around 50%. So why did we mention this? Because one of the options is carfilzomib, and we know that cardiopulmonary effects can be one of the side effects of carfilzomib. So anybody getting carfilzomib, we would want to know what the cardiac function is. This patient, although he has significant cardiac disease, ischemic, good ejection fraction, he can still be a candidate that he can get carfilzomib safely. But we are to monitor it quite closely.

So a next line of treatment would be a combination that includes proteasome inhibitor because he has not had it. His last treatment did not include it. But with proteasome inhibitor we need to give something else, and that something else can be pomalidomide because an immunomodulator works very well with proteasome inhibitor. And so that could be one of the combinations in this patient population, also good for high-risk disease, as the patient has both deletion 17p and 4;14. So that would be my next choice. We can also consider the other newer agents subsequently, which includes a BCMA-targeting agent, as well as either isatuximab and/or selinexor with exportin-targeting drug.

So that would be my flow of options down the line in this patient population. A 75-year-old, but appears to be healthy, and so he can still have a good quality of life for reasonable duration of period. Thank you.

DR LOVE: That was awesome, Nikhil, really great. If I could just ask you a couple of follow up questions. First is you were talking about belamaf and the ophthalmic problems there, and I’m just kind of curious. One thing I’ve been hearing from the gynecologic oncologists, they have an antibody-drug conjugate that also causes problems in the eye. I don’t know that it’s necessarily the same as belamaf. But they have used this cold pack on the eyes. It’s like the cold for the hair, except they do it for the eyes. Has that been done with this drug and does it help?

DR MUNSHI: No. So we haven’t done it, to my knowledge. If anecdotally people have done it, that was not done more as a global thing. The eye effect is real with the ADC. We also had in the old days a drug that has not been approved and has gone further, and it was targeting a different target. I think it was a CD56-targeting agent. And that also showed reasonably similar ophthalmologic problems. So there’s something to the eye in some of these payloads that we deliver. And it makes sense to consider. I would be all for trying because it’s a very innocuous option, and it can’t hurt, and it may help.

DR LOVE: Let me know if you see anything. What I hear from them is they just put it on during the infusion. So just while the drug’s being infused.

DR MUNSHI: I think it’s very similar to people chewing ice while getting chemotherapy.

DR LOVE: Absolutely, or also they hold ice to prevent peripheral neuropathy I’ve heard too. Some people try that.

DR MUNSHI: Yeah.

DR LOVE: So, anyhow. I just was curious. Another thing I wanted to ask you about is a drug that is not approved, but very interesting to me, and that’s melflufen. And I wonder if you could just briefly comment because honestly it wasn’t until very recently that I started to even understand what it was. I thought it was just another version of melphalan. But it seems a lot more sophisticated than that. What’s your take on how it works?

DR MUNSHI: Yeah, so melflufen is a melphalan peptide conjugate, and that leads to a 54 greater delivery of melphalan in the cell. And that’s the strength of it, that it is like — you can describe it like giving high-dose melphalan, but just to myeloma cells and not other cells, so to say. And it has shown significant activity, very high response rates of 60-plus-percent. And a larger study has completed. I think it’s undergoing FDA evaluation currently, and we are very hopeful that it may become available in the reasonably near future.

The task for us would be to then decide how best we use it in the sense that it will be in a combination, similar to everything else, even melphalan works well with bortezomib or other combination. And also whether it will have a specific use as a transplant agent or not. So there are a number of uses for that drug. We still have to also think about the long-term impact. We know melphalan can cause bone marrow and MDS-like impact, so whether this will? But because it has this differential effect with the peptide and local delivery, we believe that there would be less of the bone marrow effect and more of the myeloma effect with this drug.

DR LOVE: Well the thing that seemed really cool to me is it seemed a lot like antibody-drug conjugate, the trojan horse idea of delivering it. I didn’t realize that was the way it worked. So it’s a so-called Oncopeptide?

DR MUNSHI: It’s an Oncopeptide, yeah. It’s a peptide-based oncologic drug. I think what you said is very, very correct and interesting, that it is a different form of ADC, although it’s not an antibody, it’s a peptide drug delivery system, or peptide drug conjugate, that makes it very fascinating for many other future applications of similar drugs.

DR LOVE: I think it’s super interesting, the idea of using it with transplant. Has that actually been done?

DR MUNSHI: Not done yet, but I think that’s the natural extension of its utilization. And one could argue you might even need transplant because it is so localized. So I think there are a lot of good possibilities of using it. And what I would say, Neil, is that after all these good drugs we have, toxicity apart, melphalan is still a very good drug in myeloma. We don’t use it orally, now it’s only for transplant, for obvious toxicity reasons, but that’s a good drug. Using an alkylating agent that does not affect the body is a very good next possibility.

DR LOVE: And speaking of that, I was curious, and I don’t know if you were the one who made that decision, but in your first patient who wasn’t responding very well to RVD that got switched to CyBorD, I was kind of surprised. Is that what you typically do?

DR MUNSHI: We do quite often that. And partly because we have used the 2 best combinations, R and V, and then these are the myelomas that quite often respond to alkylating agents, cytotoxic drugs. And so this is a very common switch, and it invariably works.

DR LOVE: So another question, I think it was your second case, was a patient who progressed, I believe it was on dara/pom, and you brought up the issue of going to dara/bortezomib, I believe. And I was just wondering, would there be any temptation to switch to isatuximab?

DR MUNSHI: So I think it would be very logical to switch, partly because you’re just using a different molecule. And there are differences. We have really no data yet to say resistance to one will lead to another or not. However, we know biologically there are differences. There’s more direct impact on the signaling that is driven by this molecule, with 1 molecule versus another. So in real life, now that isatuximab is available, I would switch to dara/pom/dex to isa/carfilzomib/dex as the next line if I’m going to do it.

Potential Role of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with MM — Edward A Stadtmauer, MD

DR STADTMAUER: It's my pleasure to discuss with you the potential role of CAR T therapy in patients with multiple myeloma.

As you know, the last decade has resulted in a revolution for cellular immunotherapy for cancer. There are 3 major approaches for adoptive T-cell therapy: obtaining tumor infiltration T-cells or TILs from the bone marrow and expanding them and infusing them into the appropriate patient after lymphodepletion, or more commonly collecting autologous peripheral lymphocytes; ex vivo activation and transduction with genetic material to place on the surface either chimeric antigen receptors or affinity-enhanced T-cell receptor; expansion and then infusion peripherally into appropriately lymphodepleted cancer patients.

Most commonly used in successful adoptive T-cell therapy has been for ALL and for non-Hodgkin lymphoma, CD19-directed CAR T cells. And for myeloma, BCMA-directed CAR T cells, the B-cell maturation antigen with CD3 zeta and 4-1BB signaling domains. And then this is delivered, the genetic information is delivered by lentiviral vectors into autologous T-cells with activation, expansion, and then stimulating by anti-CD3 and CD29 coded magnetic beads acting as our artificial dendritic cells.

And the initial studies of these anti-BCMA CAR T cells were very impressive. Response rates between 64% and 96% were seen, with very good partial responses or even complete remissions seen in a third to over two-thirds of the patients with relatively reasonable toxicity, in the sense that though most of the patients did have a cytokine release syndrome, the severe cytokine release syndrome was less than 25% and was usually treated with anti-inflammatory medications. And the much more confusing, or difficult to treat neurotoxicity, was, fortunately, less than a third of the patients and usually of a low grade.

We now have, with recent reports, 3 major studies that are showing tremendous activity for these BCMA-directed CAR T cells. There’s the KarMMa study utilizing the agent called bb-2121 as a BCMA-directed CAR T cell. The EVOLVE study using the agent called Orva-cel as a BCMA-directed CAR T cell, and then the CARTITUDE studies using the JNJ^-4528 agent for BCMA-directed CAR T cell studies.

There was a similar approach to all of these studies. These patients have relapsed and refractory multiple myeloma, so heavily pretreated. They all undergo a steady state T-cell collection. And to a various degree, during this process of creating the cells, of manufacturing the cells which can take 2 to 6 weeks, the patients are either monitored or have some form of bridging therapy. And then they undergo lymphodepleting therapy, cyclophosphamide and fludarabine, and a single infusion of the BCMA-directed CAR T cells.

And this shows some of the characteristics of the patients on their studies and they're relatively similar. High-risk cytogenetics were seen in a quarter to 40% of the patients. The age range was very similar, the median age of these patients was 60, 61, with a range from 30s to 70s. The patients did have extramedullary disease in a subset of the patients. The median number of prior lines of therapy were 6 prior lines of therapy, so these were heavily treated patients. And most of the patients had been exposed to and refractory to the standard prior therapies of proteasome inhibitors, immunomodulatory agents and antibody therapies.

Most of the patients, anywhere from 60- to 90% of the patients had some form of bridging chemotherapy.

And the response rates are remarkable. With this group of patients, we see somewhere in the neighborhood of 70- to 100% responses, anywhere from a third to over 80% of the patients entering completed remission, and most of the patients who were in complete remission were MRD-negative.

The studies are all relatively small and have not had long enough follow-up to give us clear evidence of progression-free survival. But, in general, this ranges somewhere in the neighborhood of about 11 to 12 months.

These were very well tolerated therapies. CRS was seen of any grade in the majority of patients, but of a severe grade a low percentage of patients. As I said, the neurotoxicity, for this group of patients was serious in a low percent of patients. And infections were primarily related to the lymphodepleting therapy that these patients received more so than the actual treatment.

Once again, this is for the KarMMa study, the bb-2121 trial. And you can see that there are many patients who are progression-free and also have a survival after this procedure, but there is a persistent curve of relapse for this group of patients.

One of the observations in all of these studies is somewhat unlike the CD19 experience for ALL and for non-Hodgkin’s lymphoma, you see that there’s a relative quick drop-off in the concentration of these T-cells in the patients. And so, in ALL and non-Hodgkin’s lymphoma, it looks like a persistence of these cells is really important for their continued responses. These patients don’t seem to have much of a persistence. There does seem to be variable association between the concentration of the cells and whether the patients respond to therapy.

This is the study of the EVOLVE study, and you can see that the vast majority of these patients had deep responses and a significant reduction in their tumor burden. This also shows a similar result with the CARTITUDE study, the JNJ agent, that, again, the median follow-up of 11.5 months and the 9-month progression-free survival was 86% with the vast majority of the patients responding to therapy.

And you can see here that even patients who are MRD-negative, particularly in the KarMMa study, there continues to be a drop-off in terms of continued progression. And as I suggested, this is a little different than what we see in the non-Hodgkin’s lymphoma results and the ALL results, suggesting that there hopefully will be ways that we can maximize. We’re not done with analyzing this sort of data.

So why are there not more durable response? There’s a number of factors that we’re looking in to. There could be some aspects that are specific for each one of these particular constructs. Are they directed against the best epitopes? Are they most strongly binding? Are we using the best costimulatory molecules? Are there aspects about the T-cell intrinsic factors? For instance, these are mostly patients who have relapsed/refractory, heavily treated disease, and is this not the optimal time to collect T-cells and to manufacture these cells? Is there something about a heavily pretreated patient with myeloma that makes the myeloma cells more or less likely to respond to these therapies? And very interesting aspect of our research is the microenvironment. Are the really key aspects of the environment of these plasma cells that lead to success or failure of these CAR T cells. And finally, is fludarabine and cyclophosphamide the optimal lymphodepleting regimen? Do you need lymphodepletion at all? And is it really the best way of doing it?

We have a number of approaches that I sort of alluded to, to try to improve on this. Perhaps using multiple epitopes that latch onto different areas of the BCMA molecule. Perhaps having BMCA along with another CAR T cell, like CD19. Maybe novel costimulatory domains.

Fortunately, there has not been as much toxicity or at least we’ve been able to overcome a lot of this toxicity. But for those subset of patients, there still is a subset of patients who have a significant side effect, particularly the neurologic side effect and maybe that's where suicide genes or safety switches might still be something that will be useful.

Maybe there’s ways of stimulating increased BCMA expression on the surface of the tumor cells. And that’s where one of the interesting areas have been, gamma-secretase inhibitors, which seems to pop up the BCMA, and maybe will result in better outcomes. And how about, should it be a single infusion of these cells or should you have multiple infusions of these cells to optimize the therapy? And then of course, trying to utilize this therapy earlier in the course of the disease maybe will lead to better T-cells for the manufacturing, as well as less resistant myeloma cells.

One of the quick things that I wanted to show you in terms of a novel way of trying to improve on T-cells is one of the experiments we did which is to use CRISPR gene editing to try to genetically engineer the T-cells to perhaps make them function better.

One of the ways that these T-cells may be pooping out is because of PD-1. And so, if we could knock out PD-1, these cells may proliferate better and be more active. Another reason why these cells may not function as well is because every T-cell has an endogenous or an inherent T-cell receptor that competes with the T-cell receptor that we have virally engrafted onto them.

So, if we could use CRISPR technology to remove PD-1 and remove the endogenous T-cell receptor, these cells may proliferate better and may work better. And so this is what we did, just for 3 patients, 2 with myeloma, 1 with sarcoma and reported at the last ASH meeting. And this just shows that we took these patients. We enrolled them. We engineered them to take out the 2 genes that code for the endogenous T-cell receptor and PD-1. And then we gave them standard lymphodepleting therapy, cyclophosphamide/fludarabine, and infused the T-cells and then followed them very closely.

And what was most notable was that unlike what I showed you for most of the studies and most of the patients who receive the BCMA-directed CAR T cells, these cells proliferated for long periods of time, up to 9 months and counting, for this group of patients, and showed activity and showed in vitro and in vivo cell killing capability.

And so, this may be a way that we’ll be able to engineer these cells to function even better.

A final thing that I wanted to suggest to you is though patients are getting BCMA-directed therapies, more and more we have these BCMA-directed CAR T cells, but we also have the BCMA-directed immunoconjugates and antibodies and BCMA-directed bispecific antibodies. And so the question is going to come up is once you’ve had a BCMA-directed therapy, can you use serial treatments? Can you give someone who had a CAR T cell, then a BCMA-directed antibody and vice-versa? And this is just 2 examples from our center where we gave 1 patient a BCMA-directed CAR T cell. The patient did eventually progress. And we were successfully able to give them a BCMA-directed immunoconjugate with response. And similarly, a patient who got a BCMA-directed immunoconjugate did not have a significant response, then got a BCMA-directed CAR T cell and had a very nice response.

So, what’s happening in 2020 and 2021 for engineered T-cells for myeloma? We expect anti-BCMA CAR registration in relapsed/refractory myeloma. As I’ve said, these agents are not perfect but there’s tremendous responses and, despite the fact that there are people who relapse within 1 year. And then there’s next generation CAR T cell products. There’s also different direction for targets — instead of a BCMA, perhaps CD38 or CS1, NY-ESO.

There’s, of course, studies going on with less heavily treated patients with the anti-BCMA CAR. Combination trials using CAR T cells with IMiDs or checkpoint inhibitors. And then, a very exciting area in CAR T cells, which is to find an off-the-shelf or develop off-the-shelf allogeneic CAR T cells that will be available as soon as the patients are needed and using gene editing techniques in CAR T cells to — and CRISPR technology in order to create these cells.

So, thank you very much. And I’d be happy to answer questions.

DR LOVE: Okay, let’s chat a little bit.

So, one thing I was curious about is the issue of HLH. And is it seen more in the BCMA-directed therapies? And how is it expressed?

DR STADTMAUER: Well, I really think the cytokine release syndrome and HLH are really cousins. It seems that it is the inflammatory chemicals that are created from this activity that is the major issue and treating that with tocilizumab with anti-IL6 therapies, with steroids. And potentially, we occasionally, in patients who have significant symptoms, give them cyclophosphamide or even etoposide to turn it off. But I think they’re really cousins.

DR LOVE: Another question, just sort of branching out slightly, which is from a biologic point of view, even clinical point of view, do you think there’s a similarity or anything overlapping about the CRS/neurologic, the whole syndrome that you see with CAR T and what you see with COVID? And any thoughts whether any of the strategies that are being used with CAR T might be useful in COVID or are being studied in COVID?

DR STADTMAUER: I think that's an excellent question. And I think there’s a lot of similarities between the inflammatory process that's created by the COVID infection and the inflammatory process that we see when we activate T-cells and they proliferate. And it has led — now, of course, we’ve demonstrated now, that with COVID, steroids, dexamethasone in particular, has been a successful way of trying to reduce the inflammatory responses. But there’s a number of studies going on and use of the same agents that we use for CRS syndrome, with tocilizumab and siltuximab, to try to decrease this process.

So, yes, I think we’ve learned — I think in many ways it has been useful to have had the experience with CAR T cells and these inflammatory process. I think it has accelerated our treatment for COVID.

DR LOVE: I also want to pick up on the issue of prior BMCA therapy and you showed those 2 cases. But does BCMA, the actual substance, remain intact, kind of like estrogen receptor in breast cancer; you give them hormonal therapy the ER is still there. Is that what happens with BCMA?

DR STADTMAUER: So far, the correlation between BCMA levels has not been shown. It's really been an elusive issue. And we’ve definitely had patients — we had one case — well, I’ll actually show that to you — but there have been cases of patients where they had beautiful responses to BCMA-directed therapies and then the BCMA is still present, and then they get the exact same therapy when they relapse and there’s no response at all.

So the correlation, there’s still more biology that we have to understand and learn.

DR LOVE: But you still see some BCMA there?

DR STADTMAUER: Yes, frequently. Most of the time.

DR LOVE: And getting back to the issue of drop-off and why you’re not seeing these prolonged responses — and I have heard a number of people bring up the question of the immune situation in a myeloma patient after heavy pretreatment. Is there any clinical data yet that suggests it's going to be different earlier on?

DR STADTMAUER: The studies of utilizing BCMA-directed CAR T cells early in the course of the disease are just starting to come out. So we don’t have that much information. And so, I can’t really say. The problem is that in patients with myeloma, their immune system is dysfunctional from the get-go, unlike, perhaps, some of the other diseases, like myeloid diseases and other cancers that we deal with. And we know that there’s a real interaction between the microenvironment of the bone marrow and all of the associated immune dysfunctions of T-cells and other aspects, that I do think that there is something unique about myeloma immunotherapy that might be different than some of these other diseases.

DR LOVE: I’m curious, of course at Penn you have one of the leading groups in the world in this entity, Dr June, et cetera. Any thoughts from the entire group about this, I guess unexpected phenomena?

Why you don’t see the prolonged responses like you see in CD19?

DR STADTMAUER: Yes. The answer is we still don’t know. It is actually a strong area of our investigation right now. Again, looking at microenvironment. Looking at expression of these cells. Why is it different? But as I showed you, we’re trying to engineer these cells to be more persistent and maybe that will result in better responses.

We’ve done it so far, only with an NY-ESO-directed T-cell. Obviously, if we engineer BCMA-directed T-cells in the same way, we may see even more impressive responses and prolonged responses.

DR LOVE: I’ve got to say, I’ve interviewed and listened to a lot a lot of talks on CAR T and myeloma, and I don’t know, maybe they said it; I didn’t get it. But I was shocked — I did not realize that you literally do not see the T-cells stay around as long as with in lymphoma. I was not aware of that. It seems like that… You need those, right?

DR STADTMAUER: We like calling them serial killers.

DR LOVE: Right!

DR STADTMAUER: And we like having serial killers. And that they’re, even at a low level, we want them surveilling so that, should another clone of the plasma cells pop up, they’ll then proliferate and come down. And that certainly seems to be occurring in a subset of patients with non-Hodgkin’s lymphoma and with ALL. In myeloma, it doesn’t seem to be the case. It seems like there’s more going on there that we need to understand.

DR LOVE: Yeah, that's amazing. Because to me, when I first started to hear about CAR T, the first thing that struck me was that these cells continue to grow. I mean it's incredible. And they’re not growing in myeloma, that's easy to understand would be a problem. But one other thing I have heard, at least at this point, in terms of the clinical role, even in late disease. I’ve heard a lot of people talk about the quality-of-life advantage of CAR T in terms of allowing people to be off therapy. And I wonder what you’ve observed in that regard?

DR STADTMAUER: Yes, not only quality of life, though, of course, the procedure itself has a real expense, if patients can truly be off of every therapy for a while, the cost can ultimately be decreased. But, yes, I agree. Patients who have had a prolonged remission have just been able to get back to life. And it really is a blessing. And we definitely, though, as I’ve shown you, unfortunately, perhaps half of the patients who’ve received the BCMA-directed cells have progressed within a year. On the other hand, that means that there’s half of the patients who haven’t. And we’ve had patients who are 2 years, 3 years from infusion of these cells on no therapy.

We debate back and forth whether they should be on something, something that might stimulate the T-cells to continue to proliferate. Something that might improve the microenvironment to be a hostile environment for the myeloma cells to grow. But that's always counterbalanced with the blessing of not being on these therapies and having patients just get on with their life.

DR LOVE: What do you do about bone targeted therapy in patients with and without bone disease during CAR T? I mean after CAR T.

DR STADTMAUER: No, that's an excellent question. And that's a debate even for non-CAR T questions, right.

DR LOVE: Sure.

DR STADTMAUER: I mean in our hearts, I think as — putting on my myeloma doctor hat, once someone is in remission, the better their remission the less they have these abnormal cytokines that are being produced by the myeloma cells that stimulate the osteoclasts to make new bone lesions. And so, so that's really where we start debating whether any patient who’s been in remission for a long period of time, can they have a holiday of a bone strengthening, a bisphosphonate or denosumab?

But certainly, patients who are not in complete remission or patients that have continued significant bone disease, it's certainly reasonable to continue these agents, at least for a number of years.

DR LOVE: So, let’s talk about your cases. What happened with this 55-year-old man?

DR STADTMAUER: So this is one of the younger patients that we treated. This was a gentleman who had a very heavily treated IgA lambda multiple myeloma had bone marrow plasmacytosis, lytic bone lesions, serum and urine monoclonal protein. Got the standard induction therapy with VRd, high dose melphalan autologous, maintenance therapy for 2 years. Entered a very good partial remission. But progressed. And then received the standard concoction of regimens, pomalidomide-containing regimen, bendamustine, daratumumab, combinations of daratumumab and IMiDs and carfilzomib and IMiDs and continued to progress.

So we enrolled him on a BCMA-directed CAR T cell protocol. Steady state harvest. This patient was doing well enough, he had biochemical progression, but did not require bridging therapy. We successfully manufactured cells. He got the standard fludarabine and cyclophosphamide lymphodepleting therapy and then infusion of the target dose of CAR T cells.

Within a couple of days had fevers and rigors with a ferritin that increased, and a C-RP that increased, consistent with a CRS syndrome. And did receive a dose of tocilizumab. But what was most notable was a number of days later had worsening mental status and actually went to the MICU because he was having difficulty maintaining his swallowing and had agitation and delirium. And a neuro-evaluation, including lumbar puncture, CAT scans, MRIs, did not show any source of this. And so it was felt to be the neurotoxicity related to the infusion of these cells.

Our protocol is to give some antiseizure medicine. And to start up some dexamethasone. And we even gave some interleukin-1 inhibiting therapy. And we actually had to intubate this patient for airway protection during his neurotoxicity.

He, fortunately, had a nice response. But we had to monitor him very closely. And it is very difficult for both the caregivers and the family to watch a patient who undergoes one of these neurologic events. But, fortunately, and with the vast majority of patients who get this, within 2 or 3 weeks the neurologic symptoms resolve, performance status improved rapidly, and actually by day 28, the patient was discharged.

So, we don’t really understand this neurotoxicity, the ICANs that's associated with the CAR T cells. But we know that it starts a little after than the CRS, on average, and can last longer than the CRS syndrome. Is not necessarily associated with it, and it certainly doesn’t seem to be driven by the interleukin^-6, like the CRS syndrome. But patients can be completely normal and resolve after the syndrome resolves, as did this patient.

Unfortunately, this patient did relapse within a year of the CAR T cell, and this is an example where we then enroll the patient on a BMCA-directed bispecific antibody therapy, which was well tolerated and, of course, we had our breath held during this process because here we’re giving another BCMA-directed therapy that can potentially give neurotoxicity, and yet, there was no neurotoxicity with this. The patient entered a remission. And just decided, we had some extra stem cells, we did actually, high dose melphalan and a stem cell transplant to knock him into a remission. And actually, he’s doing very well after that combination of therapy.

DR LOVE: This is his second transplant?

DR STADTMAUER: Correct, yes. He had had a prior transplant. And, in fact, one of the, I guess, safety benefits of a myeloma patient is frequently, not always, but frequently the patients have had a prior autologous stem cell transplant and therefore, we have stem cells harvested away. And so, number one, we can utilize them if, for some reason, though it's been very rare, if ever, that we’ve had to do this, the lymphodepleting therapy or the CAR T cells lead to a cytopenia that is prolonged and then we can always infuse more autologous stem cells to have them recover from that. But, similarly, it allows us to do what we call a salvage autologous transplant, or a second consolidative transplant in patients who had a prior long remission.

DR LOVE: So did this patient get belamaf or some other antibody drug conjugate?

DR STADTMAUER: This patient did not get a drug immunoconjugate, got a bispecific antibody.

DR LOVE: Bispecific.

DR STADTMAUER: The same antibody has both a BCMA-directed —

DR LOVE: Right. Right.

DR STADTMAUER: — and a CD3-directed portion. And that's why in many ways, this is — it has a similar mechanism in some ways to a CAR T cell, right. It's activating the T-cells while attaching to the BCMA moiety. And that's why this is an interesting case because, remember, this was a patient who had a real significant neurotoxicity from a BCMA-directed therapy, and fortunately, did not have the neurotoxicity. And actually, did have a response to this, despite the fact that the patient had progressed from another BCMA-directed therapy.

DR LOVE: Yeah, it really is amazing that there was a response, given that the patient had just progressed on CAR T. But that's really interesting.

Let’s see your second case.

DR STADTMAUER: So this other case was a 66-year-old man who had actually an 11-year history of IgG kappa multiple myeloma. Had again, the standard initial therapy of bortezomib and immuno — IMiD and dexamethasone. Stem cell harvest. High dose melphalan. Stem cell transplant. Five years of remission with lenalidomide maintenance therapy. Then, with progression, went through the whole litany of pomalidomide, RVd, carfilzomib, and lenalidomide and dexamethasone. Standard infusional chemotherapy. Carfilzomib/pomalidomide. Cyclophosphamide and dexamethasone. Elotuzumab. A clinical trial. And had relatively stable disease.

And so this is when this patient, who’s actually one of our first patients, was enrolled on the BCMA-directed CAR T cell protocol.

So, the patient underwent a steady state T-cell harvest and continued pomalidomide and dexamethasone as a bridging therapy. And in our earliest rendition of our BCMA-directed CAR T cell trial, we didn’t use any lymphodepleting therapy. We’re one of the few studies which tried to do that without it. And the patient actually received then, CAR T cell infusion — and because this was in the early days, for safety purposes, we decided to split the doses into 3 doses, a 10% dose, a 30% dose and a 60% dose. And we treated the patient as an outpatient. And he successfully received as an outpatient the first 2 doses. And then on the day that he was going to receive the 60% dose, he had fevers, hypotension, and so was admitted and did not receive the day 3 infusion.

He was begun on empiric antibiotics. Chest x-ray showed the development of a patchy bilateral infiltrate in his lungs. Some oxygen requirement. All very consistent with the CRS syndrome. His ferritin peaked at over 4000. His C-RP went up. And with his fevers and hypotension and those increased markers, he received tocilizumab. He actually required 2 doses of it. And he improved.

He had some transaminitis, probably related to the tocilizumab. Symptomatically improved. And actually was discharged from the hospital by day 12. No further fevers or shortness of breath. Went into a complete remission utilizing this therapy and did well. And it was a gradual entry into complete remission. It took until around 11 months for him to go into a bone marrow biopsy, as well as biochemical complete remission. He did well for 32 months, in complete remission, on no therapy, and had a wonderful quality of life and was back to working full-time.

Unfortunately, developed biochemical progression at this time, that we actually monitored for a while, but by 35 months, because we still had that 60% dose, we were able to treat him again. And this time we gave him lymphodepleting therapy, the standard fludarabine and cyclophosphamide, and infused BCMA-directed CAR T cells. And his myeloma cells continued to express BCMA. And he tolerated this well. He did have some CRS-like syndrome, even with this second infusion, with some fatigue and fever and an oxygen requirement. This time did not require any tocilizumab, and it all got better. And he was discharged by day 8. But unlike this tremendously long remission that he had with the first infusion, and even this dose of BCMA-directed CAR T cells was greater than the dose that he had received years ago, unfortunately, within 28 days, had clear signs of continued progression and, therefore, did not respond to this treatment.

DR LOVE: Amazing.

DR STADTMAUER: So, I still remember, when we were monitoring him, we thought that he’s the cure. He’s the proof of the cure. And, in fact, he did have very small quantities by PCR of the CAR T cell still in his system. But it shows that even though you still have some CAR T cells, even if your myeloma cells still express BCMA, there’s probably more to the story. And it probably has something to do with his innate immune system or the microenvironment. We still are doing a number of correlative analyses on this particular patient to see if we can understand better why he responded so well the first time and why he might have progressed and why he didn’t respond the second time.

DR LOVE: That's really fascinating.

There’s one other thing I was going to ask you about, which is bridging therapy. How do you determine whether to use it or not? And whether it's adequate once you do it?

DR STADTMAUER: So, what we want is for these patients to remain well while we’re waiting for the manufacturing of the cells. And you could say that this is the biggest issue in some ways with the use of CAR T in the relapsed/refractory patients, since most of the patients don’t have wonderful, conventional dose or conventional agent therapy as a bridge. And so, sometimes it can be very difficult. And there certainly are subsets of patients who have their cells collected but never are able to go onto CAR T therapy because they get ill beforehand.

So, part of the art of this is to choose these patients when they clearly have been exposed to the conventional therapies that are no longer likely to respond well, but perhaps have stable disease or just slowly progressive disease on their current regimen so that they can get another cycle perhaps of therapy.

Of course, one of the major engineering and technical things that we’re all working on is can we accelerate the manufacturing of these cells? And, in fact, there are techniques that are looking very promising to allow us to harvest cells on a Monday and infuse the cells the next Monday and have a more rapid technique. But these are still under investigation and are not routinely available certainly, with the potentially commercially available cell.

DR LOVE: So, in terms of the CAR T itself, that's not an issue in terms of tumor bulk or amount of disease? You don’t have to reduce the tumor?

DR STADTMAUER: Correct. Yes, that's right. But this may be a difference between blood cancers and solid tumors. Solid tumors and these CAR T cells have been a real tough nut to crack. And part of it might actually be that a solid tumor is a nut, and it's really difficult to get the CAR T cells in the middle of the nut to destroy the cells. While blood cancers are truly cancers of the blood-forming tissues and, therefore, they have a circulation of these cells. And so, fortunately, in the blood cancers, if anything, the patients who have a higher bulk of disease, are frequently lysed their tumor, pretty impressively.

So, no, there is not clearly a need to put someone into a remission prior to doing that. In fact, there’s some questions as to whether there’s sufficient antigen available if the patients have such minimal disease for the CAR T cells to proliferate and do their thing. But that's an area of investigation.

Other Novel Strategies with Potential to Improve Outcomes in MM — Ola Landgren, MD, PhD

DR LANDGREN: Thank you very much, Neil, and thank you so much for inviting me. It’s always a great pleasure working with you. You gave me, this year, the topic other novel strategies with potential to improve outcomes in multiple myeloma. You asked me to talk a little bit about venetoclax, what’s the biological rationale, efficacy/safety findings with this drug, the next-generation immunomodulatory agents, bispecific monoclonal antibodies, efficacy/safety data for melflufen, and also to add in some new insights on myeloma biology and relapse.

When it comes to the BCL2 inhibitor, venetoclax, what’s the reason for going after that? Well, we know overexpression of BCL2 is a hallmark of cancer. Tumor cells, they proliferate, and they are regulated through interactions between these antiapoptotic and proapoptotic members.

We know in myeloma, this is work published several years back, that there are subsets of patients that have higher BCL2 expression and low MCL1 expression. This was initially found in the cyclin D1 subset. It was characterized by 11;14 translocation. Venetoclax, which is the drug I’m talking about here in this context, binds to BCL2 and BCL-XL, but not to MCL1. So therefore, this triggers apoptosis by interfering with these pathways.

How do you find the right patient when it comes to using venetoclax? How do you identify the right patients that are likely to respond? Well, I already mentioned translocation 11;14, and that’s what you have heard from clinical trials. But also there is a lot of work that’s been done for biomarkers in preclinical studies, including something called BCL2 priming, expression for mRNA, and also drug testing outside patients. Most of this work is not done in clinical trials.

There was a paper very recently published by Keith Stewart’s group where they looked at 113 patients with myeloma. They took their primary samples and treated them with venetoclax. There were other drugs tested as part of the study, but here I’m focusing on the venetoclax experience. They treated them for 24 hours, then they looked at which subsets of patients were more sensitive to venetoclax.

In this study, again, they showed a translocation 11;14 was more sensitive. But they also found that patients with less high-risk features, lack of MYC rearrangements, low proliferation were also more sensitive. Very similar to what has been found in preclinical studies. They also studied the transcriptomic ratios, so antiapoptotic and regulators of apoptosis markers, and they looked at ratios, and they confirmed what was found in preclinical studies.

This is a very sophisticated study, and for those of you that are interested, I really recommend you going into the details.

Very recently, the third larger, randomized trial with venetoclax was published. This came out online just in October 2020. This uses venetoclax, bortezomib, and dexamethasone versus bortezomib and dexamethasone. It’s a randomized Phase III trial, open for patients with relapsed/refractory myeloma with 1 to 3 prior lines of therapy, with 2:1 randomization.

The primary endpoint was progression-free survival, and what you see is that at 18.7 months of follow up, that median progression-free survival was 22.4 versus 11.5 months, favoring venetoclax. They also had a lot of prespecified subanalysis in this study. They looked at patients with 11;14 translocation, as well as BCL2 expression using quantitative PCR. And as you see on the lowest bullet on this slide that the response for PFS was even stronger when they did this subanalysis.

Now, very disappointing, they also unfortunately found that there was an excess death for patients treated with venetoclax. More specifically so, overall 21% and 11% for the venetoclax versus placebo arms respectively, had patients passing away.

When they looked in the treatment-emergent deaths, 8 out of the 13 patients with venetoclax, and treatment-emergent death is within 30 days of the last dose, they were infections. There were 5 patients who died from sepsis, septic shock, and 3 patients who had pneumonia. When they looked also in the venetoclax group, who are the people who were unfortunately passing away? They were primarily patients that were non-translocation 11;14 in that category.

So they speculate in this paper why is this? Does venetoclax select aggressive clones? Does it induce immunosuppression that in turn leads to susceptibility for these life-threatening infections, or are there other explanations? And the study does not fully answer the question. It asks more questions and cannot really address all the details. I think it’s important.

The study has been amended and mandates antibiotics as part of the protocol and has also triggered a new randomized study comparing venetoclax with dexamethasone versus pomalidomide and dexamethasone for patients with 11;14 translocation. So that’s the mandatory subsets of patients in this new study that’s ongoing.

Let’s switch gears talking about CELMoDs. So CELMoDs are the new generations of immunomodulatory agents. The drug called CC-92480 is the first to reach the clinical development. This binds to cereblon, and therefore it interferes with ubiquitin. And ubiquitin, as you know, is involved in the degradation process through the proteasomes.

So therefore this drug induces proteasome-mediated degradation of, in this case, particular transcription factors. And some of these transcriptional repressors are in the T cells. So as a consequence of this drug what happens is that it leads to modulation of the immune system, more specifically so by activating T lymphocytes, so the drug stimulates the immune system. And also through this same process it has antiproliferative effects and induces apoptosis. So it kills directly, and it also ramps up the immune system.

In this setting, it has been developed in Phase I trials for heavily pretreated patients. And this was presented at EHA 2020 by Paul Richardson, showing that there are parallel dosing schedules in development, either 4- or 7-day breaks continuously with these shorter breaks or a more intense with even longer break. And they’ve been developed in 4-week cycles.

66 patients that received CC-92480 plus dexamethasone were presented at EHA 2020, with a median prior lines of 6 prior therapies. Patients were enrolled, and then had been heavily pre-exposed, as you can see on the second bullet. About 50% of these patients were considered to be triple-class refractory. The findings, further, were about 30% of the patients remained on the drug and of the 51 patients who had discontinued treatment, most of them were due to progressive disease.

There were 10 patients that had dose-limiting toxicity and therefore the maximum tolerated dose had been determined. And that has been set to 1 mg, both in the setting of 10 out of 14 days and also 21 out of 28 days.

The most common adverse events relate to drops in the white cells, secondary infections, and anemia. When it comes to the efficacy, so what did the study show? The preliminary analysis showed an overall 21% overall response rate across all the dosing cohorts. If you look at patients who had received the maximum tolerated dose of 1 mg once daily for 10 out of 14 days it went up to 40% and 55% for patients who got the recommended Phase II dose, which is 1 mg once daily for 3 out of 4 weeks.

Let’s switch to the third part of the presentation, targeting BCMA for the treatment of myeloma. So BCMA (B-cell maturation antigen) is part of the TNF superfamily. It plays a key role in the maturation and differentiation of B cells. It promotes cell growth in myeloma. It also plays a role in resistance to chemo, immunosuppression in the marrow microenvironment. The antigen is expressed specifically on plasma cells and myeloma cells, and the expression is higher on the myeloma cells compared to the normal plasma cells. And that is what makes BCMA a very attractive target, and as you know there are a lot of drugs in development going after BCMA.

The first study that’s been published using BCMA-targeted bispecific monoclonal antibody is AMG^-420. This study was open for patients with progression after 2 or more prior lines of therapy. This drug was developed as a continuous infusion on a 4-week per 6-week interval. So it’s a little bit of a different way of giving drug compared to what we typically would do.

So first-in-human, up to 10 cycles of this AMG 420, 4-week infusion and then 2-week break. Patients could get up to 10 of these. There were 42 patients that received this in different doses, from 0.2 mcg per day up to as high as 800 mcg per day. The median exposure was 1, with a range, and for responders 7. Patients who discontinued, they did most due to disease progression, adverse events, death, completion of the 10 cycles.

The serious adverse events in this study also included infections, but there were a couple of cases with polyneuropathy, which is what we have seen for some of the CAR T cells. The treatment-related serious adverse events included Grade 3 polyneuropathy and Grade 1 edema. There was no Grade 3 or higher CNS toxicity. And they also did not see any anti-AMG 420 antibodies.

The maximum tolerated dose of 400 mcg translated into an overall response rate of 70%. So based on small numbers, 70% overall response rate. And there were 5 patients that were MRD negative. The end of study was set to 10^-4. And 1 patient had a partial response, 1 had a very good partial response. And all the 7 patients had responded to the first cycle, and some of them lasted more than 1 year. So this is pretty exciting, definitely strong proof of principal, that you can use this as a strategy.

Here is another bispecific antibody. This is the CC-93269 that was presented at ASH last year by Luciano Costa and updated again at EHA 2020. This study is kind of similar to what we saw for the previous one, but here we are talking about conventional IV infusions. And the patients were slightly more sick because they had 3 or more prior lines of therapy.

If you look at the prior exposures you see that they had 5, on average, prior regimens, ranging from 3 to 13. And you see how heavily pretreated these patients are, highlighted in red, for all the exposed, 96.7% and 66.7% of the patients are refractory. So pretty sick patients.

When we look at the safety signal for this drug, it’s kind of similar to what the others are in this class. I already showed you AMG 420, and in a little bit I will show you the next. So here we see that the hematologic toxicity happens in about half the patients, for all grade, and for Grade 3 or higher, most of them are that. If you look for cytokine release syndrome, it’s 76.7%, but they are all grade, and there’s only 1 patient with Grade 3 or higher. And if you move to the right, you see the maximum CRS grade for the different categories there, and you see that most of them are Grade 1.

You see that diarrhea and vomiting for all grade happens in 26.7% of the patients, and there’s 1 patient with diarrhea Grade 3. I just point that out, based on small numbers, we see some signal here. Let’s see what larger studies will tell us.

When we look at the overall response rates for this antibody what do we see? Well, overall, it’s 43%, and 17% of the patients are stringent CRs or CR. And if you look at those patients who got the 10 mg dosing of the drug, you’re talking about 89% overall response rate, and the CR and stringent CR was 44%. So I caution you, small numbers. It looks pretty promising, and is very similar, I think, compared to the previous drug. The median time to a response was about a month, or 4.1 weeks.

Here we have a third monoclonal antibody bispecific BCMA/CD3, and it’s called teclistamab. Very similar study design to the other drug I just showed you. This is conventional IV infusion, and they show dose escalation in this study. This was from EHA 2020. The prior lines were 6 on average, range 2 to 14, so very similar. Triple refractory 80%, and refractory to last line 86%. So I would say, with a little confidence interval, not that different from what I showed you so far.

The overall response rate is 67% for the 270 mcg/kg and is 30% for the middle category there. So I would say, again, looks pretty similar, and I think there is strong evidence that this drug seems to do a pretty good job.

Here we have the teclistamab duration of response, and you see over time that there is deepening of the response going forward, so stringent in the light green and CR in the dark blue, and VGPR in the light blue. Go from left to right.

What about other targets? So I spoke about BCMA. I talked about 3 different drugs. On this slide you see from Adam Cohen’s educational session at ASH 2019 how many other bispecific monoclonal antibodies there are targeting BCMA. But I also highlighted in the red box that there are bispecifics going after CD38, FcRH5, and GPRC5D, and CD38. So which is going to be the winner? How are we going to combine these? No one really knows, but it looks very exciting.

Lastly, I go back and talk about a completely different drug. So this is melflufen. This is a novel peptide-drug conjugate that rapidly deposits the cytotoxic payload into the tumor cells. So it’s a drug that dumps an alkylator into the cells in myeloma. The single-arm HORIZON study included 95 patients were presented at Paul Richardson at EHA last year, in 2019. They used melflufen and low-dose dex in patients who are refractory to pomalidomide and/or daratumumab, with 2 or more prior lines. And overall response rate was the primary endpoint.

Paul presented 30% overall response rate, and you see further details here on the second bullet. The side effects, as you see here, were more commonly neutropenia, thrombocytopenia, and anemia. So although the drug presumably is dumped more selectively into the myeloma cells than regular melphalan, the melflufen still has some spillover on the other cells.

There is another study called the OCEAN study. It’s a randomized global Phase III trial evaluating the efficacy and safety of melflufen and dex versus pom and dex. And this is open for patients with 2 to 4 prior lines of therapy, refractory to both their last line of therapy and lenalidomide within 18 months or randomization. And here you have the dose, so it’s 1 dose per 28-day cycle IV for melflufen versus having the standard pomalidomide 21 out of 28 days orally. This is ongoing, so I’m not showing you any results for this at this time.

I want to end my presentation not talking about drugs, but talking about very new insights on the biology when it comes to relapse. So whole-genome sequencing has revealed that there is huge heterogeneity of myeloma cells in the body of a patient with myeloma. But there is not so much information known on how really the relapse happens. Is relapse a matter of myeloma cells hiding, sleeping in the body, and we cannot see them, and then they kind of take off and proliferate? Or is it the matter of seeding of 1 or a few cells that reoccur at multiple sites in the body? No one has really been able to investigate this.

So this comes from a study that used warm autopsy, patients who have consented to be part of a genomic study at the time of their unfortunate death in myeloma after relapsed/refractory myeloma. So this study showed, using whole-genome sequencing, that the median number of mutations is over 10,000 detected by whole-genome sequencing.

And the study also defined the evolutionary trajectory and drivers of myeloma seeding and was able to do what’s called reconstruction of the phylogenetic tree. So you think of a disease having trunks and branches. As the disease evolves, there are new branches coming out. And by studying all these different sites that were biopsied it was possible to put together the puzzle. And the study finally showed that after a patient’s had a very deep response, when the disease has been gone, no longer detectable clinically, when these later relapses happen it is actually an accelerated seeding of 1 single cell that during a matter of months spreads throughout the body. And this is very, very similar to metastasis that you see in solid tumors.

So I think this really is so provocative and it really asks us the question when is the right time to think about reinitiating therapy going forward. We certainly need to do more studies investigating this in more detail, but maybe the start of therapy should not be at the time when the patient has the disease all over the place if we really try to improve outcomes. These are provocative questions.

With that, I would like to thank you so much for your attention.

DR LOVE: That was awesome, Ola. Just a couple follow up questions. Can I ask you a little bit more about melflufen because initially I had the impression that it was just a straightforward alkylating agent, and then I started to hear about this issue of the way it concentrates things in cells. So from your point of view, how much does it concentrate? Is it kind of like an antibody-drug conjugate or more like say a liposomal formulation? What’s the reason it concentrates?

DR LANDGREN: Well it is conjugated, so it is, in a way, similar to an ADC. It is not a monoclonal antibody, but it’s similar in that functional sense that it is designed to be linked to structures that go towards, in this case the myeloma cells, and dump the alkylator, the toxic drug, into the cells. But as I also shared with you, from the toxicity data, there is still toxicity in the marrow in more general terms. So how pure is this? How selective is it? Is it much more selective? These are things that I don’t think we definitively know, but it is a clever way to improve, I think, alkylators, definitely.

DR LOVE: Is there any thought about using it with transplant?

DR LANDGREN: Well, I think the trials I showed you do not include that, but I think that has been also — is being explored as we speak. People are developing these types of ideas. So I think you could think of it as a second-generation alkylator therapy.

DR LOVE: So why don’t we talk about your case, the patient who got venetoclax. What happened with that patient?

DR LANDGREN: Yeah, so you asked me to discuss a patient that’s been on some of these drugs, and I said let’s talk about venetoclax. So venetoclax is not yet FDA approved for the treatment of myeloma, but it’s approved for the treatment of other B-cell malignancies, and you can get approval for compassionate use. So I was thinking about the patient I recently treated.

I started this patient on venetoclax-based therapy about a year ago. Prior to that, the patient was diagnosed with myeloma in the lower 60s, is a female. She underwent regular VRd regimen. She got the bone marrow transplant. She was put on lenalidomide maintenance. She had recurrence. I think she was put on daratumumab/pomalidomide and the disease came back. She got I think carfilzomib and lenalidomide and the disease came back. And this patient also then was treated with CAR T-cell therapy.

She had a quite short duration of benefit from the BCMA-targeted CAR T-cell therapy. It lasted for less than a year, and now myeloma came back with very, very rapid pace. The patient came to me for a second opinion and said I’ve been told there is nothing else that can be done. So we went through everything, and I said I’m very sorry to conclude these details. I cannot promise that there will be drugs that will do a great job, but I can promise we will try.

So I said let’s capture all the information. So I did a bone marrow biopsy, I did all the testing, I did imaging, I did all the blood work. I found a quite low M-spike and quite low light chain because the disease was kind of oligosecretory, which happens usually when myeloma evolves. The bone marrow revealed 80% to 90% plasma cells, and a very high proportion of the cells were 11;14 translocated. So I was thinking to give venetoclax in this setting probably would be risky because she has so much disease, and she was really very sick.

So I had a conversation and said we could do debulking with old chemotherapy, so I gave a combination of the DCEP regimen, where you give cisplatin, etoposide, cyclophosphamide, and steroid. And I said let’s do a bone marrow biopsy after that and see where it takes you. So she went from 80% down to 40%, so that clearly was response. The drug made her respond, but I also knew that that’s kind of the easier step. Unfortunately, the harder step is to have a long-term strategy.

So I knew that if you just wait a few more weeks the disease will come back. And I talked to her about this, and I talked to her before we treated her that that could, unfortunately, be the path. But I said let’s do it stepwise. So I gave a second cycle of the same DCEP therapy, and now she was down to about 20% myeloma cell infiltration, and she was very happy. I was worried what would be the next step here that would really be feasible for her and that would also give a good quality of life and have good control of the disease.

She had a lot of neuropathy after the bortezomib she had been given initially. So I was thinking if I gave her bortezomib with venetoclax maybe that could work, but she had so much neuropathy, so it was really not an option.

So I gave her a single dose of carfilzomib 20 mg/m² with dexamethasone, and she tolerated that very well. The next week I increased it up to 56 mg/m2, and then I did the same the third week. So she tolerated that very well, and then the next cycle I added venetoclax. So I gave her the lowest dose, and I stepped it up. After a few days I went to the next, to the next. I took her all the way up to 800 mg/m2.

So she was on oral venetoclax daily and carfilzomib once a week, week 1, 2, and 3. And there have been other studies that have looked into these investigator-initiated studies, I’m sure you have seen those studies using carfilzomib and venetoclax.

Now she’s about 1 year out. We did a bone marrow biopsy. The lady’s in complete response. She’s in complete response. She’s doing really, really well, and she’s on these oral therapies.

So the question I don’t know the answer to is could you take her off carfilzomib and just keep her on venetoclax? So these are questions that are good, and I don’t know the answer to. There is really limited data. I think if the patient feels that it’s too overwhelming to do weekly infusion you could test and do say week 1 and week 3, and if that works maybe you could wind it off and do once a month. Because carfilzomib has only a 30-minute half-life. So you’re not talking about the drug that lasts for a very long time. You could try to back out.

But I think having a conversation with the patient and say there is no data, I would be comfortable trying, if you want, but probably staying on it is the more powerful. And so far she has chosen to be on it. She has again, about a year out. She is doing really well.

DR LOVE: That’s really an interesting case. When you said you were kind of hesitant about using venetoclax with so much disease, was it from the point of view of TLS?

DR LANDGREN: Well, so that’s a very good question. That was not the primary reason I was worried about it. I would probably in that case maybe keep her maybe 1 night in the hospital and give her fluid and give her the steroid with venetoclax to make sure that everything was fine. But my primary worry was that it would not be efficacious enough. Of course I don’t know that for a fact, but in general I think when the disease goes out of control usually a single drug doesn’t really do a very good job, usually.

DR LOVE: Let me ask you just one more question about venetoclax. I was curious. Again, we talk so much about TLS in CLL and all, what about in plasma cell leukemia? I know some of those patients are t(11;14), does it respond? And also do you need to follow the TLS thing with that?

DR LANDGREN: So it does respond. Every patient with 11;14 does not have upregulation of the BCL2 marker. And there are patients who have activation, elevation of BCL2 in the absence of 11;14. So it’s not the same thing. We know that there is an enrichment for activation of BCL2 in 11;14 translocated patients. That’s important to emphasize.

And you’re absolutely right, I am not sure, I think it’s maybe 90% or so of the plasma cell leukemias are 11;14, but that doesn’t always mean that they have to be active, even if there’s a very strong correlation with BCL2.

I think that yes, on average, they are very likely to respond. What about the tumor lysis? I am not aware at this point that that has been a big problem. But I think we probably also are taking precautious measures. We would probably hospitalize the patient. We would give IV fluid. But I’m actually not sure about what the exact detailed information is. My gut feeling is that it probably is not as bad as what has been seen in other diseases, but I wouldn’t be wild and crazy and do dangerous things. I would be cautious.