Introduction: Monday Night with Research To Practice

DR LOVE: Good afternoon, everyone, I’m Neil Love from Research To Practice and welcome to Exploring the Current and Future Role of B-Cell Maturation Antigen BCMA-directed Therapy in the Management of Multiple Myeloma. We have a great faculty today for this program, Dr Jesús Berdeja from the Sarah Cannon Center for Blood Cancer in Nashville, and Dr Noopur Raje from the Harvard Medical School and the Massachusetts General Hospital.

If you have any questions or cases you’d like to run by the faculty, just type them into the chatroom.

If you’re into audio programs, check out our podcast series, Oncology Today, including a recent program with Dr Usmani on transplant-ineligible patients.

We do quite a few webinars nowadays, as we have the last 2 years, and Wednesday we’re doing a great one on the management of small cell lung cancer, new developments there. This Saturday, we’ll be working with the North Carolina and South Carolina Oncology Groups to put on this symposium, 6 hours long, 12 investigators, 20 tumor types. Get comfortable on Saturday and spend the day with us.

We’re doing a program on immunotherapy of lung cancer the day after Valentine’s Day, and then we’ll be going out to the GU Cancer Symposium, doing programs on prostate cancer, bladder cancer, and actually we’re about to add a renal cel program.

We’ll be coming back after that with another program on AML with Dr Fathi. And then a program with Dr Williams on Hodgkin and Non-Hodgkin lymphoma.

But today we’re here to talk about multiple myeloma. And before we get started, just to kind of take a step back, because we’re always into new things at Research To Practice, I actually worked with both of the faculty prior to this webinar today and did their — we recorded their presentations. We’ll post them for you online and send you an email when everything’s ready. And this is really going to be a follow-up and we’ll talk about clinical applications of the data that they presented.

We’re going to start out, talk a little bit about where we are today in myeloma compared to 2010. And then we’ll jump into the content. But let’s start out with a little bit of an intro, and audience I want to start out with this question, and there’s a reason behind that; you’ll see in a second. I want to know what you were doing in 2010. Were you in high school or was it earlier than that? Were you in college or medical school? Were you in training? What were you doing in 2010? We’ll put that to the side and check out the histories of the audience in a second.

But last Wednesday we had an interesting experience as a CME group, we did this program on diffuse large B-cell lymphoma. We had a great faculty for that. But we try to format that we actually had seen on Monday night with Peyton and Eli Manning, where we had the Zoom on the side and the slides in the middle, and it worked out pretty well. So we thought we’d give it a try tonight. We’re actually adding on a couple of whistles tonight. But I just want to let you know what I was doing in 2010. We were doing a webinar series in 2010 — you know webinars, like what we’re doing right now! And in 2010, I had to drive out to West Broward where we had these huge satellite trucks go into this place, and when we would do a program and we’d have other people in different cities with these huge satellite trucks. And of course, things are a little bit different nowadays. But I thought you might find the introduction to this series very interesting; it kind of reflects back on where we were in 2010 in oncology in general and myeloma specifically.

Over the last 8 weeks, this webcast series has focused on some of the fastest moving areas in clinical cancer research, particularly the rapid emergence of several novel agents and new chemotherapeutic options in a number of tumor types.

We’ve talked about anti-angiogenics in glioblastoma multiforme, in ovarian cancer where PARP inhibitors are also being studied, anti-HER2 treatment in gastric cancer, and the role proteasome inhibitors, IMiDs and hypermethylating agents are now playing in a variety of hematologic cancers, including myeloma, NHL, AML and MDS.

So in preparation for the big game in an hour when the Pittsburgh Steelers visit Cincinnati to take on the Bengals, sit back, relax, and get ready for some information.

So, Noopur, I know you’re a big football fan. You’re all sad because you lost Tom Brady. I predict Tom Brady is going to be on the Eli and Peyton show next year, incidentally. I want to play him. But anyhow, maybe we can reflect back a little bit about where we were in myeloma in 2010, not that long ago, Noopur. No BCMA therapy then. No anti-CD38 then. Any comments, Noopur?

DR RAJE: In 2010 I think we were still talking about combining lenalidomide with bortezomib and that was the big, sort of advance that we’ve made, RVd. And we were still arguing about using RVd versus cytotoxic chemotherapy in those days. So certainly didn’t have anything, no monoclonal antibodies. No BCMA-targeted agents. And we didn’t – we just about had a new proteasome inhibitor in addition to bortezomib, we had carfilzomib I think, and that’s where we were. So remarkable progress.

DR LOVE: Jesús, any comments? And also, where you see things heading? What do you think we’ll be talking about in 10 years? Will we have cured myeloma?

DR BERDEJA: Just to add to what Noopur said, I have to say, back in 2010, at that point we were still debating whether transplant was necessary upfront, and we still are. So some things never change, right? So I think some things will continue.

Yeah, I think it’s amazing. We were calling lenalidomide and bortezomib the novel agents at that point still. So lots have changed since that time. I mean there’s been an explosion in immunotherapy, as has in other cancers as well. And definitely the darling targets, BCMA and CD-38, with CD-38 coming first of course. But I do think that in the future these therapies are here to stay and they’re going to be, just like everything else, sort of incorporated earlier in the course of therapy. They’ll be combined with the hope to really get to those really deep remissions and ultimately finding that cure. But I think, just like anything else, right now in myeloma we tend to, sort of can exhaust our therapies. So new targets are coming our way. And actually, I think Raje has already told us about some of those, the GPRC5D and the FcRH5, so new targets hopefully that can help us — I think at some point we will have sort of this multimodality therapy that will be all immunotherapy targeting different antigens like we do now with the IMiDs and the PIs and steroids I think will be anti-BCMA, anti-CD38s, anti-GPRC5Ds trying to really eradicate these cells.

DR LOVE: So before we go on and talk about BCMA, Noopur you were referring to the transplant question. Do you think we’re going to get an answer this year, incidentally?

DR RAJE: We’ll have to wait and see. We’ve waited very long, Neil, but I think the question of transplant versus no transplant is still out there, as Jesús has mentioned. And we’ll have to wait and see. The French data has already shown us that transplant is better than just the combination with maintenance for a stipulated timeframe. The DFCI DETERMINATION trial asks the same question with a slightly different way in that maintenance is continued up until progression, which is typically how we use lenalidomide maintenance in the United States. So really getting to that answer as to how much of a benefit does transplant offer or does not offer is going to be critical in the context of continuous maintenance therapy.

DR LOVE: So it looks like, as always, we have a lot of millennials in the audience here, actually 25% of the audience was still in train — either in school or training, had not even entered training, 25%. And almost 20% are in their first 10 years of practice. So for those of you who weren’t around in the so-called RVd days and before, CyBorD not to mention, things are moving pretty quickly.

Targeting BCMA

DR LOVE: Well, let’s talk about our topic here today, targeting BCMA. And actually Jesús, this is a slide you used in your presentation. It looks like a lot of stuff happened after 2010, particularly the introduction of anti-CD38 monoclonal antibodies. Any comments though on this slide you showed, Jesús, kind of showing that even though we’ve made a lot of progress, actually things are not all that perfect.

DR BERDEJA: Yeah, this is always a sobering slide because we start with all that excitement about the new therapies that we have, and we have made a big difference for patients with myeloma in terms of survival, but the truth is that when a patient becomes refractor to anti-CD38, and those basically the criteria to get on the study, the outcome is quite poor with the median overall survival of only 8.6 months. So clearly, a huge need for our patients after they fail the first couple of lines of therapy.

DR LOVE: We’re going to get into some of the new developments that are out there, Noopur, but I’m just kind of curious right now from a clinical point of view, obviously trials are your number one objective. But when you have a patient who’s looking like they’re about to progress, they’ve been through PIs, IMiDs, proteasome inhibitors, anti-CD38, how do you look at the patient and figure out kind of what’s going to come first?

DR RAJE: So a lot of factors play into that decision-making. I think what’s changed and what’s new right now is we’re in the era of using all of these, which you’ve mentioned, in combinations. So we’re using quadruplets. And by using quadruplets upfront, what I think is happening is you see your first relapse at around year 4, anywhere between year 4 and year 5. So it’s almost looking at the post-anti-CD38 era. We are fortunate because we have antigen targets such a BCMA and more coming down the pike, as Jesús has already mentioned, and really making sure that the patient does not have significant comorbidities or looking at all the other associated things like renal disease, etc, you then pick a strategy. And I think BCMA has become, in my mind, the next standard of care after some of the drugs that you already mentioned, Neil.

DR LOVE: I’m curious, Jesús, when you interact with a patient who’s just been diagnosed with myeloma and is going to require treatment, standard risk situation. They want to get some idea of what to expect from the future. They’re not super elderly, let’s say they’re going down the transplant route, what do you tell them to expect in terms of survival?

DR BERDEJA: So a newly diagnosed patient, at this time, standard risk, in the overall survival, we’re probably talking about a decade, with the hope there, of course, that each time we look at this we keep getting better. And I think actually the more interesting question that patients always ask is what happens — how are you going to treat me after I relapse? Which is always very interesting to me because they’re already thinking into that 4, 5 year timeline that Noopur just gave you. And I think the nice thing that I always tell them is, I actually have no idea how I’m going to treat you in 4 or 5 years because I think it will be dramatically different from what we have now. and that’s usually how I try to frame it for these patients, that the advances are coming so quickly that really I think our old way of looking at 3 prior lines of therapy, 4 prior lines of therapy before we can give something are going to potentially go away, just because I think most patients will be getting multiple combinations with the goal of either curing or inducing a very deep remission. Then once they progress off that, there will be a novel therapy.

So I suspect that will be anti-BCMA will probably be a second-line type therapy for some of these patients that are being diagnosed today.

DR LOVE: And Noopur, if the patient brings up the question of cure, how do you respond?

DR RAJE: So I’m the eternal optimist. I do think we’re actually curing a subset of myeloma already. And how does one define cure? Defining cure is you live with your disease and you’re dying of something else. And right now, at least the standard risk patients, which Jesús has mentioned, with quadruplets and with some of the immunotherapies that we have on an average they’re living 10+ years and more, I would say even more. And there is potentially a subset of patients where we’re never going to hear from the myeloma.

I think the challenging patient population right now, Neil, is the high-risk patient population which we know typically has not had the same kind of outcome. And we need to make sure that we’re giving this long remission duration to all our patients as opposed to just the standard-risk patients. So standard risk, I already think we may be curing a subset of them.

DR LOVE: So let’s talk about BCMA. And Jesús, maybe you can comment a little bit about what it is? Where it’s found? And what the rationale is to target it?

DR BERDEJA: So BCMA is a great target for myeloma because it’s really just expressed in mature B-cells and plasma cells. And as these cells kind of mutated and become malignant, the expression actually increases. And it’s not expressed in other tissues, which is really nice from a side effect stand — profile standpoint.

It actually serves as the receptor for TNS super family and is a receptor for APRIL and BAFF. And it’s a very key role in B-cell maturation differentiation. So a very important component of the cell survival growth. So a key target I think for many reasons.

DR LOVE: Well, we’re going to try something new. We haven’t done this before. But for the last 2 years I’ve been just verbally telling people what’s in the chatroom. We’re going to try to see if we can actually put it up so everybody can see it. There you go. This is from Dr McKenna who always asks a lot of great questions. So, Noopur, maybe you can respond. Any thoughts about CHF and CAR T? It sounds like she has a patient who has progressed after transplant and anti-CD38.

DR RAJE: Yeah, so the good news with CAR T cells is you don’t use very high doses of chemotherapy and therefore, more people can tolerate CAR T cells as compared to folks who need high-dose melphalan and autologous stem cell transplant. Having said that, they’d need to have some level or organ function, so in terms of an ejection fraction. And I think most of the clinical trials, they need to have an EF of at least more than 40%, depending on which clinical trial you’re looking at. But if general, as long as you can medically manage the CHP appropriately, and you think they’re going to be able to withstand toxicity such as CRS, where you might need fluid resuscitation, a patient should not be precluded or excluded from something like CAR T cells.

DR LOVE: So I want to also bring up the issue of kind of how we’ve targeting BCMA. We’ll get back to some of these other cases and maybe even revisit this one. Jesús, again this is a slide that you had in your talk, talking about the ways that BCMA is currently being targeted, and we’re doing to talk about these in this, but maybe you can just provide an overview.

DR BERDEJA: So I think these are the 3 big classes of drugs, which is interesting because you don’t see the monoclonal antibody which is also being developed. So it’s a little bit backwards in I think what we’re mostly used to. So you have the antibody drug conjugates where you have a monoclonal antibody against BCMA bound to basically a payload of chemotherapy. You have the bispecific antibodies, which I think Dr Raje talked to you at length in her talk, which basically you’re binding both BCMA and in this case, CD3. So you’re redirecting T-cells against BCMA. And then of course, you have our CAR T cells where you’re actually taking your T-cells and you’re having them express a new chimeric antigen receptor as a CAR or CAR T cell. And so those are sort of the 3 big, kind of groups of therapies against BCMA. And as you can see there — sorry. I was going to say, 2 are approved already by the FDA, and it’s ADCs and CAR-Ts.

DR LOVE: Here’s a slide from your talk. Anything you want to add to what’s being said? We’ll talk more about the details in terms of bispecifics. Anything you want to add? And also, I’m just kind of curious about your thoughts about adding — I see comb — we’ll talk later about combinations with belantamab mafodotin, any thoughts about that? I see it being used upfront for that matter.

DR RAJE: Yes, you saw that there are studies, which are ongoing, Neil, where all of these are now approved in kind of third- and fourth-line treatment, have been moved upfront. Drugs like belantamab mafodotin, as well as some of the bispecific T-cell engagers. We already have clinical data now in combinations because they’re easier to combine. And even things like CAR T cells, there will be data coming out soon wherein we’re using sort of maintenance strategies post-CAR T cells. So I think this is a field which is still under active investigation. And combinations are certainly possible with all of these modalities.

DR LOVE: So I think we’ve got another — we’re going to try out the chatroom thing again. We’ve got a couple of more questions from Daniel and Kapisthalam, we’re going to try to put those up. So Daniel wants to know what about using BCMA CAR T, Jesús, after BCMA therapy? We hear the same question in lymphoma. We were talking about diffuse large B-cell last week, same question comes up with anti-CD19 mono — antibody drug conjugates. What do we know about this, Jesús, as it relates to BCMA? And then Kapisthalam wants to know what do you think about using prophylactic steroids to reduce CRS?

So what do you think about these 2 questions, Jesús?

DR BERDEJA: So these are great questions, actually very sophisticated questions. I’m impressed. The truth is we actually don’t know. So most of the trials, and many of the current trials of anti-BCMA therapies have excluded patients who’ve had prior BCMA therapies. So we don’t know for sure what the activity is in those patients. Having said that, most of the patients that have relapsed after ADC therapy seem to preserve BCMA expression. And so, theoretically, if you have a different mechanism of action it should still work.

So there are now some trials with some of the bispecifics actually, where they’re allowing prior BCMA therapy, and we’re starting to see that there is activity. But again, very early and we don’t know if it’s the same kind of response that you’re going to see in the naïve patients or not. So, I would say that in real practice, I think it’s reasonable. I personally would prefer not to use an anti-BCMA therapy right before another one. So perhaps after a patient has had a different therapy, afterwards.

And then in terms of the steroid question, I think that’s a very good question. I think we were all very scared of using steroids early on. Now we know that the CAR Ts are not killed by steroids. They’re just attenuated. So very much like in the lymphoma literature, I think that’s not an unreasonable option for patients. Luckily, in myeloma with the BCMA CAR Ts, we haven’t seen the high grade CRS that were seen in the early CD19 studies. And so, it’s not as important. But I think that’s definitely something that should be looked into.

DR LOVE: Noopur, that sounds a little bit, I don’t want to get too far off on that, but it kind of sounds counterintuitive to be using corticosteroids in somebody you’re giving immunotherapy to. Is that something you do, or you think will be done in the future?

DR RAJE: So as Jesús has pointed out, the good news is we don’t see a very high incidence of CRS, Neil. So I don’t know if we necessarily need to use prophylactic steroids here specifically. ALL, it’s a different story and you want to try and reduce CRS quite significantly. I don’t think that’s been the problem with myeloma. And the other thing is, over the last few years we’ve used tocilizumab and gotten used to using tocilizumab for CRS. So our use of steroids is quite low.

So as opposed to prophylactic, I would suggest use it early so that you’re using it for a shorter duration of time so that your CRS does not evolve into worsening CRS, and that’s something we’ve all learned over the last 3 and 4 years with these technologies. But whether or not we need to use it prophylactically, I don’t think so.

DR LOVE: So I’m kind of curious there, in terms of that. Noopur, this is a slide you put together, sort of the different ways that bispecifics are put together. Can you kind of go through that?

DR RAJE: So I think the whole bispecific platform is such an interesting platform and we’re just about scratching the surface of these bispecific antibodies. What we have is the bispecific T-cell engager and we have also the bispecific antibodies, that is the antibody with the 2 arms wherein you target the T-cells, the CD3 cells, and bring the CD3 cells towards the tumor. the other arm is targeting the T-cells. There’s a whole lot of different things that can be done with this platform, wherein you can mutate the FC receptors. You can add ligands to different — or receptors to different ligands. You can make these dual antibodies. So there’s a lot of things which can be done from a technology standpoint when it comes to bispecific antibodies.

And as of right now, we have the bispecific T-cell engagers, and we have the bispecific antibodies. Those are the 2 which are in clinical trials as we speak.

CAR T-Cell Therapy

DR LOVE: So I want to move on and talk a little bit about CAR T therapy, but we spent entire programs just talking about CAR T in myeloma. So we’re just going to briefly get into it and really emphasize what’s new and exciting, not that CAR T is not exciting, but certainly bispecifics and also antibody-drug conjugates. But before we get off CAR T, maybe we can hear about 1 case. Jesús, this is a patient of yours, a 67-year-old man. Can you talk a little bit — we’ll kind of skip his initial presentation — I want to focus more of when he got to the point of needing CAR T, he got treated with ide-cel. Can you comment on this case?

DR BERDEJA: Yes, certainly. But I do want to just stress that everyone heard Dr Love say that CAR Ts are passe, so just so that everyone heard that!

DR LOVE: Hey, we’ve got to move onto the next thing!

DR BERDEJA: So yes, this patient went through several lines of therapy. And then started to progress with a new pathological fracture and M-protein. So he was referred for CAR T trials, at the time it was with ide-cel. So he had 70% plasmacytosis. So he underwent leukapheresis for T-cell collection successfully. And then during the CAR T manufacturing which usually takes a couple of weeks, but by the time you get it back it could be about 4, possibly even a little bit longer weeks. Patients often have to be bridged through. And so, this patient received an abbreviated cycle of daratumumab/bortezomib/dex and had stable disease to that. And then you have to go through your LP — LD chemo, which is cyclophosphamide and fludarabine.

He received his CAR T 2 days later and on day 1 developed fevers and hypertension that was responsive to fluids. And so this was consistent with Grade 2 cytokine release syndrome. He received 1 dose to tocilizumab. Resolved really about an hour after and did well thereafter and discharged home.

And then afterwards the patient was doing very well. The main issue really was persistent cytopenias, still required intermittent transfusions and GCSF as needed. Eventually resolved by about a month or 2 months out of CAR T. And at day 30, he was in a very good partial remission, MRD-negative 10^-6. And his response lasted about 20 months.

DR LOVE: I’m curious, one of the things I hear from docs who have patients that go to CAR T is how it is for patients to be off therapy after having so much therapy. What was it like for this patient, Jesús?

DR BERDEJA: They love it. And that’s actually the thing that I think struck us the most about CAR T. This is a complete mindset than what we’re used to with myeloma. And I’ve had patients who’ve relapsed after a year, and they said that was the best year of my life. I had forgotten what it was like not to be on medicine.

So, at least from standpoint, patients really appreciate that break. And unfortunately, we’re not seeing curative — there doesn’t seem to be curative, at least in the relapsed/refractory setting, so we are talking about maintenance and combinations, which may take away some of this sort of benefit of the 1 and done. But at the end of the day, as a single agent, it’s definitely probably the most active agent we’ve ever seen.

DR LOVE: So Noopur, in your talk you also presented a patient who got CAR T and actually, it sounded very similar to the case we just heard, good response. I don’t know if you picked out people with better responses. But I hear a lot of cases like this. One question to you, Noopur, is this what you expect from a CAR T? Do you expect people to respond? And also, I’m curious your patient was off therapy for 22 months. Incidentally, your patient got BB21217 with the PI3 kinase. And I guess that’s no longer being developed. That’s another story. But I was just wondering what it was like for this patient? Is this a typical course, Noopur? And what was it like for him to be off therapy for 22 months?

DR RAJE: So I think most of our patients, the first thing they will tell you is the best thing that’s ever happened is given the CAR T cells and not been on any therapy. What we’ve seen with CAR T cells is very high response rates. So the majority of patients respond; it’s close to 70- to 80% of patients who respond. And if you look at patients who achieve a stringent CR or a CR, they’re the ones who have this remission duration of close to 2 years. If you look at ide-cel or BB21217, it’s about 40% of these patients achieve a stringent CR. If you look at the CARTITUDE study with cilta-cel, their stringent CR rate is about 55%. So high response rates in a very refractory patient population. And just to put things into context here, Jesús showed us a nice slide of what happens to these patients post-CD38 antibody no matter what you use with some of the drug approvals we’ve had, their response rate is around 20%, which lasts anywhere between 3 and 4 months. So this is absolutely remarkable data which I would have never imagined seeing in this space.

DR LOVE: So Jesús, I want to show a couple of slides you showed that included the constructs. I’m still trying to figure out how antibody drug conjugates put together. We’re talking about them all the time now. T-DXd in HER2-positive breast cancer, revolutionary drug. We talked about polatuzumab last week in first-line therapy of diffuse large B-cell. But in the beginning, I was kind of getting this idea they were all the same and now as time goes on I feel that is not the case.

So Jesús, for those of us who didn’t get out of med school in the last 10 years, can you kind of compare these 2, ide-cel and cilta-cel, in terms of how they’re made?

DR BERDEJA: Yes, sure. So I think the concept here is that you’re basically using for the most part a viral vector to deliver your DNA to the cell, but then leads to an expression of a CAR. And that CAR is a chimeric antigen receptor which basically has 3 important components. It’s the antigen-binding domain which in here is against BCMA. And then you have a linker that links it to a signaling domain and then its T-cell activation. So as soon as the — it binds to BCMA, it activates the cell. And then you actually potentiate the cell, and the cell sends out cytokines and the cells actually will expand.

So the difference between ide-cel and cilta-cel is that cilta-cel actually has 2 BCMA targeting domains instead of just 1. And they also use a heavy chain instead of a single chain fragment, a variable fragment, which is neither here nor there, but that is smaller and sort of protects, allows them to be able to put the 2 binding domains. And presumably that actually leads to — confers — to bind more avidly. And it’s almost like having like a dual antigen CAR, in my opinion. But that’s really the main difference. Otherwise, the CAR constructs are very similar.

DR LOVE: So in the chatroom Steve has brought up the issue of the neurotoxicity, the non-ICANs neurotoxicity, Noopur, that’s been seen with cilta-cel. It look like maybe they’re seeing less of this as time goes on. But can you talk a little bit about that? I find not everybody is aware of this sort of Parkinsonian type thing that was seen earlier on. And Steve wants to know is this somehow related to the blood brain barrier? Or what’s going on there?

DR RAJE: So lots of good questions. I don’t think we have greater answers to those questions. So with CARTITUDE-1, which is the study which Jesús has just presented, we did see this delayed neurotoxicity. So not ICANs, but delayed after a month, as late as about 3 months, and most of these patients had this movement disorder and degenerative kind of a disorder. And it was about 10 patients of which 5 of them actually did not recover at all.

Now, this has been published just last December in Nature Medicine as well as a case report after cilta-cel. There is a report of a Parkinsonian-like syndrome, even with ide-cel. So whether or not it has to do with binding to BCMA and whether BCMA is expressed on neural tissue is something we are all thinking about and trying to figure out. I don’t think we have great answers. But the new mitigation strategies which folks are trying to use, where going in with early bridging therapy, getting responses earlier so that you don’t have a lot of neurotoxicity maybe ways of trying to mitigate some of this. Again, I don’t think we completely understand this delayed neurotoxicity.

DR LOVE: So one final point about CAR T, Jesús, and again this is a slide you showed where you talked about delayed toxicities. Can you comment on that? And also, what we know about vaccines and resistance to COVID?

DR BERDEJA: Yes, so all good questions. The toxicity, the main toxicities that are really important, especially for the referring docs, right, because oftentimes this is when a patient goes back to them. And so it’s important to realize, and we concentrate a lot on this cytokine release and the neurotoxicity, but really it’s these sort of, kind of later effects, cellular and humeral deficiencies, that often will get people in trouble. And so just realize that people could still have persistent cytopenias. I’ve had patients require transfusions as far out as 3 months from their CAR T. Patients often can still be neutropenic.

And so using growth factors and making sure that they’re monitoring their counts closely is important. But these patients have incredibly B-cell aplasia and hypogammaglobulinemia. I mean you’ll see IgG levels like you’ve never seen before. I mean they’ll be like in the 100 range or less for these patients. And so, we’ve, for the most part, i think most of us have been pretty avid about giving IVIG replacement for these patients, although it’s still kind of that same controversy in terms of whether we should be doing it or only doing it for patients who’ve had infections. But definitely just realize that these patients will be very hypogammaglobulinemic.

But they also will have T-cell deficiency. So they just received fludarabine and so the — and the CAR Ts definitely have an effect on the other cell lines and narrow aplasia. And so these patients will be T-cell deficient for a long time. So it’s important to do PJP and vis-à-vis prophylaxis, and at the same consider vaccinations against some of these.

In terms of COVID, we do know that the patients in myeloma who received anti-CD38 antibodies and anti-BCMA-directed therapies have very poor response to the vaccines. And so it is important to keep that in mind. I try to counsel patients on hopefully getting vaccinated before they receive these therapies because afterwards I think it’ll be difficult for them to mount a response.

Now having said that, that definitely is — that’s more in the acute phase that I have had patients who have had robust responses to the COVID vaccine for example, they’re about a year out from their CAR T or longer. So it’s not all patients. We shouldn’t tell patients that they’re not going to have any kind of response.

DR RAJE: I’m just going to add to that —

DR LOVE: Go ahead.

DR RAJE: Just a little color to that, Neil. This is in the minority of the patients. The majority of patients actually tolerate this treatment quite well. The cytopenias happens in about 10-, 15% of patients which is well projected. And most of the patients we’ve been able to vaccinate 3 months out from their CAR T cells. So in general, it’s well tolerated. But I agree with everything else.

Bispecific Antibodies

DR LOVE: So let’s go on and talk about bispecifics. And this case, when you presented it, I was reading it last night again, Noopur, and thinking about this woman as a person because it’s kind of an interesting story that’s woven in here in addition to sort of the medical stuff. But what happened with this 62-year-old lady?

DR RAJE: So she was obviously diagnosed a few years back now with the classic IgA kappa myeloma and required a hip replacement. We treated her with RVd. We collected her stem cells also, but she completed refused a transplant. There was no way that she was going to get hospitalized for that.

She relapsed after 18 months. We treated her with dara/pom/dex. She achieved a PR. Again had progressive disease after a little bit. Treated her with carfilzomib/cyclophosphamide. Progressed again. And then every time she relapsed, we did talk to her about a transplant, but she was very against a transplant. She had the opportunity of going onto a clinical trial, and in this case we used elranatamab, and this was at the time on a clinical trial in combination with an IMiD, lenalidomide here. She actually has had an amazing response and continues in a response. She’s close to now I think 13 or 14 months in an MRD-negative state.

DR LOVE: So really amazing. I think you told me she refused CAR T also because she wouldn’t go in the hospital, right?

DR RAJE: She didn’t want to get hospitalized. She was willing to get hospitalized for the 2 days. Yeah, she didn’t want CAR T cells.

DR LOVE: That’s amazing. So she refused transplant and CAR T and now has been this great response.

Jesús, how typical or atypical is this case, particularly with the MRD negativity? Is this something you see commonly?

DR BERDEJA: With the bispecifics?

DR LOVE: Yeah, with the bispecifics.

DR BERDEJA: Yeah, absolutely. Bispecifics are inducing very deep remission in patients. And very early on. So definitely this idea of T-cell redirecting is a good one and I think as close as we get to CAR T, that type of responses with these bispecifics. The difference, of course, here is that the bispecifics have to be given serially, and we don’t know for how long. Although, I’ll have to tell you that I do have a couple of patients who’ve come off — they get these deep remissions and then we have to hold their therapy for an infection or for whatever reason, and they’re maintaining their remissions. So I would love to see us do some trials where we do limited therapy to reach to a certain response and then actually try them off therapy. But for what it is right now, no, I think this is a very common response.

DR LOVE: So Noopur, can you talk a little bit about how often they're treated? How long it takes to be treated? And do you see this potentially being an outpatient therapy?

DR RAJE: Yes. So as of right now, as Jesús pointed out, we are doing it as a continuous therapy. We start out, with most times we’re trying to do a step-up dosing with the first dose to mitigate things like neurotoxicity and CRS. With the first 1 or 2 doses, they’re hospitalized for about 2 to 3 days, and then the rest of it is all outpatient. The ones which are teclistamab and elran, both given subcutaneously. They’re given as weekly shots and then, depending on the protocol, they go to every 2 weeks. But absolutely, I think all bispecifics should be given for a stipulated duration of time. I don’t think we have data to speak to that just as yet. And I think once we get some of these drugs, drug products approved, that would be the strategy — give them for a fixed duration of time, given that we’re seeing such incredibly deep responses with this type of an approach.

DR LOVE: Jesús, what do you see in terms of CRS and toxicity? Is it mostly the first couple of cycles, or can you see it very delayed?

DR BERDEJA: So that’s a great question. Actually, very interesting. Most of the toxicity in terms of cytokine release syndrome, is really seen in the step-up doses and maybe the first full dose. And it’s rare to see it beyond that. There is the occasional patient, and we’re talking very occasional patient, where you might see some mild, whether it’s an infusion reaction or if it’s true CRS where they might have a fever that happens in further cycles. But that is the exception. Most of these patients, this could truly be a drug that can go to the community doc, it will depend on how good we are about mitigating these early toxicities. But definitely is something that could be continued, outside of the academic center or after that first cycle in my opinion. But neurotoxicity actually has almost unheard of and it’s usually in the setting to cytokine release syndrome.

DR LOVE: So Noopur, this is a slide you showed in your talk reviewing some of the agents being looked at, as you mentioned, or I think Jesús mentioned. One of the things I’ll say is the 2 leading ones have good names, so teclistamab, I like it. I can say it. Elran, I like that, too. But anything you want to say about what we know at this point, Noopur, about the difference between these agents? And when do you think we might see that this actually come into practice?

DR RAJE: So our hope is that by the end of the year, at least 1 of the bispecifics should get approved because the studies have been done. If you look at the data though for teclistamab and elranatamab, we’re seeing high response rates, again in very heavily pretreated patients. We are seeing some CRS, usually with dose 1 and dose 2 as Jesús has pointed out, but very little in way of neurotoxicity.

Having said that, we are using a fair amount of tocilizumab early on and that may be part of the reason why, although these are off-the-shelf, easy to give, subcutaneous antibody treatments, because of the need for monitoring for the CRS and having access to tocilizumab, I’m not sure that it can be used in any kind of an office practice. But as patients stay on these drugs, I do think they can be given quite easily in any kind of a practice-based approach. It’s just that whether or not, if you look at this data now, you will see that patients stay on drugs for a long, long time. They can go on for a year or 2 years as was seen in my patient as well. The question, as Jesús has brought up, is do we need to continue them for as long as that once they’ve achieved that MRD-negative state? And those studies are still sort of ongoing.

DR LOVE: Anything you want to say about the data presented at ASH? Anything stick out in your mind, Noopur?

DR RAJE: So I think what was exciting at this year’s ASH, the single-agent data we’ve already seen, but for the first time we saw combination approaches with these bispecifics. So there was really absolutely amazing data with teclistamab in combination with a CD38 monoclonal antibody, so daratumumab/teclistamab, where you saw 100% of response rates. And to me, that was really quite striking because these were patients who were refractory to daratumumab, for example. And if you look at the data of dara-refractory patients, as Jesús has already shown us, their outcome is dismal. But when you see a 100% response rate there, it’s absolutely incredible.

So I think the future with bispecifics would be to combine, to decrease the frequency of how often we give it. So I don’t they need to be given once every week. And to then do sort of stipulated blocks of treatment as opposed to continuous treatment.

DR LOVE: And of course, I’m not going to show this question, but I think probably everybody watching this has this question, Jesús, which is, what comes first? Bispecifics or CAR T?

DR BERDEJA: Well, CAR Ts came first in myeloma. It’s going to be a great question. I think again, it’s going to come down probably to the conversation with the patient and what they would prefer. So Noopur just told you a patient did not want CAR T because of the whole hospitalization, plan her position, and was going to go on the bispecifics. Some patients will be the opposite where they’re like, I don’t want to have continuous therapy. I want the one and done. And they would prefer that.

So in reality, it’s going to come down to the duration of response, right. So we have much more mature data with the CAR T. So we know that data, particularly with cilta-cel, where it’s looking like it’s going to go beyond 2 years, the progression-free survival. So if the bispecifics show identical results, it truly will be one of those things, the ease of giving.

Now one of the issues that we haven’t talked about that those of us who try to give commercial CAR T, is that there’s a lot of roadblocks giving commercial CAR T right now with lack of vectors and waiting times. So something that’s off-the-shelf like this, definitely will be very key and most likely will be much more usable for the majority of patients, in my opinion, until something changes with the CAR T manufacturing.

DR LOVE: I don’t know why I just flashed on — I just flashed on Lutetium in prostate cancer that we’re going to be talking about on Saturday. And this kind of sounds, it’s similar. It’s going to change practice soon. I think maybe sooner with Lutetium.

Belantamab Mafodotin

DR LOVE: Let’s talk a little bit about belantamab. So many questions that we get from docs in practice, Jesús. Let’s start out with your patient, this 78-year-old man. What happened with him?

DR BERDEJA: So this patient, standard myeloma presentation. Initial treatment was just a doublet with lenalidomide/dexamethasone. Was able to stay in remission for about 2 years and then had the progressions that we normally see. This last time when he progressed, again at this point he was 78 and he also had renal insufficiency, a creatinine of 2.5. So those are the patients that at least right now, for example, the age itself is not a problem, but definitely the renal insufficiency is problematic with CAR Ts from a standpoint of giving them lymphodepletion, in particular giving the fludarabine.

And so in this case we opted to go with belantamab mafodotin, the ADC. And so the patient received the belantamab mafodotin at standard dose. He achieved a very good partial remission after 3 cycles and tolerated it very well, except he started having some odd eye irritation. In part cycle 4, he was found to have Grade 3 keratopathy on optho exam, which, as you know, the REMS requires an optometry, ophthalmologic exam before each dose. And the patient did not have any changes of visual acuity. And we were able to — we held his dose for 2 months. The keratopathy resolved and he proceeded with therapy. He maintained his remission during that hold, which is actually often what we see with this drug. But otherwise tolerated very well, with very few side effects.

DR LOVE: Noopur, any comments on this case history? How does that match up versus your experience with this agent? And, of course, I’m particularly interested to hear what both of you have to say about the keratopathy. Sounds like in this man; you hear a lot of cases like that. You hold it and it goes away.

Can you talk a little bit about your experience with this agent, Noopur?

DR RAJE: So the nice thing about belantamab mafodotin is off-the-shelf for easily available. This patient of Jesús’ had renal insufficiency, so perfect for an antibody drug conjugate such as this. Keratopathy is a problem. It happens in about 60- or 70% of patients. But I do think with the new dosing schedules, wherein we are not using it every 3 weeks, we’re going to every 4 weeks, sometimes even every 8 weeks, and with the dose reduction of 1.9 mgs, maybe the rate of keratopathy will decrease. There’s a whole bunch of studies which are ongoing, DREAMM-1 through DREAMM-14, I believe, wherein this is again a drug product that can be combined with other drugs. And by combining, you can decrease the dose of this one and, therefore, mitigate this ocular toxicity.

So I think our goal for the future would be to try and maintain these responses because we certainly see these responses by mitigating this ocular toxicity. And that’s still work in progress.

DR LOVE: So Jesús, can you talk — we were talking before about the constructs of CAR T. What about the construct of belantamab?

DR BERDEJA: Yes, so this is a classic antibody drug conjugate. So the antibody is humanized, afucosylated IgG1 against BCMA, and is bound to a monomethyl auristatin, or MMAF. And so I think the usual way we think of ADCs is you bind the target to get — the whole construct gets internalized and then the payload is delivered, and it kills the cell. But this antibody also can mediate ADCCC as well. So it also has some immunotherapy type of function, which I think is what sort of giving this sort of dual or triple approach, is what’s giving it its activity.

Unlike what we saw with the CAR Ts and the bispecifics, this is more what we expect in this relapsed/refractory patient population, what we see overall responses in the 30% range, with median PFS’ or 3 to 4 months.

I think in the patients that do respond though, that duration of response is actually quite prolonged, which is nice to see.

DR LOVE: So do you want to comment on the efficacy? Your sort of global assessment, Noopur, of the efficacy of belantamab mafodotin? When you start on a patient, what are you expecting in terms of response and duration of response? Just clinically, based on the research you’ve read about, but also your clinical experience.

DR RAJE: So I think as a single agent, as Jesús has shown you, the response rate is something like 30%, depending on what dosing you’re using. But most of us tend to use this in combination. There’s data which you’re showing out here, DREAMM-6, was in combination with bortezomib. There is other data in combination with pomalidomide, which was presented at this year’s ASH. And there’s more data with immunomodulatory ways of augmenting the immune system. And again, I think the response rates there are anywhere between 50- 60% or even higher, with bortezomib it was 70%.

I think the biggest thing with belantamab mafodotin is with these combinations, are we going to be able to mitigate the ocular toxicity? Because that can, in fact, affect the quality of life for a patient very significantly. So that’s still an open question in my mind.

DR LOVE: So Jesús, any thoughts about the alternative dosing as a way to mitigate the ocular toxicity? And also, I’m curious about, here’s a trial looking at combining it with upfront treatment in transplant-ineligible patients, the DREAMM-9 study. Where do you see all this heading?

DR BERDEJA: I mean Noopur kind of brought all this up already, but we see this a lot, right, in myeloma, where we get an FDA-approval of a single agent and then we know we’re going to be moving it in combination. When you combine it, you often have to kind of adjust the dosing, since we saw that with selinexor, right, where we went from twice weekly to once-weekly dosing. And I think the same thing is happening here. And I think the important thing here is that in the patients who get keratopathy, where they have to have had a response and then you hold the drug, and then you bring it back at a lower dose, you see that you can maintain those responses. And I think that’s where a lot of this data is coming from in terms of can you mitigate these toxicities by changing the schedule?

And so, unlike other drugs where we mostly change potentially the dose or adjust the schedule for the other drugs, here you’re using the combination drugs to try and actually allow you to give a lower dose and maybe a longer interval between dosing for your drug. So, especially the study that you showed here with — in the patients who are transplant-ineligible, looking at lenalidomide/bortezomib/dex and then adding belantamab mafodotin, you see that the dosing schedule that’s being used is quite different from what’s FDA-approved, going down to as low a 1.9 mg/kg, and as infrequent as every 8 to 9 weeks.

So I think those are great to see because I think there is room to move with this ADC.

DR LOVE: So Noopur, any thoughts about where belantamab mafodotin is going to land? Do you see it as part of — it seems like we have quadruplet therapy. Are we going to be looking at quintuplet or beyond?

DR RAJE: I do think we will be combining it like we did daratumumab with RVd, or KRd. So belantamab mafodotin has the potential of combining with this. And by dose reducing and by increasing or decreasing the frequency of this drug, we will hopefully be able to mitigate the ocular toxicity. So absolutely. The studies already ongoing as you’ve shown already, Neil.

DR LOVE: So we have a couple of more questions from the chatroom we want to put out there. One from Hassan, Jesús. What do you think about the idea of first-line consolidation with bispecifics if people are MRD-positive like blinatumomab in ALL?

DR BERDEJA: Yeah, I thinks that a great use of these drugs. And I think you’re going to start, not necessary just MRD-positive patients, but I think we’re all waiting for the world in myeloma where we actually will have more directed interventions for our patients and the use of MRD, of course, is the best tool I think we have. And so we are starting to see some of these studies where if a patient is MRD-negative you can actually — after 2 different assessments, so an MRD that is sustained, potentially thinking about stopping therapy. And for those patients who are MRD-positive, continue therapy or perhaps kind of enhancing or accentuating the therapy further. And so something like a bispecific would be great from that standpoint in terms of — as consolidation.

Same with CAR T. And I think any of these immune therapies that can induce really deep remissions, if our goal is to get to MRD-negative, this is probably the best way to do it.

DR LOVE: Particularly, Noopur, the issue of using it with patients getting CART T. I’m curious, the idea of maybe consolidated them there. And also, any comments about these 2 questions from Raja and Kapi: Anything you can do to treat the keratopathy? Any drops or anything you can do other than holding it? And Dr Kumar wants to know what’s the pathology of what’s going on there?

DR RAJE: So I’ll take the first part first, and I think this is an incredible question. We all want to sequence them, combine them, and use them as consolidation approaches. So those will be ongoing studies. And I think some of these already being asked in early trials upfront, the role of CAR T cells, the role of bispecifics.

In terms of the other questions on how do you mitigate the keratopathy? So when you’re on belantamab mafodotin, as Jesús has pointed out, prior to your next dose you always have to have an ocular exam. You’re given a very stringent protocol for the use of steroids. Nothing else seems to have made a difference. I think the biggest difference is holding the drug because the toxicities, the corneal epithelium is what gets impacted and they have these little cysts which are formed. And it’s interesting, Neil, because this ocular toxicity seems to be somewhat of a class effect with antibody drug conjugates. And it doesn’t matter what the payload there is. So I don’t think we understand this completely. The Payload could be completely different, but yet you’re seeing these ocular toxicities.

So the question, usually those epithelial cyst formation, it goes away after holding drug. And that’s why Jesús has told us already, do it every 4 weeks, every 8 weeks, and those are ongoing trials.

DR LOVE: I mean we’ve talked about tisotumab vedotin. That has ocular toxicity in cancer of the cervix. So a lot of eye — erdafitinib in bladder cancer is not an antibody drug conjugate. That causes ocular problems. So I think there’s going to be a whole new specialty of — we have cardio-oncology. It should be ophthalmo-oncology, I guess.

Another question from the chatroom, Jesús. Where do you see the new — just to bring up another topic, but I think relevant, and I think I saw one of this on your slides, where do you see the new generation of IMiDs fitting into this increasingly complicated schema, Jesús?

DR BERDEJA: I mean that’s very exciting. So we talk about new classes of drugs, but there’s also advances in sort of the old classes for more active and hopefully less toxic therapy.

So the new IMiDs, or so-called CELMoDs, are coming our way and showing amazing data. In particular, we have data with iberdomide, which is sort of the furthest along which is actually quite impressive in terms of its effectiveness. But what’s even more impressive to me is the decreased toxicity compared to lenalidomide and pomalidomide, which lends itself very well, I think, the combination to maintenance strategies, and all those studies are ongoing.

And then you have coming right on its heels is other agent, CC-24480, which appears to be even more active, but definitely I think with a little more hematotoxicity, which will probably fit a little more in the relapsed type of setting. But absolutely, I think these new drugs potentially have the potential to replace some of our current IMiDs. And I think that’s where they’re heading.

DR LOVE: So I think when I was driving out there to that big satellite center in 2010, I could never imagine what was about to happen, not only in myeloma, not only in oncology, but to the world. But in any event, here we are. We’re still moving along. And I want to thank so much Jesús and Noopur for joining us today.

Come on back on Wednesday, we’ll be talking about small cell cancer, immunotherapy and new agents in second-line and beyond.

Be safe. Stay well. And have a great night.

Thanks, Noopur. Thanks, Jesús.

DR RAJE: Thanks.

DR BERDEJA: You’re welcome. Thank you.