Multiple Myeloma — Proceedings from a Webinar Held in Conjunction with the 2025 ASCO Annual Meeting

Good evening, everyone. I'm Neil Love from Research to Practice, and welcome to Questions from the Community, as our faculty today will discuss available research guiding the care of patients with relapsed refractory myeloma. We have a great faculty today, Dr. Ajay Nuka from the Winship Cancer Institute at Emory University School of Medicine in Atlanta, and Dr. Paul Richardson from the Dana-Farber Cancer Institute.

in Boston. We're here today to talk about myeloma, and as in all of our programs, we will be discussing the use of agents that are not approved. So please refer to prescribing information for specific information for each product. Here's where we're heading. We're going to start out just chatting a little bit about what happened at ASCO, and then we're going to go back and forth between presentations and showing you some questions from a survey.

that we did of general medical oncologists. We asked 50 general medical oncologists, what would you like to ask the faculty during this myeloma program? I went through all these, picked out the ones that were most common, and we'll give you some samples.

as we go here today. But before we kind of get started, I just want to take a breath and reflect back on a couple of things that happened outside of myeloma. I'm kind of curious whether you see any analogies to some of the strategies going on within myeloma. And first, in yesterday's plenary session, we saw much-anticipated the first adjuvant trial of immunotherapy of a checkpoint inhibitor with MSI-high disease, in this case, atezolizumab.

showing a significant hazard rate of 0.5 improvement. Didn't have an arm that had immunotherapy alone. A lot of people think that would have been just as well, but at least we finally have a trial. showing that in this specific population. Last night in our GYN meeting, we actually had a case presented of a patient with a poly mutant disease, even more sensitive to immunotherapy. The patient had been on checkpoint inhibitors for five years.

So targeted therapy for immunotherapy. And then again, in the breast cancer session, we saw the Serena 6 trial. It was in the New York Times this morning. Basically, patients on first-line therapy for metastatic disease were monitored. for the development of a mutation resistance, ESR1 mutations, and those patients, even though they were stable clinically, were treated with a different form of hormonal therapy.

a CERD, and again, impressive results, 0.44 hazard rates. Seems like it's not pretty likely. to go into practice. And finally this morning, a presentation we were really looking forward to in breast cancer. And believe me, tonight with Hope Rugo and Al Burstein, your colleague at Dana-Farber. Paul, I guarantee you we'll be talking a lot about Destiny Breast 09, the use of an antibody drug conjugate in first-line therapy, trastuzumab, duroxacan.

Compared to what has been the standard chemotherapy with protuzumab, trastuzumab, hazard rate 0.56, no big surprise. Really, this drug clearly works well. Downside, of course, with this, you see interstitial lung disease. They actually had two grade five events out of 383 patients. But again, antibody drug conjugates and first-line therapy. Even in hematologic cancers, we see that now with diffuse large B-cell lymphoma.

polituzumab, our chip. We see it in urethily bladder cancer and fortumab, vidotin, and pembrolizumab. And I guess my question to you is when we start talking about bilanumab, you think the day might come that ADCs will be part of... first-line therapy, and we're going to get into that today. But just to take a step back, Ajay, I know these are all solid tumors, but I'm curious what your perspective is on some of the strategies that we saw here.

Thanks, Dil. The best analogy that I can think about is the risk stratification. So if you think about where the mismatch repair... the cancers were treated quite differently with significant improvement. So this, I would say, I would put the analogy as a high-risk cancer of the standard risk patients.

how to move them, how to separate them, and try to treat them with intensive therapy or less intensive therapy depending on the risk. So that's the best analogy that I can think of. And there are more trials that are developed in this space exactly asking that specific question. Paul, any thoughts?

Well, yeah, I absolutely agree with Achai that this tailored approach that's risk adapted makes great sense. And we'll touch on that a little bit more in a moment, I think. But I wanted to pivot back to your point about antibody drug conjugates, Neil. I think you're absolutely right. you know, belantamab, mafodotin, you know,

Cut to the chase. Bella is back. And I want to show you today and our audience just how important we think the data is that we're going to share with you, pointing to the fact that we need kind of all hands to the pumps, you know, whilst we've had great success with bispecifics and cartons. We've recognized immune exhaustion. We've recognized the challenges of real world practice and true off the shelf capability.

And belantumab, mafidotin, not a moment too late or too soon, in my opinion, has shown real benefit in combination. And we'll touch on that again. So to see the breast cancer story emerging so positively resonates certainly with me. And actually, now that I think about it, at this ASCO, we also saw first-line ADC and triple-negative breast cancer, the antibody drug conjugate to trope 2, sasuzumab, govitecan. Again, probably going to become first-line therapy for triple negative disease.

So ADCs are on their way. All right, so again, we're going to really focus on relapse disease, but we had to bring up the issue of upfront treatment. Again, this is the survey that we just completed over the last couple weeks. I thought this was kind of interesting comment. Myeloma is so complicated now. Well, to me, it's always been complicated, but I have to agree. There's no way you can cover it in an hour, and that's why we're just picking out a few things to talk about tonight.

So I guess one thing about upfront treatment, Jay, is should all patients be getting anti-CD38 antibodies? You know, now we have two. At this ASCO meeting, we saw data. on the on-body sub-cue device for ESA. It's going to be really interesting to see how that evolves. Are there situations where you don't use either ESA or DARA up front or J, and any comments about what's going to happen once ESA's sub-Q?

Yeah, this is a great question. So we had seen over the last 10 years, Neil, so what we had seen was the improvement in the response rates, the depth of response rates with the triplets. started with the doublets, the triplets, and the quadruplets. The quadruplets giving us such good depths of responses that we started to not only use in the transplant eligible patients, now we started to use in the transplant ineligible patient population.

So now, which is the best CD38 antibody to use in this specific setting? We have data for both the acetuximab as well as daratumumab. And just to give a flavor of what can be expected from a PFS standpoint, not even an overall survival standpoint, this is a disease where we're used to seeing three-year survival rates.

Now, just with a quadruplet in the Perseus trial, the expected median PFS is close to 15 years. So the whole landscape has changed. So in my opinion, unless you find a strong contraindication. Everybody should get a CD38 antibody in the upfront setting, a quadruplet, if the patient can get. Yes, I would agree, Neil.

Sorry. Paul, another thing I want to ask you about, because we're going to kind of jump around here and just get your take on some of these things, of course, was the big diratumumab presentation at the last ASH meeting on smoldering myeloma. A lot of questions about that, Paul. We could spend 15 minutes or an hour even talking about smoldering disease. But bottom line... Are the data compelling enough for you to want to use daratumab or any other therapy for smoldering disease?

Well, I think in high risk for sure. And I just want to echo a point that Aceh made so nicely about the quadruplets. I mean, they were transformative in terms of PFS, but in the transplant ineligible population, those who have traditionally been a very much more challenging population,

quadruplets generate median PFSs, you know, approaching eight to nine to 10 years with just the quads alone. And that, I think, in itself is a remarkable milestone. And I think in the smoldering space, to have the ability to deploy daratumumab safely in a high-risk population and see survival benefit in the Aquila study, I think is really encouraging. And so I think we've entered a whole new era of antibody-driven strategies where, in particular, targeting CD30.

either with daratumab or izotoximab is showing real benefit. And one side point here to Ajay's point earlier about targeted or tailored therapy. we're really seeing that in the 1Q-amplified population, which is up to 40% of newly diagnosed myeloma, there may be some differences in which there may be more benefit from izotuximab compared to daratumumab, although...

Those differences do not appear to be marked, so we want to be careful. But I do think we've got a really exciting new time with both CD38 antibodies available to us. So, LJ, any comments about smoldering disease? You know, we've seen trials in lenalidomide. We've seen RVD, and now we're seeing DARA.

Right now, in what situations do you want to employ therapy, if any, and which therapy? Neil, the biggest challenge is you're asking the right question. So who is the right person that needs the treatment? Yes, all the interventions that we had seen have helped to the hazard ratios of 0.29 with the lenalidomide-based therapies and 0.5 with daratumab.

So there is no doubt that there's an intervention with a primary endpoint of delaying the progression. The interventions are helpful. The biggest challenge comes here to identify the right patient that needed to be treated with. So the Mayo Clinic 220 risk stratification is probably where we can go with. We can all agree that if somebody has two or higher risk stratifiers.

in terms of paraproton of greater than two gram per deciliter, free light chain ratio of greater than 20, and a bone marrow plasma cell percentage of greater than 20. If somebody has all three or more than two, their risk of progression is within the two-year timeframe. The only caveat I would say is in evolving paraprotein, if you're seeing these, somebody hits these criteria and they're evolving, those are the patients that in my case,

clinical practice, I would certainly start to act on. Yeah, completely agree. And which therapy, RJ? So daratumumab, it's a finite period of therapy for three years or 39 cycles, has shown, as Paul was saying, an overall survival advantage where 92% of the patients were alive at the six-year mark. compared to 86% of the observation arm. It's almost a 7% survival improvement that you're seeing with a very, very short window of six years.

So I'll be favoring daratumab. And the second option is lenalidomide. And with lenalidomide, the best benefit from the ECOG study as well as acquired X trial is the therapy given within the first two years. So if I'm using it, I'm not going to use it indefinitely. I'm only going to use it for two years.

So I'm going to move on now, and we're going to have Paul present some slides and data. And Paul, you know, I was just kind of reflecting back when I first started working with you, you were part of the group bringing RVD to practice. And wow, that was such a gigantic change. for this disease. Then we add the anti-CD38. Antibodies come along, another big bump. Then we add CAR-T, another exciting bump. Then bispecific. So everybody's getting more and more things on board, more and more confused.

And then all of a sudden, ADCs show up again, antibody drug conjugates. Well, I'm curious where you see that fitting in. But let's just talk about the data right now. So take it away, Paul. Thank you, Neil. So really a pleasure to be here, everyone. And I just wanted to echo the point that Neil made so nicely and echoed also by Ajay.

Lots of options. And I'm going to focus on belantimab, mafidotin, and belantimab as antibody drug conjugates, or the naked antibody in the case of belantimab. And then, if time allows, a pivot to the cell mod story. I think what's very interesting... is that as a BCMA-targeted antibody drug conjugate, belantamab mafidotin is our first in class and the first improved in 2020. Unfortunately, the DREAM3 study had some kinks in it, and as a result of that, whilst it showed an encouraging...

DOR, which we'll come to in a minute, it didn't meet its primary endpoint of PFS. But I want to bring your attention to some of the mechanisms of action of the antibody drug conjugates. The fundamental message is they're profoundly immunogenic. And what they generate is a highly...

targeted approach driven by the BCMA target to deliver a cytotoxic warhead. And in that regard, there's important advantages over bispecifics and CAR-Ts, at least in theory, not least of which based upon immune exhaustion. Now, in that context...

The initial approval was led by Saga, Sagalonio, and it was a privilege to be part of this trial, the DREAM2 trial, in which we were able to establish from monotherapy, essentially, of balantamab mafidotin in a heavily pretreated population, a highly considered... consistent response rate, a decent DOR, and a PFS that was adequate to get the accelerated approval category filled. We also did a lyphalized presentation cohort, small number of patients here, but again, response...

signal very respectable at 52% and encouraging PFS as well as DOR and median overall survival. And real world data certainly has matched that. Now, when the first study of the randomized setting of DREAM3 came in, comparing bilantimab mafidotin to pomalidomide and dexamethasone as third-line therapy, the challenge was that the PFS, whilst different and in favor of bilantimab, did not achieve this level of significance.

that was needed. But I would bring your attention to the DOR of 77% one year for those who responded versus just 48% for the control arm. So that in a way was the signal.

And then when you started to combine bolantimab, mafidotin, with other drugs, such as in this case, in the DREAM6 study, lenalidomide and dexamethasone, and then most importantly, in a cohort, which I was part of, which was the combination of bolantimab combined with bortezomib, I just want to bring your... attention to the response rate at 78% in this study, which I think was an important clue as to what was coming.

So Dream7 arrived and was published last year. I want to especially acknowledge the investigators led by Dr. Vania Hungria. And what you can see here is a striking PFS advantage against a daratumumab-based control arm. clearly an active control compared to belantumab VD. And there you can see a hazard ratio in favor of the triplet with the antibody drug conjugate of 0.41.

And I think this is incredibly important because not only did we see this PFS benefit, but with an updated analysis that Vania presented at ASH in December last year, you see a striking survival advantage with overall survival generating a hazard ratio. 0.58 in favor of belantamab, mafidotin combined with bortezomib and dexamethasone over the Darabase combination. And again, this immunogenic signal clearly being the key part. Now, excuse me, not to be outdone, but...

MRD was a very important part of these trials. And I just want to emphasize striking benefits not only in response rate, but also in MRD negativity in favor of the belantumab-containing combinations with a manageable side effect profile. Now, the ocular toxicities are...

real, but very, very importantly, the rest of the toxicity is exquisitely manageable, as is indeed the ocular toxicity, which we'll come to in a minute. And then if you looked at PFS in patients by MRD status, there was a very consistent signal.

And if you achieved CR with MRD negativity with bilantumab-based therapy, the median PFS was over two years compared to one year for control, which I think is very important. And at this meeting, Mary V has presented some very nice data looking at high risk, which again gets...

to Achai's point earlier. If you look in a risk stratified way, you can see here that the balantamab-maphadotin combination combined with bortezomib-dexamethamum was exquisitely active in high-risk disease with a median PFS of 33 months seen.

this subset analysis, which I think was particularly important. Similarly, you touched on upfront therapies or early use, just worth mentioning that Belantimab is moving earlier. And in that context, the combination of Bella RBD in early relapse is very active.

In that same context, Dream 8, which was led by Thanos Timopoulos and others, Combining Belantimab with POM-DEX compared to POM-VD as an adequate control showed a striking hazard ratio in favor of the Belantimab-POM-DEX combo with a hazard ratio of 0.52.

This was very interesting, I think, because if you looked then at MRD, really the differences were quite remarkable. MRD negativity for Pomvaldex, which is an active control, well-tolerated generally and certainly widely used, the MRD negative rate was just 5%. In contrast, the MRD negative rate for the use of Belantamab combined with POMDEX was striking, in my opinion, at 32%. And again, a manageable tolerability profile. What about high risk?

year, this was really, I think, very interesting. In the high-risk group, the medium progression-free survival of the bolantimab-containing combination was 21 months compared to just nine months for the control. So again, a striking difference in favor of the volantimab-containing combination. And outcomes by MRD status quo, no surprises here, but if you achieve median, sorry, MRD negativity,

Median progression-free survival has not been reached, and I think that's really very exciting and points to the value of these platforms. This obviously all resonates on the Algonquin trial led by Suzanne Trudell, which has shown a median PFS of 22 months

with a median overall survival approaching three years. And then a couple of other last quick points. Belantimab combined with other drugs is proving very exciting and active with a highly consistent signal. And then finally, at this ASCO meeting, there's been the Belantimab naked. antibody experience. No corneal events of note. Very interestingly, a response rate pointing to the value of this going up front, or rather being used in combination.

Now, what about polantumab and ocular toxicity? Well, the important news here is this has proven much more manageable than was initially thought of. And to cut to the chase, essentially from a patient standpoint with dose. and schedule change, this becomes much more manageable and much less of an issue. And at EHA, our team, which is led by Evangelos Turpos, will be presenting a clinical management of balantamab mafodotin-associated ocular vents with practical guidance from an expert.

experience program. Now in the last couple of minutes, I want to finish by touching on the cell mods.

I think it's important to remind everyone that targeting Cereblon, of course, has been the platform for the success of immunomodulatory treatment, and protein degradation underpins this process. Mezigtamide, which has been a privilege to be part of the investigative team for, together with also ibertamide, are in a different class, in my opinion, to the classic immunomodulatory drugs. They're much more potent. And in this regard, they're able to degrade substrate.

much more actively and strikingly. And they closed the cerebral E3 ligase complex dramatically with iberdamide doing so by 50%, mesignamide by 100%, and pomalidomide in contrast by 20%. Now, this effect... results in dramatic properties pharmacodynamically. And this is summarized here. The other thing that's really important to understand is there's an intriguing observation that there's a substantially decreased risk of second malignancy from the

cell mod compounds from both iberdamide and mozigtamide in contrast to lenalidomide. So with this striking panel of preclinical activities so demonstrated by a whole series of elegant experiments... Cancellating this to the clinic has been really a joy. Mesictamide first, this has just been shown as an oral combination.

to be highly active in heavily pretreated disease with a response rate of 41% and an overall response rate in BCMA-treated patients of 50%, just for the oral combination of mesictamide and dex. And a striking example of this is my patient. here.

who unfortunately was much challenged by extramedullary disease. And as you can see, in the context of four months of mesictamide and dexamethasone therapy, he enjoyed a complete response to treatment. And this particular drug is actually designed to target EMD. The excitement really...

grows when you combine mesictamide with other drugs, be they proteasome inhibitors or in that regard, both portezomib and carfilzomib, response rates are going as high as 80%. And if you combine mesictamide with monoclonal antibodies, the story is even... or as exciting, with response rates of 75% with DARA, somewhat lower for elotuzumab in DARA-exposed patients. And then finally, when you combine mesictamide with other novel agents, such as tazimetastat and indeed trimetinib,

even in very heavily pre-treated patients in whom, unfortunately, BCMA-targeted approaches have failed them, including CAR-T. We're seeing really encouraging results, and it's been a privilege to be part of this study with Luciano Costa as our PI, with response rates of no less... than 75% in these heavily pretreated patients.

Now, what about ibertamide? Ibertamide has been really equally a pleasure to work with. This work led by Saga. And as you can see, the combination of ibertamide first with dexamethasone and then with other drugs has been remarkable. And I just bring your attention to the combination of ibertamide.

combined with bortezomib and dexamethasone at 100%. And then when you put into earlier relapse these combinations, they've performed exceptionally well. And with that in mind, there are a number of studies that are showing other combinations are equally promising for this highly convenient. all oral approach.

And at the ASCO meeting, there's been a very nice presentation from Dr. Le Shokin from the Memorial Sloan Kettering Cancer Center team of ALRA combined with ibertamide in relapsed refractory disease, so-called magnetism MM30 study, which is getting underway. excited to see that.

The phase three studies of cell mods in relapse refractory myeloma include successor one and successor two. It's been great to see Excalibur fully enroll. That's the ibertamide study. And it's also great to see successor one and successor two doing extremely well with successor two near to. completing its enrollment, and success of one not far behind. So in conclusion, I really wanted to emphasize that we think Belantamab is back.

Well, antimemafidotin is really, I think, an important potential treatment option for our relapsed patients. And obviously, we're looking forward to regulatory approval to really establish its value. I think in the same context, the cell mods have real importance and real world value as oral agents combined with other backbone agents to improve outcome. And in that context, we have an increasingly busy novel therapeutic landscape.

But I would argue that we need all hands to the pumps. In immune-exhausted older patients, for example, these agents are invaluable. Thank you very much for your attention. Thank you, Neil. So, wow. That was amazing to go through that, and so understandable. I was just flashing on the fact that a medical oncologist contacted us and said, I listen to your podcast every day on the way to work, half an hour back.

But he listens at double speed. And I was just imagining him listening to that last 10 minutes at double speed. It was hard enough for my brain to comprehend it in real speed. But it was really a great review. Now let's talk about... What are some of the questions that we've been getting about these entities? But also, I wanted to ask you, Ajay, about this interesting trial, the DREAM-10 study.

looking at Belantimab with Lend-X versus Dara Lend-X. You know, when Paul presented the fact that, you know, when comparing Belantimab to Dara, you know, one of the best, if not the best, That's the active agent of myeloma hazard rate 0.5 or lower. You know, amazing. Any thoughts about this trial? And if it's positive, AJ, what are we going to do about it? Neil, this is a beautiful study. The way that I put this is take the analogy from the dream seven that Paul presented.

So data plus VD, I always am a sucker for these control arms. So data plus VD is a beautiful control arm where the median PFS was 16 to 17 months. How did the control arm perform? compared to what was expected of the control arm. That control arm had 14 months, which is beautiful where you see a three-time improvement in the PFS. with Belantumab plus Bortezomib index. So let's bring the analogy to the upfront setting. DRD, Datatumab-Lanindex, from the Maya trial.

In overall survival beyond the seven to eight year mark for transplant and eligible patients, you have to understand this specific study. 40% of the patients in this specific study were above the age of 80. So not only that they're reaching their life expectancy, they've done extremely well. In that specific patient population, if you're exchanging...

Belantumab for daratumumab, what would be the benefit that one could expect in the frontline setting? The expected median overall survival in these patients were in their 80s, probably in the range of 12 years is what I heard. So looking forward to see how this pans out with a planned hazard ratio of 0.7, I guess. So let's talk a little bit about some of the questions we're getting from oncologists about...

Belantimab, what clinical scenario? Like, Paul, right now, if Belantimab were freely available to you, in what situations would you use it? What combination or combinations would you be thinking about? Well, I think I'm going to bounce off Archer here and just say I...

Couldn't agree more about this whole idea of, you know, you've got DARA-RD, ALA-MAYA up front. Then, obviously, if someone relapses in that setting, and that may be several years, hopefully, in an older transplant-ineligible patient based on the data, then think BELA-VD. you know, a perfect safe, not cardiovascularly toxic, well, generally well tolerated strategy could be ideal there, or for that matter, Bella Pondex.

recognizing that in older patients, sometimes the IMIDs aren't delivering in quite the same way as one might expect in their younger counterparts. That being said, you've got both choices to consider for a patient. And you can imagine here the value. of Belantamab.

Because if you can generate three or four years of disease control and you haven't actually hospitalized the patient, you've treated them with truly outpatient strategies throughout. For an older patient, you're looking at a seven to ten year horizon. two lines of therapy so this is kind of a lovely slide actually because you're really asking I think the key questions

The other question is, how do you how do you dose Bella? Well, I think all of us are aware now that essentially, you know, every four to six. even to eight to 12 week dosing works in individual patients. And you can start up front with a slightly more intensive schedule in my experience and then drop back and you preserve response and you manage the ocular toxicity very favorably. And what's so exciting, Neil,

is that we don't see CRS. We don't see significant infections. And actually, in my own practice, I frankly have never hospitalized a patient from a bolantimab complication. And every patient I've treated, and it's now... many over the years of dream one dream two and beyond i have never seen ocular toxicity not prove reversible so i think these are all incredibly important points to share with our community partners

So, Jay, any comments, again, about where, you know, again, if you had it right now, could use it any way you want, where it would fit in? And also, in addition to Paul's scenario of the 80-year-old, what about the younger patient who would be eligible for CAR-T? specifics. Where do you see Blantamab fitting in there? Absolutely. This is an evolving field. What we've seen here is the benefit of the combinations.

So before I say who I would be using and how I would be using this patient, the Bella Combozen, I would not be using it as a single agent.

A single agent BELA response rate is in the range of around 30%. You get a median PFS of close to four months. Not what I would be looking forward for. But if you start to combine with a... amide or a PI, even at a lower dose, and extend the interval between the dosings of Bela, that would be the most ideal scenario, providing a structure of how this should be given in the long run.

I have an investigator-initiated trial using Belantimab in the high-risk patients in the maintenance setting. Where we are using is, we gave it every two months for the first two doses. then changed it to, it is 1.9 milligram per meter squared, then changed it to every three months. So literally the patient is coming to my clinic four times in a year, if it's given every three months. Ocular toxicities are minimal.

And none of the patients of the first 30 patients that we, you know, 28 patients that we have accrued. So there is zero progressions in these high-risk patients with Bella and Palm Index maintenance. So this is a highly active combo. And this could be extended and still be able to get that benefit. Always, always combine it with a partner rather than giving it as a single agent.

Now coming to how to use this in a younger patient population, the higher patient population, where we saw the significant benefit, both in the DREAM 7 and DREAM 8. where the high-risk patient population got benefited significantly compared to the standard of care arm. So... If I have to choose a specific regimen and a specific patient population and a younger patient population, those are the ones I would be certainly choosing.

So, Paul, we see here in the Dream 10 study, you know, Bella versus anti-CD38 or daratumab in this situation. You already have the quadruple therapy. What about adding it? Quintuplet. Right. And that's a great question and a fascinating one. The question would be sequencing and also that allowing to even further reduce your ocular tox because essentially you're sandwiching or you're syncopating with a CD38. I think at the same time as thinking of that.

I think we also have to recognize Ache's point about high risk and its use in maintenance, for example. So I think those are all very interesting questions. Personally, I think that the entity of immune exhaustion must not be underestimated. And what I'm impressed by...

is that belantumab doesn't appear to contribute to that. We have several lines of evidence for that coming from the trials. And I think that's very important, particularly in our older patients. But to your point, Neil, earlier, may also have real value as we think of sequence in our younger patients.

patients. So you don't burn a bridge for a bispecific, or you don't necessarily burn a bridge for a CAR T at a later date, where you may have some legitimate concerns that bringing something as powerful as Siltacel too early into the game for a particular patient might carry.

with it unacceptable risk given what we know about the toxicities. You know, bilantimab in contrast may not bring that to the same issue to the table. So I think it just opens the door to further tailoring therapy for our patients, Neil. And I think I really... like the way I tried.

pivoted not just to older patients, which has kind of been my focus, but also to younger patients in whom one might think of this. I personally have a patient in my practice who absolutely did not want to be hospitalized. He runs his own business. He's an electrician, younger man. And he's had almost four years now of benefit from Belantimab and done remarkably well.

Yeah, the idea of maintenance sounds really interesting. Yeah, mentioning four years, we did a series a couple years ago where I did some video interviews. with patients with myeloma. And I actually interviewed a patient who had been on Belantamab for four years, just about the same time it got pulled off the market, which was kind of like, wow, why are we doing this? And I guess now...

Now we realize it's not an issue. So, AJ, I don't have to tell you that the number one question we got about belantamab, and in addition... to how to use it or where it's going to fit in is the issue of ocular toxicity. It's something that... It's starting to creep into oncology. We're about to do a CME program on ophthalmic issues in oncology because you see this throughout oncology. ADCs, erdofitinib in bladder cancer, so many different ADCs. Now.

but a lot of concerns about it, how are patients going to react to it. This one doc, his wife is an ophthalmologist. So, you know, there's lots of questions or challenges. Can you use an optometrist? of an ophthalmologist. Jay, can you give us a little granularity how this plays out? And also this delay of giving between doses seems like it is very effective and very patient-friendly. Absolutely.

We have to understand why is there a concern at the ophthalmic adverse event to be of a significant concern when grade 3 infections are so common with other biospecific antibodies. Eye is a very sensitive organ. everybody gets affected, and we don't want to make anyone lose their sight. And what the green trials have shown is...

All the toxicities are reversible. There's not even a single patient that lost his side because of Belanclin. I want to emphasize this very clearly before we talk about the strategies. So what is the toxicity in the eye? So it's all keratopathy. So it is all about how the stem cells migrate and how belantimab holds off and leads to the corneal ulceration as the worst side effect that anything can be possible.

So if you divide them into their gradings, so grade four is the worst, and again, grade one is something that people don't even feel, but yes, they can see it on a cardinal exam. So now... How do we dose them? So when you're giving them every three weeks, absolutely the grade three keratopathy was seen in 80% of the patients. So we know that's not the dose that we need to give. That's not the schedule that we need to give. That's where the extended interval comes into play.

So how long can the interval be? So after the first two doses, everybody has this toxicity developed after the first two doses. So go with the first two doses, then extend the interval to even two months because patients who are responding continue to have... a good response. That's what Paul was talking about, the duration of response earlier in 70% of the patients, even in DREAM3. So overall, an optimist can do this.

And the key here is the toxicity prior to the next dosing has to come down to less than grade one before you dose it. Otherwise, you're okay to skip off the dosing and responses are preserved even if you skip the dosing. So very interesting drug. And the more that you use it, the more that you get comfortable with. And optometrists can exactly do this. And there's a scoring grade sheet or a grading sheet of what. what causes the toxicity and when the toxicity needs to go down.

So, Paul, we have got a bunch of questions about cell mods in particular is when are we going to actually have them available? Because we've been hearing about this for a long time. You went through the data very eloquently, but can you kind of summarize the bottom line? of, you know, sort of what the characteristics are of ibertamide versus mesignamide versus lenalidomide and pomalidomide and where you see in particular ibertamide and mesignamide fitting in clinically.

Yeah, super question. They are distinct, in my opinion. I mean, obviously, both classes of drugs modulate the cerebral and E3 ligase complex. Immunomodulatory drugs or IMIDs are far less active in this space and have a different molecular structure. And so I think it's important to share that with everyone. The secret sauce lies in this closing of the cerebral and E3 ligase complex. If you close it, 50%...

or greater, which ibertamide does at 50, mosigdomide does at 100%, the targeted degradation of key transcription factors is stratospherically greater. And so as a result of that, basically these become degraders. in the classic sense. And so mesictamide is the most potent and in the relapsed refractory setting is also designed to penetrate extra medullary disease, which was the case I showed of my patient had a really quite miraculous response. And the second point is that they are very well

tolerated and iberdamide shines in that regard so i see personally iberdamide moving early or earlier in disease and up front is obviously where we're looking to really excitingly study it and as part of maintenance because it's so well tolerated and too

mesictamide becomes the new kind of oral agent of choice in relapse where it partners so powerfully and with other classes of drug. Finally, and this is very important for iberdemide and to perhaps a lesser extent mesictamide, The same oncogenic or second cancer signal that is generated uniquely by lenalidomide...

valuable as that drug is, is not seen with either iberdamide or mesignamide. So they really raise the promise of no second cancer risk, of more favorable tolerability profile, generally speaking, and much greater potency.

So we're going to move on now and let Ajay talk about more issues in the relapse refractory, mainly about, of course, what we get most questions about, bispecifics in CAR-T. And we've done two-hour programs just on bispecifics in myeloma, so this is just a little tasting menu. But, Jay, let's talk about some of the key data sets. Thanks, Steve, for having me.

So I'll be talking all about the cellular therapies, the CARTs that are existing out there for myeloma, and who are the right patients that you can identify for the specific construct. And we'll be talking about the... the bispecific antibodies and where we have started and what are the key differences and where exactly we're heading. So the biggest question here that there were some of these abstracts that were presented at ASCO talking about

What are the key differences in terms of Idasil versus Siltasil? So from the CARMA-1 trial, Idasil was approved based on the median PFS of close to nine months. From the CAR-2-2 trial, the Siltasil was approved based on... a median PFS of close to three years. So quite different patient populations that you can see. The real world data sets are the ones that can help us to understand.

Is this the representative patient population that one can see? And what are the indications and how to use them in the different indications in this setting? So in this specific analysis,

They used the Trinitex global real-world data platform where they identified a total of 485 patients that received the Idicel and 392 patients that received the Siltacel. They did a propensity matching for... the demographics, the patient characteristics, the clinical characteristics, the disease characteristics, to identify an equal group of patients with 252 patients in each of these groups.

So at a median follow-up of close to 14 months for the Idicel and 8.5 months for CeltaCel, as CeltaCel was approved at a later date, what the... looked for was the primary endpoint of time to next treatment as well as the overall survival. You have to understand the granularity with these real data sets or the real world data sets that you can find the PFS.

as you delineate in a clinical trial. So here what they saw was that time-to-next treatment was favoring cell-to-cell, just as expected with a hazard ratio of 0.6. And the overall survival was not reached. At the two years, it was 77% for IDC versus 73% versus cell to cell. There's a lot of things that one can see here. Yes, cell to cell is able to deliver that benefit in the long run.

in terms of delaying the treatment, the time to next treatment, but the overall survival has not been proven based on this real-world data set. There are other real-world data sets that one can see. This is a real-world data set based on those patients that had seen four prior lines of therapy. And this was the academic real-world data consortium led by Doris Hansen, where she... gotten close to 650 patients that received the IIT patient population.

what you see is the infused patient population is close to 550 patients. There is still an attrition rate of 9%, which clearly tells how to identify that specific patient population. who would get benefited from a CAR T? So what you see here on the far lower right corner is the... patients are the differences between both these constructs. Severe CRS greater than grade 2 is very common with cell to cell. Delayed neurotoxicity, the odds ratio is almost 20 times.

infection is higher with cell to cell. So the way that I look at this is the PFS, as we heard that... The PFS is significantly favoring Siltacel, but there is that specific patient population, maybe now older patient population, where you don't want to take these risks. They're the perfect candidates for Siltacel.

So again, PFS and overall survival were favoring the cell-to-cell. Yes, you get the bang for the buck, but the risk is higher as well. Moving on to the CARMA-3 and the CARTITUDE-4 trials, where... IdaCell and CeltaCell were evaluated in the early relapse setting. This is wonderful data that is presented by Surbisadana for the different subsets of the CARTITUDE-4 trial, including the high-risk patients. First, let me look at the CARMA-3 trial. So this is a...

patient population randomized to relapse patient population of more than four prior lines of therapy, two to four prior lines of therapy, randomized to standard of care versus CAR T. It's a two to one randomization. There is a crossover on this specific one. survival may not be the right endpoint here. Coming to the cartridge at four, no crossover and cell-to-cell versus data PD or...

PVD among patients with one to three prior lines of therapy. These patients were, again, early lines of therapy. And what you see with CARMA-3 is a PFS benefit of 13.3 months versus 4.4 months. for, the hazardous ratio was 0.29, favoring the cell-to-cell at a large follow-up of almost three years. And at the three-year mark, 60% of the patients continue to be in remission.

So when you look at the long-term outcomes, the overall survival is being favored with Siltacel versus the standard of Geram. When you start to look at when Siltacel has such good... benefit even in the late relapse setting. You saw the data presented by Pete Voorhees showing that those patients on cartitude 1. the overall survival was five years for them. So think about even 10 years ago, median overall survival is not even five years. In this patient population,

Overall survival from the time of cardiac receipt is five years, and a third of the patients still continue to remain in remission. Probably that tail, who we can call as a cure, if the patients continue to do that over the long run. So what this also showed was in this specific analysis by Maria Mateos showing that If you give the CAR T at an earlier stage, as well as in CAR Titude 4 versus CAR Titude 1, those are the curves showing the benefit as an earlier line of therapy.

Coming to what Sudhbi was presenting was, how did the benefit extend between the standard of care arm versus the selfless arm? And as you can see, the standard of care arm versus high risk in every subset that is seen, the benefit favored. the cell to cell. So in the extramedullary patient population, the median PFS was 13 months versus four months with a standard of care arm.

If you look at the lines of therapy, I'd like for you to look at the comparator arm. The standard of care arm had a median PFS of 17 months for one prior line of therapy. 12 months for two prylans of therapy, eight months for three prylans of therapy. This is exactly what I would expect. And none of these median PFS was reached for the arm that received the cell-to-cell. So extremely good data. favoring cell to cell in the early lines of therapy.

Now, coming to the biospecific antibodies, we have two biospecifics targeting BCMA, teclismab, and elanatomab. Both of them were approved based on the Majestic 1 and the Magnetism 3 studies. These are single-arm studies where the approval is based on... The EMA and the FDA differ, and these approvals for three prior lines of therapy in Europe and four prior lines of therapy in the U.S., and this is what, again, accelerated approval based on.

Phase II study, based on the overall response rates, the confirmator trials are ongoing as we speak. There are a few key differences in this. Magnetism III study had... So some extremity disease that is higher, which was in 31% of the patients, was in 17% of the patients. Pentadrografractor patients were higher in the Magnetism-3 trial. And the studies had shown an overall response rate of 60%.

as a single agent with both these constructs. The median PFS for teclistimab was 11.5 months. Median PFS for elternatomib was 17.2 months. And what was presented here at ASCO is... If you look at the magnetism 3 study patient population that were enrolled in the U.S., there are 40% of the patients that were enrolled in the U.S. And look at the median PFS. This was 27 months that was presented, and the median overall survival was 43 months.

our patient population, and this likely reflects the availability of treatments post-progression, and that's probably why you're seeing such improved benefits. Coming to you, the TALCADMAP trial, the Monumental I trial, there is an update at ASCO. For those of you that are aware, the Monumental I trial had three cohorts.

0.4 mg per kg given weekly, 0.8 mg per kg given every other week, as well as a TCR prior, a T-cell redirecting therapy exposed group at 0.4 mg or 0.8 mg. So the median follow-up of more... than 30 months was what was presented here. And what you see is impressive. Across the board, the median PFS was 7.5 versus 11.2 versus 7.7 months, and the 36-month overall survival rates were significantly higher across all these three groups.

The most common adverse events that one could see are the CRS of all grades were similar, 79% versus 72.4%. This is two weekly versus two other week. So what I want to stress on in the last minute is the GPR CFID-associated adverse events. So there are four different adverse events that one can think about.

taste-related, skin-related, nail-related, and rash-related. And these are all based on the expression of GPRC5D on these specific surfaces. These are on-target, off-design side effects as I put in. What I'd like to... show you is the rates of discontinuation due to any of these adverse events. It is almost 0% across the group. So if only one can know how to give these drugs safely, you can derive all the benefit from this specific agent.

There is one specific signal that was seen. This was ataxia that was seen in one patient in the monumental one. And likely there is some cerebellar expression of GPRC5D which could explain this ataxia. That probably is why you see that adverse event. There is no other new deaths or any AEs related to Telcatamab.

Wow, you both are great presenters and so much information in a short period of time. Let's take a look at some of the questions we got from oncologists about QAR-T and bispecifics. One, actually, we heard this. We did a program on Hodgkin. lymphoma on Saturday night, and of course there CAR-T bisphysics also, but the issue of access to tertiary centers, particularly for CAR-T therapy. Paul, any comments about whether bispecifics can be at some point administered by...

community-based oncologist. And also, Paul, you know, we've kind of gone back and forth with CAR-T. Initially, there was a lot of excitement. We kind of had just seen the diffuse large B-cell data looking like we're seeing cures with CAR-T.

hoping in the beginning that that was what we were going to see in myeloma. Then it seemed that from my point of view, listening to you all, then there was kind of some disappointment for a while. Now I'm hearing more talk about excitement, particularly with Siltacel coming along and even... the cure. So, Paul, any comment about the challenge of accessing CAR-T therapy in tertiary centers in terms of access? And also, do you think we're moving in the direction of cure with CAR-T?

Well, fabulous questions. I think access is actually key and it's a major challenge. I think this is where... Bispecifics obviously offer a very important platform that has a greater ability to deploy in the community setting, in my opinion. I think very important is where the antibody drug conjugate space also has real value because it truly is off the shelf.

shelf and community-based. I do think CAR T, and certainly speaking to my own experience with my own patients, has been miraculous in some patients and remarkable. Soberingly, however, in my own real-world practice, I've encountered substantial toxicities, and very importantly, late Parkinson's in one patient whom I very sadly lost. So I think one has to be very realistic and say, it's amazing.

Using it earlier, to Achai's point, I think is a very important new direction to go in. But I do think we need to work seriously to reduce toxicities because... The real-world data actually show about a 10% TRM, don't they? In our own group, we had a rash of HLH.

which was lethal in three patients last year. So we've got to be a little bit careful. And I think when we think about CAR-T, the new platforms to me, recognizing the incredible power of Siltacel, the value of IdaCel, to me, some of the newer... CARTIs like ANITA cell are really interesting because at the end of the day, they do appear, at least with the caveats of cross-trial comparisons, to be offering perhaps less toxicity, which I think is so important.

And the flip then, and I think actually did such a nice job of this, you know, looking at the bi-specific space, you know, we're seeing really a much more convenient, much more patient-friendly strategies being developed where you can move to the outpatient setting and not have to hospitalize even.

with step-up dosing and we're doing that on our own program i think what's you have to be careful of though is and especially from my own experience with with biospecivics is as you move into the real world and you treat much sicker patients because your sort of hand is forced still need to be very much aware of the side effects. And to Achai's point earlier, the reality of infections with biospecifix is absolutely there. And we see that as a major challenge.

Conversely, we're seeing great results. So I think excitement, but with a healthy dose of caution around managing side effects. So audience, at the end of the slide deck, we have some papers we pulled out from both. ASCO as well as EHA. I'm not sure we're going to get to them. But OJ, one of the papers that we pulled out was from EHA looking at this other CAR T therapy, ANITA cell, the Imagine studies. Can you talk a little bit about how it differs? from, for example, Siltacel.

Also, your vision of, you know, the pathophysiology of the neurologic issues with siltacel, why you see this Parkinsonian thing, and then what you see with this Anita cell and whether or not, you know, this maybe in the future may be going to replace siltacel. Great question. We're all struggling to understand the exact pathophysiology for the neurological toxicities. How anita cell differs from the construct with cell to cell or ID cell, in fact, is it has a...

less off rate where you're expecting to see the engagement not to be as much. So I don't know whether that is purely the reason for why you see the differential toxicity. where you see lesser rates of neurological toxicity, significantly lesser rates of neurological toxicity compared to the existing ones, but thought to be one of the mechanisms. What makes it a good construct? Number one,

is it should be safe, it should be efficacious for all the given reasons. And comparatively, again, we cannot be doing cross-layer comparisons, but what is existing... out there to what Anita was bringing in. Impressive response rates with impressive safety. That's what makes it a little more appealing so far. But as we... go on to these large randomized phase 3 trials with anita cells that are currently ongoing, we'll uncover more of these toxicities, whether they're real or not.

So, Paul, I don't have to tell you what the most common question we get about this, which is sequencing, and people are eligible for both CAR-T and bispecifics. So what comes first? I was kind of surprised how, you know, the PFS with bispecifics, specific is similar to what you see with CAR-T. So how do you decide what comes first? Of course, CAR-T has the incredible advantage of one and done. But in terms of PFS, how would you compare them? And how do you think about sequencing a different...

Well, I think it boils down to what I consider... efficacy. And efficacy is a function of activity and toxicity. So personally, I'm a big fan of bringing bispecifics earlier. I think that makes great sense to me. I'm a little bit more careful with CAR-T only because I'd love to to see the results of cartitude 6 and cartitude 5 to really inform that decision. But broadly speaking, I think the idea of the immunotherapies coming earlier in the treatment of myeloma makes great sense.

deploying a potentially toxic platform too early. Because at the end of the day, as Achai and I were discussing earlier, a quadruplet can gain you seven, eight, nine years of disease control with minimal toxicity overall. A bispecific can prolong that even further, arguably, again, with manageable toxicity. And where belantumab belongs and all of that, we all will see.

CAR-T can be miraculous and fabulous. However, for a very small subset of patients, we can run into real difficulties that can be lethal. So all of these factors have to be thought through, I think, as we sequence treatments. choices to pick from to tailor treatment for each of our patients.

So, AJ, what are some of the longer-term toxicities that you see, both with CAR-T and then also bispecifics that a community-based general medical oncologist wants to be aware of, particularly the issue of infections, cytopenias? how you approach vaccination, preemptive antibiotics, both CAR-T and bispecifics. I know that's a huge topic, but any specific pearls you want to share with us, Ajay?

Absolutely. I would have very less threshold to start antibiotic in somebody that's receiving bispecific or somebody that has received a CAR-T. If you have to understand the target, the BCMA targeting... agents really completely eliminate, deplete the B cells. So if you can see that functional hypergamma globinemia, that...

Last six months beyond, you stop the BC metodontine by a specific antibody. I would be giving IVIG through the course to minimize any risk of infections for these specific patients. So less threshold to start antibiotics. Putting the patients, increasing the layers of security is how I look at it. Giving IVIG to everyone. Giving neoprogen, which is not a contraindication in any way in all these settings.

And the CAR-T is specifically, if there is an option for a stem cell boost, I'll be proceeding with a stem cell boost after the first six months of time where the patient is not having recovery of their cytokines. So the strategies need to be dynamic. You need to be starting to watch out for. And we have seen some of these viral reactivations, similar to what we've seen in the post-allergenic transplant space, because these are all diesel.

defective patients that likely the viral reactivations tend to happen. So I routinely check for most of these viral reactivations on an ongoing basis and holding off the drug. Not starting the drug when the patient has an active infection is the most key. If there is one take-home point that I would need to convey, that's what I would go with.

So, Ajay and Paul, this hour flew by. It was so interesting. I'm sure we could go on for another hour or so. Be safe, say well, and have a great night. Thanks so much, Ajay. Thanks so much, Paul. Have a great night. pleasure neil thanks everybody thank you very very much