iwMyeloma 2024 | Clinical trial updates in myeloma: managing bone disease, the use of isatuximab, belantamab mafodotin & more

Hi, I’m Ola Landgren, I’m here in Miami at iwMyeloma, the workshop that happens every year. And I’m here with my three esteemed colleagues, and we have had a great discussion yesterday.

My name is Suzanne Lentzch, I’m the director of the Multiple Myeloma Amyloidosis program at Columbia in New York.

Hi, I’m Tom Martin, and I’m the associate chief of hematology oncology and a myeloma physician at UCSF in San Francisco.

Hi, I’m Suzanne Trudel, and I’m a clinician scientist and consultant at Princess Margaret Cancer Centre in Toronto, Canada.

So yesterday we had a whole day of a lot of discussions. And I think the beauty of this meeting is that we are a small group, we share a lot of unpublished data, we share new ideas. So it’s all about collaboration and helping each other, moving the field forward.

So, Suzanne, can you give us a little update on what you were talking about?

Yeah, yesterday I talked about bone disease, and the title of my talk was bisphosphonate, and what’s next? We pretty much know how to treat or how to manage bone disease. I think most of us use bisphosphonates, zoledronic acid, and that’s per the International Myeloma Working Group recommendations from 2021. I would say the best approach. I give a little bit an update, how often we should use bisphosphonates, if we should start treatment in multiple myeloma patients with active bone disease, that the time and duration of the bisphosphonates should be limited, but that we have a good alternative with denosumab. Denosumab is a little bit more costly, but more, I would say convenient to use because we can give it subcutaneously. And especially it , I would say has an advantage in patients with renal failure, so you can also dose this when zoledronic acid is not recommended anymore. But I also tried yesterday to give an update what is next, because, you know, it’s a little bit an old treatment which we should not forget. But I talked about the research we’re doing in bone disease, and we found that the metalloproteinase MMP13 is highly expressed by multiple myeloma cells.

And interestingly, we identified that this metalloproteinase, which is an enzyme, acts also as a protein and we identified the receptor, which was a surprise for us because it’s a checkpoint, PD-1H, PD-1 homolog. PD-1 homolog is expressed on osteoclasts. And we found that MMP13 secreted by multiple myeloma cells binds to PD-1H on osteoclasts, activates those osteoclasts and leads to more bone destructions in vitro but also in mice.

So it’s a very interesting finding, it was unexpected, for two reasons, that, checkpoints, are involved in bone disease, but also I think it opens up, you know, a new approach in the future because PD-1H is also expressed on T-cells, and we have some very preliminary data which we shared that MMP13 secreted by the myeloma cells, binds to PD-1H on T-cells and inhibits those T-cells. So it’s, I would say an interesting axis, you know, on, bone disease and an immune suppressive environment in multiple myeloma. A little bit early for a clinical trial, but we found it very interesting, and we thought, you know, it’s worth to share it.

Yeah I was really impressed. And you do really cool science in the lab, you do a lot of functional work, and that’s really exciting.

I was wondering, these type of alterations with the PD-1, are they reversible as you get rid of the disease? Now we have all these therapies that take patients into MRD negative. For how long do they continue to be skewed these markers in the setting of osteoclasts?

I mean it’s a very interesting question. And what we see more and more is that bone disease doesn’t play the role which it played, you know, 20 years ago where we saw patients with multiple fractures. Why is this? Once we control the multiple myeloma and once we eradicate the multiple myeloma, also we eradicate the bone destructive environment, let’s say this. Without myeloma cells, you don’t produce osteoclast activating factors, and you take away the fuel for the activation of osteoclast. So what I’m talking about is a mechanism. But I would say also an opportunity here to treat bone disease, which we have in the beginning, but also maybe focus on the immune suppressive microenvironment and to go back what could we do? There are PD-1H antibodies. Yeah they were in clinical trials taken off the market, I don’t know exactly why, but maybe we can you know further consider it or liberate this.

Interesting, interesting work.

So Tom, you talked about ways to go after CD38 and you talked about isatuximab. Can you give us a brief update?

Sure. I gave an update on isatuximab, and it’s been a long journey for isatuximab but I focused a little bit on, everybody knows the mechanism of action of the CD38.

I focused more on, you know, isatuximab and really what stands out with the isatuximab and why it was selected for clinical development was its ability to induce apoptosis. And more than ten years ago at UCSF in vitro we combined isatuximab with carfilzomib and saw at least synergy between the two. And so we actually started a clinical trial back then. I presented those results over ten years at this meeting ago, and then that actually led to the IKEMA trial, I showed a little update on the IKEMA trial. That was Isa-Kd versus Kd in the 1 to 3 prior lines of therapy showing, you know, basically a much improved PFS, 36 months to about 19 months with a very high level of MRD negativity. And also that when we broke up the patients in the Isa-Kd arm into functional high-risk because yesterday we talked a lot about high-risk, too. We talked about functional high risk. The patients who had less than 18 months PFS and then went on to get Isa-Kd had a PFS actually of about 26 months. So their second PFS was better than their first PFS, which is pretty amazing actually. And then I actually focused more on the front line therapy because the data for isatuximab is really just coming to fruition with the front line studies. Based on our discussion with the FDA a few days ago and the improvement of MRD as a, you know, potential early accelerated approval endpoint, the GMMG-HD7 trial, which was presented at ASH in 2021, the primary endpoint was MRD negativity after induction after just four cycles. And so basically it was Isa-VRd which showed a MRD negativity rate of just over 50% versus RVD, and the MRD negativity rate was less than 40%. And that was statistically significant. You know, showing a benefit to the quadruplet, obviously. And then back then, three years ago, it wasn’t approved by the FDA because they really wanted PFS. It wasn’t an early accelerated endpoint.

And so we’re still waiting for PFS because as we know, these studies are given us very long PFS, it’s pretty amazing actually. And then I talked also about Isa plus KRd and two trials, the IsKIa trial that was just recently presented and the CONCEPT trial, which was also Isa-KRd and high risk patients, which showed MRD levels that are quite high, almost greater than 70% in those trials after the post-consolidation phase. So really, it’s a great marker. I think the last thing I talked about was that we found in the 1q gain patients that potentially isatuximab, may be a better in my mind, a better CD38 antibody, and there is actually a mechanism behind that. So basically those people that have 1q gain actually also have CD55, a complement inhibitory protein that’s upregulated. Daratumumab works more by complement than isatuximab, and that’s the hypothesis of why Isa might be a better drug to use in the 1q abnormality patients. You know, honestly, we haven’t seen the data much for daratumumab, but for isatuximab, it actually looks quite good in the 1q gain. That was a summary.

Thank you so much. So would you go straight from a daratumumab to isatuximab in your clinic, or would you go to another therapy in between?

Yeah that’s the that’s always the question of CD38. What’s, you know, what’s the strategy and is there a sequencing strategy etc. I do think that no matter if you start with Isa or you start with Dara, and you give it in a regimen, if they were refractory, then you have to wait at least 6 to 12 months before you can go back to a CD38 antibody.

I think we all agree on that kind of strategy. But if you have a break, say they responded really quite well, but then when on maintenance Len or on maintenance Len for 12 months or two years or whatever, then you can use whatever you want. At that point in time, I think they will be sensitive, yoou’ll have CD38 on the cell surface would be fine.

And that’s similar to, I would say, the majority of drugs we use. Right.

So you don’t become completely refractory usually to drugs, it’s a matter of transience, refractoriness. So if you swap to some other therapies you can probably go back. Suzanne. Thank you.

So, Suzanne, you talked about belantamab mafodotin, so give us an update, please.

Yeah. So I talked about belantamab mafodotin or shorten it to belamaf. And unlike having a long journey, it’s had more of an up and down journey in its development.

So as you know, so this is an antibody-drug conjugate that binds to BCMA and it’s conjugated to a monomethyl auristatin-F or MMAF. And originally it was received conditional approval by the FDA and the EMA based on a single arm DREAMM-2 study. And then the results of DREAMM-3 read out which was a Phase III study that compared single agent belamaf to pomalidomide and dexamethasone. And although the progression-free survival was longer for belamaf at 11 months versus seven months for Pd, it didn’t meet its primary endpoint, so it was withdrawn from the market.

But if you looked at the Kaplan-Meier curves, they actually crossed over at 3 to 4 months in favor of belamaf and remained superior. And then the duration of response was quite strikingly different in favor of belamaf compared to Pd in that study and really suggests, you know, talks to this duration of response that is seen with belamaf in all the DREAMM studies, which we think may be due to immunogenic cell death.

But it led to this, the logic that if we combine belamaf with other active anti-myeloma agents, we might be able to induce more rapid responses and prevent that rapid progression before the crossover and then really allow patients to benefit from that duration of response. And this is indeed what we’re seeing with the results of DREAMM-7 and DREAMM-8. So DREAMM-7 recently read out, and it was a very favorable study in favor of belamaf. So it combined belamaf with bortezomib and dexamethasone and compared it directly to daratumumab, bortezomib and dexamethasone, and the progression-free survival was 36 months for bela-Vd versus 13 months for dara-Vd.

So very favorable progression-free survival benefit with a hazard ratio of 0.441. The subgroup analysis showed that the benefit was seen in all the different subgroups, regardless of prior lines of therapy in the len-refractory patient population, which only at this point made up 33% of the patients, but there was definitely a positive benefit in that patient population and there are various high-risk subgroups that included those with what we call functional high-risk that progressed within one year of treatment, those that had high-risk cytogenetics and those with extramedullary disease.

So really benefiting also the patients with high-risk disease. And then I talked about are the ALGONQUIN study that I led out of Canada, which combined belamaf with pomalidomide and dexamethasone. And in that study, patients were a little bit more heavily pretreated, three prior lines of therapy and the patients who received the recommended part two dose, which we had established at 2.5 mg per kg every eight weeks, 63% of the patients were triple-class refractory. And in that group of patients, we had not reached a progression-free survival at 13 and a bit months of follow up, and estimated progression-free survival at two years was 52.8%. So again, we see these really sort of long PFS when we combine bela with other anti-myeloma agents, the safety profile looks as what we would expect with belamaf and with the individual agents. Of ourse, I also highlighted that corneal toxicities is a known side effect of all MMAF containing ADCs in addition to belamaf, and that this continues to be an issue, but that it didn’t affect quality of life in the DREAMM-7 study, that it is reversible, generally manageable, and that we’re looking at different strategies to try to reduce this risk of or mitigate a bit of the corneal toxicities by looking at longer dosing schedule, lower doses, and then highlighted that there was a press release of the DREAMM-8 study that is comparing bela-PD, as we did with the ALGONQUIN study, comparing it to pomalidomide, Velcade, dexamethasone. And that study also liked the DREAMM-7 study has a PFS benefit that was statistically significant, and also both studies very importantly at an interim analysis, are showing a trend to overall survival benefit, which we don’t see very often in myeloma trials, so that I think is also quite impressive.

Then I finished off talking a little bit that we don’t know much yet about mechanisms of resistance to belamaf. Data suggests that maybe you don’t completely lose antigen expression, but there’s no data looking at mutations in BCMA that you see as a mechanism of resistance with bispecifics and highlighted a little bit very early work that we’re doing correlative studies in the ALGONQUIN patient population, where we do see that patients who maybe don’t respond have less of a TCR repertoire, less of TCR response to the treatment, and that may signal sort of more T-cell exhaustion in those patients, and maybe one of the reasons why they don’t respond. And then finally talked a little bit touched on, I think, what is really important right now is the idea of sequencing BCMA agents, as we’re really now going to have BCMA agents as second line. And can we sequence the various classes of BCMA agents?

Thank you, that’s a very thorough review of your presentation. Actually, the last thing you bring up is something I very frequently get asked the sequence, and I’m sure we all get that question. And I think you said at your presentation that the CAR-T cells have a better impact if you give them earlier on, but then if I look at the literature and I look at this literature often because people ask me this question, I’m going to ask you this question. Now, is time an important factor? Meaning if you gave a bispecific antibody or belantamab mafodotin, if there was a longer time window and then you give the CAR-T cell, is that different versus if you gave the bispecific or belantamab mafodotin and then went to the CAR-T cell, basically buying time to reset. And a little bit along the lines of what I was asking Tom. So what do you think about that?

Yeah, I don’t know that we have enough data to answer that question yet, but I think it seems logical. Like we talked about all of these.. We see that resistance is not always fully resistant and there’s that fluctuation and expression and recovery of T-cell function. And that I think it makes sense to either go with another agent in between and allow those T-cells to recover, or BCMA expression to recover as well with a clone that comes back. So I think, you know, we need more, real-world data, more clinical trials, looking at those questions. But I do think it will definitely impact how patients respond to resequencing.

But that is a very important clinical question. We really need to know how to sequence these drugs and we all know that the access to CAR-T cell is not where the needs are.

There are many more patients than there are slots. So in reality we will have to use the antibodies for the majority of patients as it is right now. That may change, we just don’t know how the field is evolving.

And I think that, especially belantamab might be interesting for the older patient population. I mean, I have more and more patients who are over 90 years old, and 20 years ago, we rarely had those patients or we said, should we really treat those patients? But I think belantamab is a really safe approach for the patients, the really frail and older ones, so probably that would be my preferred patient population to treat, you know. Yeah.

And with longer dosing intervals too, they don’t need to come to the hospital as often, especially if they’re on a combination with pom-dex.. And no risk of CRS and ICANS in those older patients. Right.

I also gave a presentation. So I just very briefly want to say I was asked to talk about the bispecific antibodies, we have three approved antibodies right now. And I was asked to talk about how they could be further developed in the clinical setting and considerations for drug trial development. So that’s a pretty broad topic. So I thought it was appropriate to talk about what Tom brought up just here a minute ago. The ODOAC meeting from April 12th, 2024, I think that’s a big milestone for the myeloma field. And I had the honor to present the evidence meta-analysis up in Washington, DC on the 12th of April. So we had worked, I pioneered this work for 15 years, we put together all the available data sets in the world with MRD data from Phase II or Phase III randomized trials with MRD as a primary, secondary or third endpoint in the protocol and in collaboration with all the drug companies and academia that had high quality data sets 10 to -5 or better, we worked for all these 15 years with the government, with the FDA to develop a statistical analysis plan, and about a year ago, we handed in the data to the government, and we didn’t hear from them for six months. And then they came back right after ASH of 2023, and they said, we want to have a meeting, and I thought they probably want another analysis. And they said, we love it, so we’re going to invite you to ODAC, but the ODAC will make the decision, and that’s what happened here on the 12th of April. So ODAC very carefully had reviewed the data and the I2 team was also there.

And I think it’s great that there are two independent studies in front of ODAC that really gives confidence. Like scientists, we wouldn’t really believe one study we’d like to see two studies in particular if they show the same thing. And I think the data was very convincing, showing that MRD works as a surrogate endpoint, reasonably likely to predict clinical benefit, and that’s exactly what the language is to get MRD approved as the surrogate endpoints for the accelerated approval path. The decision will be made, obviously, by the FDA, but we hope that they will follow ODAC’s 12 to 0 vote.

It’ll be hard to decide that 12 to 0 vote, 12 to 0. Congratulations.

It was a clear message.

For sure that this will get approved, really, it will be the devil’s in the details of what they say: how we can design clinical trials, when is the MRD endpoint going to be? What’s the accelerated approval pathway, and then what’s the next approval? Is it full approval, is it based on PFS, OS? It’ll be really interesting to see… But congratulations, and to you and the I2 team with Brian Durie and Ken Anderson I think Nikhil Munshi and Bruno Paiva. Everybody there at the ODAC was huge for the ODAC committee to vote it.

It’s a huge step for drug development and bringing drugs faster to the patients. Yeah.

So what it means is that instead of waiting for 10 to 15 years, we can have a drug approved in three or four or five years, so we’re basically double or tripling the speed. Patients get access faster. So coming back to the bispecifics, what I was trying to allude to is that how would this impact drug development in that setting, so I outlined the example of a randomized study even in the first, second and third relapse, where you could have randomization of patients versus a control arm, and having a bispecific arm as the experimental arm. And then you could capture MRD, say about a year into the study. And if you read favorably that there is a benefit of MRD in the experimental arm that could grant accelerated approval, then the study has to be properly designed. It has to be powered to capture progression-free survival, because that is going to be what gives you the full approval as a company. And also overall survival has to be captured and provided. It will be looked upon as a totality, both MRD, PFS and OS at the time of submission for accelerated approval. So if you think about trials like the BELLINI trial that had a better MRD but inferior overall survival, obviously that would not be granted approval. So that would be using the clinical endpoint also as safety measures, which is very important. And obviously the independent Data Monitoring Committee would carefully continue to review, like we all serve on these committees.

But based on the PERSEUS study and the studies that we have now, that the readout for frontline therapy is looking like it’s going to be 7 to 8 or plus years, this is huge. This is a huge advantage. So. Congratulations again.

It will decrease the cost tremendously. I mean we all know what it means to open a clinical trial and how much money industry has to pay. Or if we do an investigator-initiated trial, because the follow-up is many, many years. So you have to pay your institution, research nurses, coordinators, IRB, I mean the costs really accumulate and we know that the drug is already very good, you know with the bispecifics.

I would like I agree with that. But I think those costs will not change because we are never going to lower the safety bar. So the trials will have to go the same way. The difference is that the approval will come sooner. So from a company side, it means that once the drug is found to be efficacious and safe, you can get accelerated approval and you can start selling your drug, but you have to do the study the same way for safety purposes, and you also have to provide the clinical benefit with progression and overall survival. So the costs for the trials won’t go down, but the time to market will shorten.

So that’s the really big, big difference. Otherwise the safety will be jeopardized, which is never going to happen. Right.

But for all of us, the most important thing is that the patients get access to that.

That is the key thing, the patients are the winners.

They are complete winners because they get access to this even better therapy than we have now and our therapies are good now, but we need them to be better because patients are not being cured with myeloma therapy 100%.

And the last thing I try to address where also how beyond the trial design where I thought there are a lot of topics that I think needs to be addressed and I’m sure we have very similar perspectives and maybe not everything we agree on, but I think the dosing interval may not have to be as frequent. I think having it once a week to me seems to be very over overly excessive. When do you switch? When do you step back? If you look at the updated labels, they talk about certain number of cycles so you can work patients up. In my clinic, I usually restage patients after 4 or 6 cycles if they have been, I try to go off the CR and add a couple of more cycles and then I work patients up if they are MRD negative I have gone to every other week. I did immediately when these drugs were approved, and I wonder if you can even give them once a month. And I also talked about could there even be drug holidays in a similar way as we have for CAR-T cells? I think one of the big holdbacks is the lack of reliable blood based MRD tools. I think if we have very sensitive tools that probably patients and doctors would be more open to entertain. This is obviously an area where we need to do studies, but I could see even in the absence of the definitive study, if those tools were available, I think people will start thinking about it and probably playing with it. That would be early adopters, and I think this is an area. And the last thing was I talked about the safety work, and I actually was inspired by work you presented at ASH, I think, two years ago, Suzanne, from your work from FcRH5, when you premedicated with tocilizumab, the IL6 receptor inhibitor. So work that we did here from Miami, we gave a single dose the same exact way you did for FcRH5 with CD3. We gave one hour before BCMA and CD3, and we reduced the CRS rate from about 72% down to 14%. And that could also be part of a strategy to try to get these bispecifics in the outpatient setting, which I think is important. So I try to highlight on how to monitor, how to think about dosing, how to improve the safety, and also get the drugs completely outpatient around the world eventually. And of course, as I mentioned then the study design.

Yeah, I think your work was very important because it like you said, we don’t just go by one study. So now we have two studies showing that you don’t compromise efficacy by using an anti-IL-6 before you give a bispecific and two different bispecifics we see the same effect. So again, I think this is a win for physicians who are looking to do outpatient treatment and for the patients where their safety is better.

Right. And I think there are other attempts, people are doing more of a slightly cheaper approach because tocilizumab is a costly drug, even if it’s only one dose, and it is not yet FDA approved for this indication, that should be emphasized, but I think there are people also giving steroids, which is less effective, but it is effective to some degree and it’s obviously much cheaper. So I guess this is an area where we also need to do more work.

A lot of fun discussion.

Thank you very much. Thank you, all of you. Welcome. Thank you.