iwHRMM 2025 | Immuno- and targeted therapies in high-risk myeloma: ADCs, targeting GPRC5D & more

Ross Firestone:

Hi there. My name is Ross Firestone. I’m an assistant attending at Memorial Sloan Kettering Cancer Center. 

Nisha Joseph:

My name is Nisha Joseph, one of the myeloma physicians at Emory Winship in Atlanta, Georgia. 

Ajai Chari:

And Ajai Chari from the University of California, San Francisco, also myeloma at UCSF. 

Ross Firestone:

All right. So we just finished our discussion section at the high-risk multiple myeloma workshop. And we had a number of interesting discussions about targeted and immune-related therapies. And I think I wanted to review some of that discussion, particularly about a few different topics, the first of which being combining different multi-antigen targeted therapies in a single therapeutic regimen and sort of how you think the future of that looks in the context of relapsed and newly diagnosed myeloma. 

Nisha Joseph:

Sure. So one of the things Dr Voorhees went through is some of the clinical trial data we have targeting multiple antigenic targets at once. So whether that be one compound, like a trispecific antibody, or via two compounds together, so like the RedirecTT-1 study that looked at talquetamab in combination with teclistamab. And I think some of the discussion that we had was looking at how efficacious these combinations or some of these compounds can be, but what are some of the risks or, you know, advantage and disadvantage of each of these strategies. When we think about targeting multiple antigens at once, is that really preferential to sequencing therapies that target different antigens as opposed to doing it all at once? We talked a little bit about potential safety issues and what that might look like long term. 

Ajai Chari:

I think the challenge also is there’s three major antigens that we’re talking about right now in terms of what’s being studied clinically. We have BCMA, GPRC5D, and then also CD19 in the CARs sector, and of course, FCRH5. So if we add that, four different antigens in various combinations. And then there’s also three modalities of therapy, right? We have ADC, bispecific, and CARs. So I think when you put all of those, it’s like a stats question, how many combinations and permutations are there? But I think the audience might be interested in also hearing a little bit about each of our presentations. So maybe, Nisha, you could start with your presentation about the ADC. 

Nisha Joseph:

Sure. So I talked a little bit about the role of antibody-drug conjugates in the treatment of high-risk myeloma. And so a majority of the conversation was around belantamab mafodotin, which is an anti-BCMA antibody drug conjugate. There are also a few antibody drug conjugates in clinical trial development, but certainly belantamab we’ve had commercially before and hopefully we’ll have commercially again in the near future in the U.S. And so I talked about a few things. One of the things I talked about was kind of in a larger context, how we can optimize maintenance strategies for high-risk patients post-transplant. And so at Emory, we have long used for over a decade what we call a risk-stratified maintenance approach, meaning for high-risk patients post-transplant, we use kind of an enhanced maintenance strategy as opposed to Revlimid monotherapy until progression. And recently, Dr Ajay Nooka at our institution has designed a trial looking at belantamab in combination with pomalidomide and dexamethasone. And so post-transplant, patients are started on belantamab. What’s unique about this trial, in contrast to some of the belantamab trials ongoing and previously published in the relapse space, is the dosing. So some of the issues with belantamab and corneal toxicity, and a lot of these trials, the belantamab was dosed every three weeks, and there was a high need for dose reductions. And so from the get-go, and of course, we’re dealing with a different patient population, which has a low tumor burden going into a maintenance trial. But from the get-go, the belantamab is dosed every eight weeks with the option then of going to every 12 weeks after the first two cycles. So I showed some of that data that was presented at our International Myeloma Society meeting last month, showing really high depth of response. And there’s very limited follow-up to date, but so far looking very promising. And then I also talked about some of the high-risk cohort data in the DREAMM-7 and -8 trials, which also looked quite promising, that even in patients with one or more high-risk cytogenetic abnormalities, we’re seeing that those belantamab combination strategies, so belantamab in combination with pom or belantamab in combination with Velcade, are really able to maintain that high-depth of response and PFS benefit even in the high-risk cohort. 

Ajai Chari:

Well, I guess, unlike Belantamab, because I think today we’ll be getting the FDA vote on it because of two pivotal phase three studies read out, my talk was on GPRC5D, for which we don’t have a phase three readout yet. So talquetamab, which is the only approved product targeting GPRC5D, is a bispecific. And what was interesting, I think, with the data update from this year’s paper is that PFS for high-risk is actually about 18 months versus standard risk about 12 months. And you almost never see high-risk patients having a longer PFS than standard risk. So I think that needs to be validated in larger data sets in phase three studies, but that’s an interesting signal suggesting that maybe high-risk patients do benefit, and also older patients had a better PFS. But then I think there are still a lot of unmet needs, like EMD, double-hit myeloma, and prior bispecifics. That’s probably the new unmet need, because even talquetamab’s PFS goes from 12 to 13 months if it’s prior CAR-T or non-exposed, to three to four months with a prior bispecific. And so we talked about combination strategies that might hopefully improve on these. So TAL-DARA showing a PFS of about 19 months, including in prior bispecific failures. TAL-DARA-POM also showing exciting data. And then kind of leading back to, I think, Ross’s earlier question, the RedirecTT-1, TEC-TAL, showing in the initial Phase I New England paper encouraging data, but confirmed at this year’s EHA and IMS meeting that the PFS, in a dedicated, the largest cohort to date of EMD, 90 patients, the PFS was 15 months, which I think is super exciting for this patient population. But I’m curious to get our moderator’s input, because you’ve done a lot of work on antigen and combination versus sequencing. 

Ross Firestone:

Sure. So I think before we get to that, I also… you’re hitting a really important point right now in the context of high-risk disease in the context of these sort of newer generation therapies in that we’re not really sort of seeing the same stratification with our standard high-risk cytogenetic abnormalities as we are with our traditional therapies. But it seems that EMD is sort of one of the biggest things that’s coming up, it’s something that’s related to high risk with these treatments. And we saw some presentations earlier today where they were talking specifically about EMD and how one of the challenges that they suspect is sort of coming up with these bispecific antibodies is something related to inability of the immune system to penetrate those EMD sites. Yet we see data when teclistamab and talquetamab are used together, we’re seeing very high response rates with EMD, despite the fact that these two drugs use the immune system in a very similar way. So I guess my question to the two of you is, why do you think the response rates were so high in that study? And do you think this really provides validity to that approach? 

Ajai Chari:

I think part of it, it’s hard. EMD, we say kind of loosely, but there’s a lot of heterogeneity, right? You can have patients with marrow disease and EMD. You can have a solitary site. You can have a large solitary site. You can also have multiple sites. And so I think part of that is we need to kind of get into the little bit of the weeds of that, because I think there could be pharmacokinetic or pharmacodynamic reason for the failures of these, right? So pharmacokinetic is if it’s a bulky tumor, can a drug penetrate adequately? Pharmacodynamic would be, and we’ve seen some data that perhaps there’s heterogeneity in these antigen expressions so that one compound alone doesn’t do the trick. You need the dual targeting to really get at that. So I think when you put all of that together, it’s hard to have a quick answer to this, but I think it’s exciting to see these improvements, and it would suggest that it is more pharmacodynamic, right, because you’re just giving two together. But I think it’s also one of the things we brought up is that cilta-cel data, which even though siltuximab’s PFS is worse in EMD, there’s still patients with EMD that can do very well. So I think, again, speaking to the heterogeneity. 

Nisha Joseph:

Yeah, yeah, I completely agree. And I think another thing we talked about kind of going to the initial question is when we’re thinking about who, which patients really should be benefiting from some of these combination strategies, I think most of us agreed in the room that, you know, TEC-TAL, for example, that combination isn’t something that we would, you know, utilize for all comers, but might be specifically for those difficult to treat EMD patients, you know, that might be an ideal strategy. 

Ross Firestone:

Yeah. I think on the other hand, we have to think of some of the potential risks with regards to these combination strategies, which is what you were getting at earlier, Dr Chari, which is that with a lot of these therapies, we’re seeing pretty significant antigen escape, which is limiting the ability to sequence therapies that have the same target. And so one other thing that was presented during the session today are a couple of new prospective trial designs for high-risk patients at the time of diagnosis, where they’re really being hit with all of our best targets all at once. These are the total immune therapy trial that’s being discussed, as well as the TRIUMPH study, which are using the GPRC5D-directed therapies, FCRH5-directed therapies, BCMA-directed therapies. What type of patient do you think you’d consider enrolling on that type of study? And what do you think of the challenges that that study is going to present, given that we’re giving everything up front and thereby maybe having some challenges with sequencing those therapies later on, if it’s not a successful regimen in terms of yielding long-term cures? 

Nisha Joseph:

Well, I think, first of all, these are proof-of-concept trials. So, you know, in terms of long-term complications, I think, you know, you said what kind of patients would we target. I think right now we’re really, what Ross is referencing, is we are designing trials now that we have the idea is do we have enough therapies? We have such novel, highly effective therapies that are targeting different antigens on the surface of myeloma cells. Are we, in fact, in a place where we have enough therapies, we have the right therapies, that we can essentially get to an operational cure or at least longer-term remissions than what we’re seeing? And can we hit the myeloma at newly diagnosed when it’s the most sensitive? And so these kind of trials, for example, are alternating between bispecific antibodies that might target BCMA or a CAR T-cell therapy that might target GPRC5D or FCRH5, which is cevostamab, and essentially hitting the myeloma back-to-back with these therapies in rapid sequence for a fixed duration. And so these are initial trials, know, initial trials looking at does this, is this concept, first of all, safe? And are we seeing a signal? And then we can kind of think more about, you know, long-term implications. I think it’s particularly interesting for high-risk patients because the standard paradigm or standard approach of induction, transplant, maintenance, we tend to know where that leads for high-risk patients. And so I think it’s exciting to shift how we’re thinking about approaching those patients and seeing if we do something completely different, do we, in fact, get better outcomes? And maybe we won’t. Maybe we’ll run into, you know, safety issues and other issues. But I think it’s a really exciting concept to explore. 

Ajai Chari:

Yeah, I think what you’re alluding to is there’s basically efficacy and safety. So another way to reframe the question would be, what are the unmet needs in newly diagnosed myeloma? And I would say frail and elderly. So if you have a new immunotherapy that’s very safe and well-tolerated, that would be amazing because these patients don’t always get to the multiple lines of therapy. Right now, let’s say, for example, we have current bispecifics approved for four lines of therapy. How do you get a frail elderly person to get to fourth line? That’s really difficult. On the other hand, from the efficacy side, I would say there’s two unmet needs. One is, as Nisha alluded to, treatment-free interval. So on the one hand, we’re saying PERSEUS with quadruplet induction transplant maintenance has a projected PFS of 17 years. I’m not sure it’s that long, but the point is, that’s great, but how do we keep people off therapy if they’re going to do that well? And I think the other unmet need, which is the purpose of this conference, is really the aggressive high-risk patients, right? The double hit, EMD, these patients who, again, not because of frailty, but because of their explosiveness of disease, you’re not going to get a third and fourth chance to salvage. So why not be innovative and treat them? It’s kind of like, I think I always say that we always have lymphoma envy because the pathologists tell you if it’s indolent, moderately, or highly aggressive, and you treat accordingly. The pathologists tell us myeloma. It’s like, OK, go. Wouldn’t it be nice to be able to segment patients into those categories and say, okay, novel immunotherapy for high-risk, quads for everyone in standard risk, and another novel for frail? 

Ross Firestone:

Thank you, everyone, for listening. And thank you to our two speakers from this session for sharing their insights. And I hope I’ll see you at the High-risk Multiple Myeloma Workshop next year.

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