iwMyeloma 2026 | Immunotherapies in myeloma: novel bispecific data, off-the-shelf CAR-T, and trispecific approaches

Faith Davies:

Hi everybody, we are at iwMyeloma 2026 in Miami and we’ve just come out of an incredible session updating us about some of the latest data on the immunotherapies in myeloma treatment. And so I’m really pleased to be joined by two experts. Do you guys want to introduce yourself?

Binod Dhakal:

Hello, good afternoon. My name is Binod Dhakal. I’m an Associate Professor of Medicine at Medical College of Wisconsin. I focus on multiple myeloma.

Hans Lee:

And I’m Hans Lee. I’m the Director for Multiple Myeloma Research at Sarah Cannon Research Institute in Nashville, Tennessee, also focused on multiple myeloma.

Faith Davies:

Excellent. Thank you, gentlemen. So, yeah, we had this, half the session was about the bispecifics, some of the latest data, and we were really fortunate. We weren’t just like thinking about BCMA, but also thinking about some of the data about FcRH5, I get my alphabet wrong, anyway, cevostamab, and some of the other new targets. Do you want to tell us a little bit about that?

Hans Lee:

Yeah, thanks, Faith. So I think we can all agree that T-cell redirecting therapies have transformed the myeloma treatment landscape over the last three to five years. And one modality of those types of therapies are bispecific antibodies that target BCMA, that target GPRC5D. Certainly FcRH5 is under investigation with cevostamab as well. And so we’re seeing, you know, great response rates, you know, 60 to 70% response rates in heavily pretreated myeloma universally across these agents. And of course, now we’re seeing them used in earlier lines of therapy. We see the tec-dara now approved based on MajesTEC-3 and then other data from ongoing studies in a newly diagnosed patient. So I think really the future is pretty significant and exciting with these agents. And I think moving forward, just thinking about what’s the sort of optimal way that we can deliver these agents from a sequencing standpoint but what combinations but also want to emphasize operationally how can we find a path to give these agents that provide the greatest access to as many patients that need these drugs.

Faith Davies:

No, I mean, I think there’s no doubt about that. We’ve got clearly one of the interesting things was how within all of the talks and the audience that some of the concerns about managing CRS, for instance, have very much decreased. And if you want to step up dosing and toci use and so on.

Hans Lee:

Yeah, absolutely. So, you know, certainly we’re seeing cytokine release syndrome with most of these agents. I think the good news is that most CRS is low grade, grade one, which is just a fever, which is fairly easily manageable. But I think, you know, occasionally you get the grade two, rarely grade three, so you need to be prepared to potentially deal with these adverse events. So I think one of the advances, I think, in terms of trying to figure out ways to more safely administer these drugs is the incorporation of prophylactic tocilizumab prior to the first step up bispecific dose, which is now in the NCCN guidelines. So that really has changed the incidence of CRS from going from 40–70% to 10–15%, mostly grade one. I know, you know, I practice in the community oncology settings. So many of my community oncology colleagues have adopted this approach and has really enabled them to actually use bispecifics in this context.

Binod Dhakal:

I would like to add one quick thing on top of that. That’s a really good point. That’s why that enabled the community to start you know adopting this very quickly and also the first step up dose is where most of the CRS and ICANS happen so subsequent doses is you know very low rates of those so I think it’s really easy for the community. even if they don’t want to start the step up dosing, they can start with the maintenance doses get some hands on and then go back to you know starting. That, I think, has been really you know, helpful for them to get some kind of experience to bispecifics.

Faith Davies:

Yeah. No, I mean, I remember back a couple of years ago, we were all scared. Whereas now, I guess it’s like any new therapy. It’s just learning and understanding what you need to do and following the recipe.

Hans Lee:

I think back to when daratumumab was first approved. It was intravenous. We’re all kind of, you know, a little bit wary of the infusion-related reactions, right? Now, of course, subcutaneous daratumumab is utilized, and now we kind of don’t think twice about giving it, right? So hopefully, we’ll come to that point with bispecifics.

Faith Davies:

I think one of the other things, I think you brought it up in your talk as well, was how there actually is a place for all of the different bispecifics, because they’re either targeting, although some of them target the same molecule, they maybe slightly do it slightly differently, and therefore the resistance mechanisms are slightly different. But then we’ve not only got the BCMA, we’ve got our GPRC5D, our cevostamab, etc.

Hans Lee:

Yeah, great point that you bring out, Faith, in that, you know, certainly we’re learning more about mechanisms of resistance to BCMA T-cell redirecting therapies and GPRC5D T-cell redirecting therapies. You know, I think one major mechanism is antigen escape, in which the antigen itself gets mutated, either deleted, or there’s a point mutation that renders ineffective binding of the drug to the extracellular domain of the antigen. And while we can say that, well, if a patient, for instance, is resistant to teclistamab, which is a BCMA bispecific antibody, will this render resistance to all the BCMA bispecific antibodies as a class of drugs? And I think we’ve learned a lot from our colleagues, for instance, Nizar and Paola, who’ve looked at this extensively, of really doing detailed profiling of the antigen. And not all mutations are the same. Some render resistance to certain bispecifics that target BCMA, others that still are potentially sensitive. And so I think this really highlights that for precision medicine in the future, we do really need to profile these antigens, right? Because then we can really determine, is this drug likely going to work or not work? And I think hopefully that won’t be too far away in the future.

Binod Dhakal:

And I think in that context, I think using a peripheral blood assay, I think Paola mentioned a little bit about the cell-free DNA, where you look at this antigen status and mutation from the peripheral blood, it would be much easier for the patients to select these type of therapies.

Faith Davies:

Great. Thank you. And I think one of the things we enjoy about the bispecifics is they’re off-the-shelf, but you were talking about some off-the-shelf CAR data, which I think was also really interesting.

Binod Dhakal:

Yeah. I mean, you know, I mean, people always question, do we really need more CAR T-cell therapies? But I think off-the-shelf CAR-T has not been really seen their prime time in myeloma. We don’t have, you know, a lot of attempts have been made to make that kind of successful in terms of both efficacy and safety. But I think the data we saw today was quite promising to that end. I think of the shelf CAR-T still has a role in my opinion because one, we’re using these T-cell based therapies much earlier now and sequencing these frequently in these patients. So T-cell health is going to be a pretty critical, important question when you’re starting thinking of another T-cell based therapy. So in that case, if you can design an off-the-self CAR-T where you don’t have to rely on the T-cells and if the antigen is available, then I think that might be quite useful. So I think the data that you saw is quite, you know, you see the safety wise, quite good. Low rates of CRS, ICANS. So this is something that you can think of doing in the community, in the outpatient setting. But more importantly, in the BCMA, I mean, the data is mainly on BCMA and naive, but there we are seeing quite impressive responses. Almost 92% response rate with almost 75% CR and better. So I think, I’m hoping this will translate into longer durable responses as you follow these patients.

Faith Davies:

And the one you were talking about was an allogeneic CAR where they knocked out beta 2 microglobulin.

Binod Dhakal:

Correct. So this is like based on this called immune cloaking, where you have this beta 2 microglobulin knocked out for HLA class 1 expression removal, which is a significant step. But at the same time, you’re worried about the NK cell mediated rejection. So there they insured this, you know, HLA-E with the beta 2 microglobulin so that they prevent the NK cell from taking and getting rid of the CAR T-cells. So it’s kind of a balancing those two approaches so that you can improve the persistence.

Faith Davies:

But I think the exciting thing is, as you say, it’s, you know, we don’t have that issue about engineering the actual CAR. We already have it, and it seems to be safe and effective.

Binod Dhakal:

Right now, we’re expanding this to prior BCMA treated patients in both CAR-T and T-cell engager. I think that we have to see what the data looks like. In that case, it will be pretty important for… We all have those kind of patients, then we think of what to do for these patients. We really need the new kind of a healthy T-cell for those patients. So I think in that case, the alloCAR probably would be something useful.

Faith Davies:

And then in the last part of our session, I gave a talk about some of the next steps that’s going on. And that’s essentially saying, okay, yes, we can have a target on a T-cell and a target on a myeloma cell, but what’s wrong with having two targets on the myeloma cell or two targets on the T-cell? So we’ve got lots of these tri-specifics that are coming through, which are either trying to overcome resistance from the myeloma cell perspective and the antigen loss, or trying to activate the T-cell more by using CD28 and CD3. Or there’s also some that are coming through where they’re trying to increase the length of time the antibody is in the system. And I think it’s really, really fascinating. The early results look great, but also one of our colleagues presented the data of the tal and the tec together, which seems incredible in extramedullary disease. And then you were mentioning about putting kind of four targets together as well. I don’t know if you want to just expand generally on that.

Hans Lee:

Yeah, I think the next frontier when bispecifics work well, why not target multiple antigens on the myeloma cells? I think there’s a lot of excitement with the tri-specific antibody-based approach that he presented on some data with ramantamig, which is a tri-specific antibody that targets BCMA and GPRC5D. The first data was released last summer regarding a first in human trial, 100% overall response rates in BCMA and GPRC5D naive patients. I think that’s, you know, sort of on par with what we’re seeing with CAR-T, if that makes sort of, if you make that comparison. And I think one thing also that’s really encouraging about that particular compound is that I think we’re seeing less the GPRC5D on-target of tumor adverse events because we’re seeing more selective on-target on-tumor binding of ramantamig to the myeloma cell, not to the hair follicle, the keratinized tissue of the skin. So I think potentially from a safety, tolerability standpoint, and efficacy standpoint, you know, those approaches are very, very encouraging.

Binod Dhakal:

And they are being combined with, like, let’s say CD38, daratumumab. So I think you can clearly think of, like, three antigen targeting at the same time and being off the self-therapy, which is community-friendly. I think this is probably going to change the paradigm quite a bit.

Faith Davies:

Yeah, great. And it’s going to be interesting over the next couple of years as we try and figure out which targets, when, in what combination.

Hans Lee:

It’s hard to keep up.

Faith Davies:

Yeah, no, it is hard to keep up. But the key is this. I’m going to say, now whenever we look at a new drug, we are expecting 100% response rate. I think that’s where we’re at. Excellent. Thank you so much for joining us. We’re going to sign off from iwMyeloma 2026, and we look forward to seeing you again in 2027.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.