2025 Updates on Bispecific Antibody Therapy for Multiple Myeloma

In part 2 of this discussion series, Beth Faiman, CNP, PhD, Cleveland Clinic, Ohio, and Donna Catamero, NP, Mount Sinai, New York, New York, discuss recent updates from the 2025 ASCO and EHA meetings on bispecific antibodies in multiple myeloma. 

In this video, they explore some hot hot topics including exploring the use of bispecifics in earlier lines of treatment, sequencing bispecifics with CAR-T therapy, emerging therapies like linvoseltamab and talquetamab-teclistamab combinations, and the role of MRD tracking for optimizing long-term patient outcomes. 

Watch part 1, where they discussed important considerations for patient selection and side effect management with bispecifics for multiple myeloma.

Transcript:

Beth Faiman: Welcome to APP Institute Oncology. My name is Beth Faiman and I'm joined again by my friend and colleague, Donna Catamero from Mount Sinai. This next section is going to be recent updates on bispecific antibody therapy post-ASCO and EHA.

And Donna, I just wanted to share that there were several great updates and studies. So we know that bispecific antibodies are currently approved in the United States after 4 prior lines of therapy. So, they have to have been heavily pretreated. We know CAR-T is available earlier. We talked a little bit in the first part about the sequencing and how do you decide BCMA to BCMA and can you get back to back a little bit?

But what's exciting and presented at these recent meetings was that we're evaluating bispecific antibodies earlier on, such as in the MagnetisMM-6 study, that's elranatamab. And so that's in combination with daratumumab and lenalidomide in patients with newly diagnosed multiple myeloma. In this study that was updated, it's a phase 3 open-label randomized study looking at elranatamab in combination with lenalidomide or daratumumab. And there's various arms, but the part 1 of the study evaluates the optimal dose of elranatamab, daratumumab, and lenalidomide or elranatamab and lenalidomide in patients with relapsed/refractory multiple myeloma or newly diagnosed multiple myeloma.

And what we saw here is that while we know that there's a risk of infection, any grade neutropenia was like 70%, we did have CRS in about 62%. It seems to be pretty similar safety profiles in terms of the bispecific antibody. And so far, it doesn't have any cumulative increase.

We do know that we haven't gotten to where we are in 2025 without enrolling our patients in clinical trials. What do you think about moving bispecifics early on? If it's a BCMA bispecific then what is the implication for BCMA/CAR-T? What are your thoughts about this whole moving bispecifics earlier on in the treatment paradigm?

Donna Catamero: I think we need to move our best agents upfront because we see historically that there's an attrition rate from first line of therapy to second line of therapy from second to third and so on, so that we lose patients from each line. The patients we treat in first line might not ever make it to fifth line. So, we want to use our most effective drugs upfront. So yes, let's move our bispecifics, let's move our CAR-Ts to the newly diagnosed setting.

I do still think I have the preference of getting our patients who are eligible to CAR-T first. So, I'm still trying to think out what does the sequencing look like in that newly diagnosed setting. For patients, just because they're not CAR-T eligible now doesn't mean they're not going to be CAR-T eligible later. So, it is really trying to think out how we're going to use CAR-Ts and bispecifics in that newly diagnosed setting.

Beth Faiman: Yeah, absolutely. And I think what we saw at the International Myeloma Working Group meeting, which was held in advance of EHA in Milan this year. We were both fortunate to attend. There was a talk by Dr Chari that was looking at T-cell fatigue. And so one of the things that we're concerned about when you're moving these drugs up front is like, are these T cells getting fatigued from cumulative lines of therapy or what's the mechanism of why going from BCMA to BCMA doesn't necessarily work as effectively.

But I think if you're moving these drugs earlier and somebody gets elranatamab and then they have an effective long remission and then they're just on maintenance with daratumumab and lenalidomide, for example, they won't have had T-cell engaging therapy for an extended period of time and then you can consider them for CAR T-cell therapy down the road. So, I think getting more information in science, getting these drugs to people early on, and as you mentioned, attrition is real. And some studies say most patients won't even make it to second line of therapy because of many different factors.

And so, thank you for your insights. I think that this is just a hot topic right now in myeloma, and you're hearing some of the debates on your end. Another paper that I found quite interesting on bispecific antibodies was linvoseltamab. Now linvoseltamab is a BCMA-directed bispecific antibody. It is approved in Europe, but it's not yet approved in the United States. It's given IV and it has a different side effect profile.

In this study, it was given in combination with carfilzomib in patients with relapsed/refractory myeloma. In this LINKER-MM2 study, we did see results reported at ASCO of deep high rates of response and durable responses. And the safety profile was similar to the individual drugs like carfilzomib. You know, you worry about hypertension a little bit, make sure you're watching the blood pressure, no significant increased risk of infection or cytopenias. And then the linvoseltamab has a little bit of a different CRS profile. It's given differently on a weekly dosing. And so that is an opportunity for patients to get it in the hospital day one go home. And so, I think that that might be attractive as you're getting patients used to that drug as well. And again, the dose of linvoseltamab at this study was 200 milligrams and the carfilzomib is variable.

But Donna, where do you think linvoseltamab, if it becomes approved in the United States as a bispecific antibody to treat patients with relapsed myeloma, where do you think it's going to fit? Because we already have elranatamab and teclistamab available.

Donna Catamero: The common theme here is first that the bispecifics are really showing that we have a great overall response rate and durability of response. As you said, linvoseltamab is given differently, it's an IV, but the step-up dosing is a little bit different. We're not having these prolonged hospitalizations. You give the medication; patients are usually in the hospital overnight and then discharged.

I think it's an easier step-up dosing. Maybe I see this more in the community. Another attractive, I would say, feature of linvoseltamab is we see less CRS. So again, I see this fitting more into community settings where it is not a long hospitalization and we're not seeing the CRS rates that we do with other bispecifics.

Beth Faiman: Yeah, absolutely. A major focus, we had a lot of talquetamab updates at EHA and ASCO this year, and one that I'm super excited about to hear as you are Donna, because you participated at Mount Sinai in this study was the phase 2 study of talquetamab and teclistamab (tec-tal or tal-tec, whatever you want to call it) in relapsed/refractory myeloma.

And especially what was interesting is extramedullary disease. For those of you that aren't familiar with extramedullary disease, those patients have poor outcomes. It's high-risk disease, especially at diagnosis, but can occur at any time. And that's when the soft tissue plasmacytomas are not in the bone. It's just kind of floating around in the body. And so, these extramedullary disease patients have poor outcomes and rapid relapses.

And we know that talquetamab and teclistamab each, if you give somebody with extramedullary disease teclistamab or if you give somebody with extramedullary disease talquetamab by itself, the response rates are low, like 40%.

And so, in this study as of March of 2025, it was presented at ASCO that 90 patients received the tal-tec combination. Many of them had 4 prior lines of therapy, but the overall response rate was pretty high in 79% of these patients who had otherwise conferred a poor prognosis. Infections were about the same, 79% or so. The patients were supported on antibiotics, antivirals, IVIG, at least 1 dose most people got. And so, I know I have quite a few patients that are still doing extremely well on this study that had really, really bad disease.

Donna, what are your thoughts about this study? What are you worried about? What are you excited about this study and do you think this is going to change the way we manage our patients with myeloma in the future?

Donna Catamero: I think extramedullary disease has been one of the most challenging types of myeloma that we try to treat. So historically, these patients have very poor outcomes. And now there is a combination therapy that we can offer patients where the majority of patients are responding and again, have that durable response.

I think this treatment is not going to be for everybody, but I think for those patients who have challenging disease to treat, especially the extramedullary disease, we can combine the two bispecifics. The caution is though that the majority of patients had severe infections and there can be mortality/morbidity with these infections. So these are the types of infections where we're giving IV antibiotics or a hospitalization.

So that's something we do need to keep in mind when we're giving combination with tec and tal. But we do see very high response rates and very durable response. But the caution is that infection is an issue with this combination. So we just have to manage patients appropriately, put them on prophylaxis and monitor them very, very closely.

Beth Faiman: Yeah, absolutely. Those are excellent points. And so I know there was a lot of talk about the trispecifics. Now this module is about bispecifics and it's focusing on some of the other drugs, but the trispecifics seem like super exciting. Dr. Core had presented some data about these high response rates, very well-tolerated drugs.

Stay tuned because not only the trispecific antibodies, we have also it was published anito-cel at EHA and ASCO, which is a new CAR T-cell therapy with high response rates and lower CRS and neurotoxicity. And then finally, the study that I wanted to share that was highlighted that was also published in a peer-reviewed journal the same week was the MIDAS study. It's looking at the MRD-directed therapy to try to decide the best therapy for patients, 1 or 2 transplants. It was a French Myeloma Group study.

But again, really looking at the role of minimal or measurable residual disease in patients and underscoring that the best responses you can get early and sustain those responses can translate in some groups to overall survival. So, it's that sustained MRD negativity, not getting to MRD negative, and then you deescalate therapy.

What are your thoughts? And again, this is really a bispecific antibody discussion, but I think relevant because bispecific antibodies are a way to achieve MRD negativity. Donna, how do you assess MRD-negative status in your patients on bispecific antibodies or other therapies at your center?

Donna Catamero: Right, because I think using MRD to make treatment decisions is going to be possibly how we dictate treatment in the future. So, I do think it's important, and we know that sustained MRD equals superior outcomes. At our institution, we're checking MRD status at least annually in our patients, especially those patients on bispecifics or post-CAR-T because we know those patients are going to do better.

Beth Faiman: Yeah, absolutely. And so, I think that's where the science is changing. And clonoSEQ is the assay that's FDA cleared, and that's what most people will send out. You have to identify the bad clones at diagnosis, and then you have to track the clones through an MRD tracking assay on the bone marrow and that's what you'll have to have a bone marrow biopsy annually.

And some patients don't want to do it. And so we say, well, it's a nice to know, not need to know information. So outside of a clinical trial, I give all my patients the opportunity to see what their MRD status is. If they don't have any evidence of myeloma protein in the blood or the urine, and we think they're in a complete response. And then I say, it's not going to necessarily help us now, but if you're MRD negative, then we know that your treatment's working and we'll check you again in a year and then maybe down the road we're going to learn how to use this information to better care for you.

I think that the last thing I wanted to do is, Donna, it's not bispecifics, it's CAR-T, but we just had some exciting updates presented on CAR-T, the CARTITUDE-1 study. Do you want to share your thoughts on that? Because this is in the New York Times and all the patients are talking about it and providers. What are your thoughts on the CART-1 study, because you participated in that, right?

Donna Catamero: Yes. This is using the CAR-T cilta-cel, and this is 5 year plus follow-up data. And we talked about COVID flattening the curve. We actually see the progression-free survival, the overall survival curve flatten. There is a third of patients more than 5 years out who have not relapsed from their multiple myeloma. So, they're still in remission. And these are patients mind you, the CARTITUDE-1 trial median prior lines of therapy was 6, and some patients had up towards 15, 16 prior lines of therapy. So very heavily pretreated patient population.

The fact that a third of patients are still in remission after their one-time CAR-T infusion is really changing how we think about the possible word cure in multiple myeloma. Now we're rethinking, can we say the word cure in multiple myeloma, that we are having these durable long-term remissions in a very heavily pretreated patient population.

Beth Faiman: Yeah, absolutely. That was one of the big debates there. It was so great to be in Milan around EHA and to hear these debates. And with ASCO, it's just that was a big thing. Can you call it a cure? If somebody gets a therapy for myeloma and then at 5 years later they're still in remission and not on any active therapy. It's still considered a living drug, so I'm not sure that the definition for cure in myeloma will be the same as the definition for cure in other cancers. But I think we're getting there.

And then like you said, these were heavily pretreated patients that confer to poor prognosis. You look at the MAMMOTH study and what the overall survival is when patients are refractory to therapies and it's really, really poor. And so it provides hope. And so I think that's where advanced practitioners are well poised to learn about these updates, share the updates with the patients, and help them to make these decisions.

Dr Fonseca from the Mayo Clinic Scottsdale had a really important piece that he wrote recently about why we aren't doing bispecifics or CAR-Ts or these innovative therapies earlier. Patients are a lot more worried about what they'll lose than what they're actually going to gain. And so just shared decision making and advanced practitioners are really good about that and really encouraging their patients to take in the risk-benefits and alternatives to treatments and hopefully find the right drug and the right dose at the right time for the right patients.

So anyhow, with that, I want to say this has just been so fun, Donna, spending time with you. And this concludes this discussion series and thank you for participating and thank you to the audience for watching this, and thank you to APP Institute Oncology for organizing this talk. And please visit their website to catch the rest of this discussion as well as other updates in cancer care. Thank you.