The Intricacies of Bispecific Antibodies in Multiple Myeloma

At the 2025 International Myeloma Society (IMS) Annual Meeting in Toronto, Canada, a panel of experts gathered to discuss the current state of bispecific antibodies, including talquetamab-tgvs (Talvey) and teclistamab-cqyv (Tecvayli), as therapy for patients with multiple myeloma. The experts discussed the various factors that weigh into treatment decisions, such as comorbidities, prior treatments, and disease burden.

The panel was led by Ajai Chari, MD, professor of clinical medicine and director of the Multiple Myeloma Program at the University of California San Francisco. He was joined by Adriana Rossi, MD, assistant professor of medicine and director of CART and the Stem Cell Transplant Clinical Service at the Center of Excellence for Multiple Myeloma of Mount Sinai Health System in New York, New York; Amrita Krishnan, MD, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope in California; and Larry Anderson, MD, PhD, professor in the Department of Internal Medicine at the University of Texas Southwestern (UTSW) Medical Center in Dallas; director of the Myeloma, Waldenström’s, and Amyloidosis Program at UTSW’s Harold C. Simmons Comprehensive Cancer Center; and codirector of the Phase 1 Clinical Trial Research Program and the Cellular Immunotherapy and Autologous Stem Cell Transplant Program.

Real-World Data From IMS

Chari / Adriana, can you walk us through some of the data that we heard at IMS about real-world data and how those compare with study data?

Rossi / Even though we call it the real world, we’re talking about patients who wouldn’t be eligible for studies, and these tend to be older patients with a lot of high-risk cytogenetics and more comorbidities. Amazingly, time and time again—we’ve now seen this with specific agents, as there are data with teclistamab, with talquetamab, and with [elranatamab-bcmm (Elrexfio)], repeatedly—the efficacy seems to be the same. We’ve seen academic centers and community centers very much highlighting what Amrita was saying about lessons learned in the management and learning how to decrease the incidence or the grade of [cytokine release syndrome (CRS)] has made this a universal therapy. Everybody is able to provide the therapy. It doesn’t need to be in an academic center.

Chari / Sometimes we dismiss real-world data because it’s not a randomized clinical trial, but we have to keep in mind that, currently, bispecifics only have single-arm studies that have led to accelerated approval.

In the US, most patients are being treated in the community, yet there’s been very little community uptake of bispecifics. We hear from doctors, “It’s the [Risk Evaluation and Mitigation Strategies] program. I’m concerned about CRS, and I don’t know how to do all that.” What’s your advice on getting past these hurdles?

Anderson / It’s a little complicated, but right now, technically, most of these [patients receiving] ramp-up or step-up dosing are being treated in academic centers because we have the experience with CAR [chimeric antigen receptor] T, with the [CRS], and with neurotoxicity. We’re typically starting their step-up dosing and potentially sending them back out into the community for their follow-up cycles. But now that we’re seeing more data with prophylactic tocilizumab and prophylactic dexamethasone, we’re seeing less and less severe toxicity, and more low-grade CRS, which is essentially a fever that can be treated with Tylenol or another dose of [dexamethasone]. Those patients, as we have more data for that, hopefully can be transitioned to the community setting for their step-up dosing.

Patient Case No. 1

Rossi / That’s the classic triple-class exposed—the perfect candidate for a BCMA [B-cell maturation antigen (bispecific)]. Certainly, the comorbidities make me a little hesitant to do the CAR T, as we had mentioned before. Once the cells are in there, they’re more difficult to titrate. The bispecific is an ideal option, in my mind.

Anderson / She’s had 4 prior lines of therapy, has rapidly progressive disease, and has rapidly declining performance status, with poor [activity of daily living] capacity. An off-the-shelf product that you can give within a week probably makes the most sense, like a bispecific.

Krishnan / I tend to go first with the BCMA bispecific because some of the other [adverse] effects are not there…with talquetamab. It is a little bit easier to manage the durability of responses, especially in patients who get a complete remission. It is significant. Over a year, if you get a [complete remission], it can be up to about a 21-month duration of response in [patients with a complete remission]. The expectation is that these patients will get a response—[the bispecific has a] 70% response rate—and it is very well tolerated, as long as you do the appropriate supportive care in regard to infectious prophylaxis.

Patient Case No. 2

Chari / How would you all treat this very young patient who has double-hit multiple myeloma—primary, functional, high-risk—with a short relapse after CAR T?

Rossi / The post-BCMA [setting] is our biggest unmet need, and the [GPRC5D] target is one new thing that we could use.

Krishnan /I don’t think that’s wrong. Data from your institution suggested a 6-month interval; some studies say 9 months, and then treating with a BCMA-targeting agent would be reasonable. In this patient, this is an aggressive relapse. You may only have one shot. If it’s an indolent relapse, perhaps you would try BCMA. If it doesn’t work, switch to something else. Here, I agree with [Dr Rossi]. We agree that we’re going to change modalities. We’re going to go from CAR T to bispecifics. Changing the target also makes sense.

Anderson / In this case, it’s the gray zone [because] it’s at 8 months. There are data [that show] if it’s beyond 6 months, you’re OK with another BCMA—some data show…after 9 months. Since it’s an aggressive relapse and right in that gray zone, the GPRC5D would make the most sense. I would also agree with sending for BCMA mutation testing in case that doesn’t work. Then you have a backup plan to see if the BCMA therapy would work after that.

Chari / For those who are interested, there’s the [International Myeloma Working Group] consensus paper on sequencing, and, in that, a bunch of people were able to agree. Currently, it seems like every BCMA therapy adversely affects the next one. For example, in [the phase 2 CARTITUDE-2 trial (NCT04133636)], [with ciltacabtagene autoleucel (Carvykti)], the [progression-free survival (PFS)] of 3 years drops to 5 months if you have a prior BCMA bispecific, and to 9 months with an [antibody-drug conjugate]. Then, similarly for [teclistamab] and [elranatamab], the PFS of teclistamab goes from about a year down to 4 or 5 months, whereas [elranatamab] goes from 17 to 10 months.

It seems like every BCMA product is adversely affecting the next one. The caveat is that up till now, everybody was getting these therapies until progression. Might fixed-duration and longer treatment-free intervals change that? The jury’s out. The good news is that talquetamab’s PFS was about 11 to 12 months, and even 13 months after CAR T, so their target switch seems to be the right way.