Bispecific Antibodies for Relapsed/Refractory Multiple Myeloma
An expert panel discusses bispecific antibodies and their mechanisms of action in the treatment of relapsed/refractory multiple myeloma.
Transcript:
Ola Landgren, MD, PhD: What’s the mechanism of action of teclistamab? Can you talk about that?
Benjamin Diamond, MD: Teclistamab is a bispecific antibody. There are several, but this is the first one to achieve approval. It’s a bispecific antibody where one of the effectors is binding to CD3, which is on T cells, and the other effector is binding to BCMA, which is a marker that’s ubiquitous on plasma cells. The idea is to cross-link them to cause an immune effector–related reaction from the T cell to the myeloma cell.
Ola Landgren, MD, PhD: There’s more than teclistamab. There’s elranatamab. We’ve had a couple of trials that have been presented at meetings, such as ASCO [American Society of Clinical Oncology Annual Meeting]. Could you comment on the MajesTEC and the MagnetisMM trials?
Benjamin Diamond, MD: These are 2 of the front-running trials. MajesTEC is teclistamab, so it’s in the name and easy for us to remember. On the other hand, the MagnetisMM study is looking at elranatamab. Both agents are targeted against BCMA. They’re both bispecific antibodies. In both phase 1/2 studies, they have similar ramp-up dosing, where we try to minimize toxicity with a lead-in. Followed by that are different groups with weekly or biweekly dosing schedules. Both have fantastic response rates considering the line of therapy that they were introduced to. Patients have durable responses on both of them.
Ola Landgren, MD, PhD: Dickran, there are other targets as well. There are additional BCMA-targeted antibodies that we could talk about. But let’s talk about the other targets. We have the cevostamab drug and the talquetamab drug. Could you talk a little about what they target and how things work?
Dickran Kazandjian, MD: The mechanism of action is very similar, except the target on the actual tumor cell or, in this case, the myeloma cell is different. For cevostamab, it’s FcRH5; for talquetamab, it’s GPRC5D. These targets are different from traditional BCMA. One important difference between talquetamab and teclistamab, for example, is that it seems that a myeloma cell doesn’t need GPRC5D to survive. That’s how a myeloma cell, in trying to trick the immune system, can stop expressing. But BCMA is needed for cell survival. Either way, there are a lot of promising data with talquetamab. It’s even more important once you’ve exhausted the BCMA target. We have many drugs using the BCMA target. We’re talking about bispecifics but also how CAR [chimeric antigen receptor] T-cell therapies target BCMA. There are even antibody-drug conjugates that target that. GPRC5D is a nice target that gets away from the BCMA. It’s the same thing with cevostamab. That’s a unique target compared with other bispecifics, and it gives patients a chance to continue to benefit from immunotherapies after exhausting BCMA-targeted therapies.
Ola Landgren, MD, PhD: You mentioned some of the recently discovered mechanisms of resistance. We and other groups have drilled a little into that, but it’s probably fair to say that it’s quite early on. You talked about biallelic loss for GPRC5D. Although we were part of that work, I’d like to emphasize and add to what you brought up because that’s not in every patient. It also doesn’t happen right away. There are very strong efficacy data showing you have great, durable responses. But for those cases where you could lose it, maybe the mechanism of action could partly involve biallelic inactivation. Do you agree with that?
Dickran Kazandjian, MD: Yes, I agree. The activity is very impressive post-BCMA targeted ones.
Transcript edited for clarity.
