Should Additional BCMA Therapy be Utilized After Prior BCMA Treatment for Multiple Myeloma?

At the 2024 Great Debates & Updates (GDU) in Hematologic Malignancies meeting in Los Angeles, California, Ajai Chari, MD, University of California, San Francisco, California, participated in a debate in which he argued in favor of using additional BCMA-directed therapy after prior BCMA-directed therapy among patients with multiple myeloma.

“I think all of these concepts tell us that we're still early in our understanding, but our current data do suggest that you can give BCMA bispecific after prior BCMA CAR-Ts and get good responses,” concluded Dr Chari.

Transcript:

Hi, my name is Ajai Chari. I am a professor of clinical medicine and the director of the myeloma program at the University of California, San Francisco. It's my pleasure today to be here at the [Great Debates and Updates in Hematology meeting] in Los Angeles. My second debate is about whether or not patients should have (B-cell maturation antigen) BCMA-directed therapy after having had prior BCMA-directed therapy.

We now know that you can target this antigen with either a (chimeric antigen receptor T-cell therapy) CAR-T, a bispecific and probably pretty soon again, an antibody drug conjugate. I mentioned that last part because belantamab, which was the only antibody drug conjugate approved for myeloma, was taken off the market in the [United States] but we have 2 positive phase 3 studies—DREAM 7 and 8— [that] will likely lead to their reapproval I think because of the outstanding results of those studies.

The question becomes if you give 1 BCMA-directed therapy, does that make other BCMA therapies downstream less practical and feasible? [First], I think we have to acknowledge that the current data sets do suggest there is an issue. When you have both (idecabtagene vicleucel) ide-cel and [ciltacabtagene autoleucel] cilta-cel CAR -Ts being given after prior BCMA-directed therapies, be they an antibody drug conjugate or bispecific, we see significant reductions, particularly in (progression-free survival) PFS with cilta-cel, for example, going from 3 years to down to 5 to 9 months, which obviously gives us great pause about doing that. But what we know is that these initial studies were constrained by the fact that people did not have a lot of options. Patients were getting all of their BCMA therapies at full-dose intensity until progression, which could have changed both the biology and the T-cell health.

For example, if you're giving a BCMA bispecific regularly at full-dose intensity, you're more likely to get exhaustion of those T-cells, and potentially more impact on the antigen. I think newer studies are saying maybe we don't need to do full dose intensity, maybe we can reduce the intensity, maybe do fixed duration. I think the preliminary data should not be the de facto plan for how we should operate.

I think we need more studies, but with the CAR-Ts in particular, we need a little bit more data. But let's just say CAR-Ts are going to be given first, which I think is the case, because of CARTITUDE-4 data looking at a really unprecedented hazard ratio, almost, of 0.26, you know, 75% likelihood in improvement of progression or death with CAR-T compared to standard of care. I think many patients who are young and fit will get CAR-T in early relapse. Because of the tremendous treatment-free interval for that patient population, I think it's very reasonable to do another BCMA-directed therapy after that.

So that, I think, we have data already that bispecifics, for example, can work even after CAR -T, particularly when you have a long PFS. Probably belantamab we could also do again. I think in terms of the belantamab going first, I'm not as worried because if you're getting belantamab, chances are you're probably not a CAR-T candidate. I think that's okay to do.

I think all of these concepts tell us that we're still early in our understanding, but our current data do suggest that you can give BCMA bispecific after prior BCMA CAR-Ts and get good responses. I would add that just the alternative to doing this would be to try to switch targets.

So yes, we do have a (G-protein-coupled receptor) GPRC target, which I've been involved with a lot, but there we see that if you go from a BCMA bispecific to a GPRC bispecific, you still have an impairment in PFS. So just because you switch targets doesn't mean that's going to solve the problem. If the debate is, can 1 BCMA be given after another? I think the data suggests yes.

Source:

Chari A. Debate- BCMA Therapy Followed by Another BCMA Therapy Is Appropriate -YES. Presented at the Great Debates and Updates in Hematology meeting. July 27-28, Los Angeles, California.