Relapsed/Refractory Multiple Myeloma: Sequencing BCMA-Targeting Therapies


Shared perspective on available novel therapies in relapsed/refractory multiple myeloma and how best to sequence these agents.


Ajai Chari, MD, PhD: I think the one final thing I wanted to highlight from this and get your thoughts on was the sequencing issue. Where we’re at in myeloma, as I alluded to when I was a fellow, we had, I think the first IMiD [immunomodulatory agent] was starting, thalidomide, and now we have so many drugs. It feels like we’re drinking from a fire hydrant, and one of the questions is how you sequence these agents. I think you showed some data about sequencing, particularly with talquetamab’s activity in prior T-cell redirection. I’m curious to hear your thoughts about what you think is going on with talquetamab after prior CAR T [chimeric antigen receptor T-cell therapy] and after prior bispecific, and how they may be different. And how that might impact how we use this agent going forward.

Carolina D. Schinke, MD: I think that’s really a hot topic, and it’s been discussed a lot. Now, how to sequence. I think the idea we have right now is obviously that bispecifics, post bispecifics, [it] can work well. However, you have this phenomenon there of T-cell exhaustion, which is target independent. So if you already have a patient who has had treatment with a bispecific and then starts to relapse, obviously T-cell function will not be ideal, because there is this exhaustion phenomenon where they just have decreased functionality and decreased activity. So if you then start with another T-cell–directing treatment, if it’s CAR T or bispecific, then obviously efficacy can just be lower or is lower as compared to being a patient who has not received any of these T-cell directing treatments. So I think what we try to do is obviously in a lot of our patients now or what we also have seen in clinical trials is trying to have a little bit of time in between T-cell–directing treatment. So, if you have CAR T-cell infusion, obviously most patients don’t get any more treatment; hopefully [they] respond and then have a monthlong treatment break where then you can reexpose to bispecific antibody treatment. And these tend to have—the response rate there seems to be a little bit better from what we are seeing now, though the data is also very early, compared to those that come off a bispecific had continuous treatment, as you were saying, relapse, come off and then right away start on another bispecific antibody. Or have CAR T right after that, where response rates I think are a little bit worse just because T cells are probably not functioning properly. So I think it will have to be seen how to sequence. What we do in practice always is obviously trying to get as much pause as possible between those T-cell–directing treatments. Then hopefully when talquetamab will be approved, as you said by the end of the year, I think switching the target will also be one thing or one mechanism to do to hopefully improve the efficacy of subsequent T-cell–redirecting treatment.

Ajai Chari, MD, PhD: I think some of the other exciting data that we heard at ASCO [American Society of Clinical Oncology] and EHA [European Hematology Association] was really about cilta-cel [ciltacabtagene autoleucel], probably which I think many would agree, is the single best product and therapy we have in myeloma. And we heard from CARTITUDE-1, the heavily treated patients, that the PFS [progression-free survival] was about 34 months. That CARTITUDE-4 comparing cilta-cel to the standard of care showed an unprecedented hazard ratio of around 0.26, which means nearly 75% improvement in likelihood to progression or death. Which I think means that cilta-cel is not only cemented in relapse, but will probably be moving earlier. As you alluded to, one of the things we now need to be mindful of is antigen switching. We heard at ASH [American Society of Hematology] 2022 that when you do prior BCMA-directed therapy, whether it’s ADC [antibody-drug conjugates] or bispecific prior to cilta-cel, that 34-month PFS became 6 to 9 months. The responses went from 98% to like 60%. So to me, if you’re going to do cilta-cel, you want to avoid a BCMA-directed therapy. So this is a natural place for GPRC type therapies like talquetamab to come in. Although as you alluded to, when to collect somebody’s unknown, should you maybe collect before starting talquetamab, because we don’t know if you collect at the end of T-cell exhaustion, what we’re doing there. It’s nice to have a different target. I also think, let’s say the opposite happens, somebody gets cilta-cel and now you have a relapse, because it’s a fixed-duration therapy, we are seeing encouraging results from the data that you presented with a response rate of 75%. I think what’s an unmet need is probably, what do you do with a prior bispecific failure. I think we’re going to hear some really exciting other options coming forward at both ASCO and EHA. And we’ll be talking about that abstract as well. But really exciting data. Thank you for sharing this.

Carolina D. Schinke, MD: I think just one more comment on moving up these treatments earlier in treatment lines, I think that will be definitely exciting and obviously they will be, probably be even more effective. It’s just the question is we have so much effective treatment upfront already, that for those it will be more identifying those that really need that kind of treatment upfront. Because again, there are some [adverse] effects that are unique and maybe not encountered in what we have right now. Maybe not everybody will need it. That’s kind of, I don’t want to say it’s a counterargument, but it just needs to be taken into consideration when we have so many options now available and likely more options even in the future for frontline or upfront treatment.

Ajai Chari, MD, PhD: That reminded me of another important point from the talquetamab data, which is really, in some ways, teclistamab and talquetamab are actually historical contemporaneous counterparts. Both were accruing during COVID, both have similar populations and yet in teclistamab you saw almost 27 out of 68 deaths were due to nonprogression. You’re not seeing that with talquetamab. And for the ability of these drugs to move up earlier, we have to keep in mind that we don’t yet have randomized phase 3 studies of the bispecifics. We heard those now for CAR Ts, both ide-cel [idecabtagene vicleucel and] cilta-cel showed that the response translated into PFS, which is trending favorably toward OS [overall survival], but at least we’re not seeing harm. I bring that up because I think as we move these bispecifics up, we’re going to need to see that OS signal. Because we’ve had a precedent in myeloma with venetoclax, the BELLINI study, where the response was better, PFS was better, but it actually translated into worse deaths. And so, I think what we’re seeing with talquetamab, which I think perhaps is one of the most reassuring things, is the lack of infectious deaths. Because what’s worse than dysgeusia is a grade 5 event. So you can always modify the dose and schedule, but once you lose a patient, especially if it’s a myeloma patient who’s responding, that is tragic beyond belief. I think that really speaks to the setting up talquetamab, I think going forward for both combinations and moving up. And perhaps being able to get away with less drug to mitigate some of those AEs.

Carolina D. Schinke, MD: I think that would be great for sure.

Transcript edited for clarity.

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