Targeting BCMA and CAR T Therapy in RRMM

Nina Shah, MD, leads the conversation of using BCMA-targeted antibody-drug conjugate belantamab mafodotin, and the emerging role of CAR T-cell therapy when treating RRMM. 

Paul G. Richardson, MD: Nina, we’d love your opinions on DREAMM and antibody-drug conjugate [ADC] approaches. Then dive into CAR [chimeric antigen receptor] T-cell therapy, and then give us your download on the incredibly exciting data presented on CAR T-cell therapy.

Nina Shah, MD: It’s been an exciting year for BCMA because, for the first time, we have an approved drug [belantamab mafodotin]. It is an ADC that conjugates MMAF, which is a toxin to an antibody against BCMA. This is important because it’s the first FDA-approved drug that targets BCMA for [multiple] myeloma (MM) and the first ADC for MM. As such, there are 2 novel things about it. This approval was based on the DREAMM-2 data, which showed an overall response rate [ORR] of about 30% in their 2.5-mg dose and a duration of response of 11.1 months, and those data were updated at ASCO [American Society of Clinical Oncology Annual Meeting] last year.

One of the things that it does have is a 70% rate of keratopathy. I just want to be clear that keratopathy is a physical exam finding, an ocular exam finding—not necessarily a symptom. But it can be eventually associated with changes in vision or best-corrected visual acuity. Because of this, there is a REMS [risk evaluation and mitigation strategy] program in there, which means that patients who are prescribed this medication also have to work with an ocular health specialist—for example, an ophthalmologist or an optometrist—to do visual measurements and corneal examinations every cycle.

This is something that is just being launched. The drug was approved in late 2020, so people then got on board with the REMS.…Once you get the system going, it can work. One of the reasons that people are interested in using this drug, as I mentioned, is new mechanisms of action. And it doesn’t require being referred to a specialized center per se. Notably, you don’t have to get T cells or go for CRS [cytokine release syndrome]. It has manageable toxicities in the outpatient setting. As a result, for a lot of our patients who cannot make it from a community-based practice over to a large academic center, this would be something they could consider.

They will not have seen another BCMA category before, a BCMA-targeting agent, because there are no other FDA-approved BCMA-targeted agents. For that reason, this has been 1 of the exciting drugs that launched in the past year, and we’re starting to see how that works. No drug is an island in MM, so that’s why we’re having a bunch of combinations of belantamab mafodotin with other drugs, including bortezomib. These data were preliminarily presented at ASCO last year.

The ALGONQUIN study presented by Suzanne Trudel at ASH [American Society of Hematology Annual Meeting] last year was interesting because they went a long way to try to understand dosing for this drug, because we want to limit the keratopathy. They were still able to get a nice ORR, of over 80%, but they did still have keratopathy. The question is, are we going to be able to modulate the doses as it goes forward, to maybe increase the interval between doses so that patients have a chance to recover? From there, we can consider redosing, because we know from the DREAMM-2 data that several patients held doses for a while because of the keratopathy, then recovered, and maintained their response. That speaks to the novel mechanism of action of this drug. Like all new drugs that are approved for myeloma, we must learn how to use them. Not just how they were done in the clinical trial, but how they can be feasibly done in a community. Overall, we’re looking forward to that.

There is this new BCMA-targeted ADC, the MEDI2228, presented at ASH by Dr Shaji Kumar, which I thought was very interesting with single-agent activity. There were a lot of median lines of prior therapy. I believe the median prior lines of therapy was 5, and patients here had a 66% ORR. As we say, “40 is the new 30.” I think 60 is the new 30. 60% ORR is the new 30% ORR. You must meet that, and MEDI2228 did that. Interestingly, it had around a 60% photophobia toxicity. Not keratopathy—it’s different and a different experience. Anybody who has used this would be able to say that it’s true photophobia. It’s as if you had your eyes dilated.

These are new toxicities for us. We’re used to nausea and thrombocytopenia, and we even somehow got used to neuropathy. But this is something new and a new way on how we’re going to make do. These are ways to target a new protein that we haven’t targeted, and we’re looking forward to some developments, not with a single agent but in combination.

But always stealing the show is the CAR T cell, and we were able to get a lot more CAR T-cell therapy data. We have 2 buckets of CAR T data. We have ORR from phase 1 and early phase 2 trials, and now we have duration of response, we have PFS [progression-free survival], and we have subgroups. That’s where we need to go because just getting your light chains to go down to 2 is not enough to say that this CAR T cell is worth it. Because of that, I was very happy that they did give us long-term data from the CRB-401 trial—the original bb2121 phase 1 trial—which people on this call participated in. Here, you were able to see that although the median PFS—they got all the groups together because there were various dosing regimens for a phase 1 trial—was greater than 8 months. The overall survival [OS] was over 32 months. That was very impressive to me because these guys were heavily pretreated. What that meant to me was that perhaps these patients, after they progressed, went on to other clinical trials. Moreover, the progression itself for some of these patients was IMWG [International Myeloma Working Group] based and not referring. We do not know the quality of the progression or what happened. It was just a very interesting piece of datum, with that much difference between the PFS and the OS in this heavily pretreated population. It’s an important piece of datum to know because this is how we’re going to start working other CAR Ts.

We do know from ASCO that for people who are on the KarMMa trial, which is the phase 2 bb2121 ide-cel [idecabtagene vicleucel] trial, those patients on the 450-mg dose, which is the upcoming FDA approved dose—well, we hope that we’ll get it approved by the FDA. Those patients had about a year of PFS, and if you had a CR [complete remission] you did even better. The cilta-cel [ciltacabtagene autoleucel] data this year from the Janssen [Pharmaceuticals, Inc] CAR T—which is a little different from the ide-cel [idecabtagene vicleucel] CAR T—targets 2 different epitopes of BCMA. These data were also very impressive, specifically a 97% ORR with a deep VGPR [very good partial response] of more than 94%. Regarding the 12-month PFS, they know that it’s more than 50%. They don’t know what the median PFS is yet, but it’s 77% of patients are still maintaining the response that they got, which basically was VGPR or better; we know that. That is the next contender for CAR T. We finally have more data than just bb2121, which was good for us to see. There were different toxicities in both, but all the people on this call know that now we know how to manage these better so that we’re getting clearer on how long we need to keep people inpatient, etc.

Finally, there were a host of other CAR T-cell therapies. I don’t want to get into all the details. The up-and-coming ones after the 2 that we’ve discussed, the bb2121 ide-cel [idecabtagene vicleucel] or the JNJ-4528 cilta-cel [ciltacabtagene autoleucel]. After those, we have treatments like Poseida Therapeutics, Inc, which showed us about a 60% response rate with their new manufacturing. We have the LUMMICAR STUDY 2, which is Carsgen Therapeutics, Ltd and was originally studied in China and has a nice ORR. This is their first cohort of patients in the United States, so we don’t have long-term follow-up.

We also had Allogene [Therapeutics, Inc], which is an allogeneic CAR T cell. This is an option for people you think may not make it to the AutoCAR and may not be able to collect. There are very early data and a lot of variables, such as the lymphodepletion and the dose. We do not know how that is going to play out, but we know that there was about 50% or 60% response rate in their higher doses. There are a lot of data for the later CAR Ts and a lot of up-and-coming data for the earlier CAR Ts. As I said, 60% is the new 30%. You must get to 60% ORR, or you can’t even pay attention to it.

Paul G. Richardson, MD: Excellent, Nina.

Transcript edited for clarity.

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