Using CAR T Therapy for Relapsed/Refractory Myeloma – OncLive

Keith Stewart, MD, ChB, MBA: Nina, lets move on to the granddaddy of BCMA-targeted agents, which is CAR T therapy, with chimeric antigen receptor T cells. Lets set the stage. Tell the audience where were at with CAR T therapy, particularly with respect to FDA approvals.

Nina Shah, MD: With BCMA and CAR T-cell therapy, theres 1 product approved, which is IDE-CEL [idecabtagene vicleucel]. Thats approved for patients with at least 4 prior lines of therapy. The data that led to approval was the PRIMA study, which showed a progression-free survival [PFS] of 8.3 months, and 8.7 months, but in the 450-mg dosewhich is going forward, the FDA-approved dosethe PFS was 12 months and 20 months if youve gotten a CR [complete response]. Thats the first approved product. There are other products coming down the line. Were hoping to see how we might be able to transition from a research thing to a standard-of-care thing, much as our lymphoma colleagues did.

Keith Stewart, MD, ChB, MBA: If I understand it correctly, its approved only for people whove had at least 4 lines of prior therapy?

Nina Shah, MD: Correct.

Keith Stewart, MD, ChB, MBA: Do you think thats fair, or do you think the FDA was harsh on that company with that?

Nina Shah, MD: They were a little harsh considering that the clinical trial enrollment criteria were at least 3 prior lines, but what ended up happening is that the patients were so sick, they went on the trial, did so well, and that made the FDA say, If youre going to have any risks for a therapy, it has to match the benefit, and it looks like your fourth-line people are doing as well as the third lines. In fact, there was an analysis this year to look at that. It showed that. So they figured it was OK to use IDE-CEL [idecabtagene vicleucel] in the later lines because the patients would still benefit from it. Its going to be hard for us to get there. Youre going to be using daratumumabRVd [lenalidomide, bortezomib, dexamethasone] up front, and then youre going to use carfilzomib second, selinexor, melphalanI dont know whats going to happen. But theres going to be a single-agent dexamethasone going onto the fourth line.

Keith Stewart, MD, ChB, MBA: Youre going to end up using 4 drugs, plus data, and rather than maintenance when we fail, youre going to go to the CME [continuing medical education]. Thats my guess.

Nina Shah, MD: Yeah. If the insurance company loves it. Correct.

Keith Stewart, MD, ChB, MBA: If the insurance company eventually loves it, and if its up to date. Youre right. Christina, what about adverse effects? Weve heard that these can be quite toxic therapies. Whats your experience with toxicity?

Cristina Gasparetto, MD: Yeah. Fortunately, the majority of patients will adapt, but to develop CRS, cytokine release syndrome, also with cortisol, we learned how to manage this type of toxicity over the last few years. If you look at the toxicity profile, we dont see a lot of the grade 3 and 4. Its more manageable with the tocilizumab [Actemra] intervention. In neurotoxicity as well, to learn to mitigate, theres an association between higher neurotoxicity with a high tumor burden. The study tried to bridge patients, to decrease the tumor burden, to minimize. Thats very important as well. In early intervention, it looks like theres also a link between prior CRS and neurotoxicity. So early intervention with tocilizumab or steroids, and were learning how to use the CAR T-cell as well.

Keith Stewart, MD, ChB, MBA: Joe, todays theme, as were learning, is how to manage this. Do you have any sense of CAR T in the same theme emerging?

Joseph Mikhael, MD: Yeah, I absolutely do. Were not discussing the detail, but lets unfortunately remember that some of the earliest CAR T trials in myeloma left a significant fraction of patients with real, very significant toxicity and even death. So I agree. You know, we have groups around the world that are convening to enhance our management of CRS, of the neurological toxicities that can emerge, and even cytopenia. Theres a deliberate learning curve. Even within the KarMMa trial that Nina described, there was a learning curve. Were becoming more aggressive in using, as Cristina said, the tocilizumab early up front, so it will become significantly safer. Theres always going to be a boutique component to it, Keith. Right? At least until we can start doing AlloCAR T [allogeneic CAR T-cell therapy] or over-the-counter AlloCAR T. Its still going to involve someone having their T cells collected, weeks to do manufacturing, etc, but its going to become considerably safer. It will be safer earlier in the disease course when people arent as beaten down by their myeloma therapy.

Keith Stewart, MD, ChB, MBA: Joe, who would be there? If I work in a community, I want to know who to send to you for CAR T therapy. Whom should I be sending?

Joseph Mikhael, MD: Aligned to the criteria, its interesting. This triple-class refractory space is becoming quite congested. We have selinexor [Xpovio], we have belantamab mafodotin, we have melphalan flufenamidethe artist formerly known as Melflufenand now we have CAR T. Any of those are legitimate medications in that space. We tend to move toward CAR T as quickly as we can because the response rates are double the response rates of any of the other drugs, to be respectful but true. Were seeing response rates over 60%, 70%, and evenas were going to discuss in a moment90%. When you have a patient that you feel can go through the process, which is a little less onerous compared with transplant, with the exception of renal function. Right now, if someone has compromised renal function, were still working through how to do that. But if theyre going to have access to a transplant-like centertheyre the ones that are basically doing CAR TId be favor looking into CAR T-cell therapy after those 4 lines of prior therapy. We hope, with time, that well have indications for CAR T that can allow us to do the therapy earlier.

Keith Stewart, MD, ChB, MBA: Sagar, what about the health of the patient? Is this for everybody? Is it only for the young? Where do you draw the line for this?

Sagar Lonial, MD, FACP: If you draw the line at, Could I take them through the transplant or not? then youre probably missing a lot of people whom you could give CAR T cells to because, in general, its better tolerated than that. Its the frail patient who cant get through it, but dont let age or anything else make that determination. Its harder to make this determination than it is for transplant eligibility.

Keith Stewart, MD, ChB, MBA: We talked about belantamab mafodotin a moment ago. If you saw a patient referred who failed everything in the community, would you use belantamab mafodotin or CAR T?

Sagar Lonial, MD, FACP: Are you asking me?

Keith Stewart, MD, ChB, MBA: Yeah.

Sagar Lonial, MD, FACP: To me, you go through the potential risks and benefits of each of the 2 treatments and lay it out for the patient. There are patients who say, I dont want to go into the hospital for whatever youre going to do to me. That takes CAR T cells away. You describe CRS to them, even though its mild in most patients, but they dont want to be put through that risk. There are other patients to whom any concern about loss of the ability to read or to drive is a deal breaker. For those folks, you know the BLMF is not necessarily going to be the right answer either. Theres a little more to this.

Keith Stewart, MD, ChB, MBA: Let me ask you the same exact question. A patient comes in who was referredand they want some kind of BCMA-targeted therapy. Which of the 2 would you steer the patient toward, or is it individualized? Does cost factor in?

Nina Shah, MD: Yeah. All things are equal. For example, if the patient has support and desire to come to the center, I would pick CAR T-cell therapy because its 1 and done, and has a higher overall response rate and, at this time, a higher PFS. But thats not always the case or isnt always possible because there may be different factors that go into this. But if theyre coming to me, Id like to be able to offer it. The next question is: Can we offer it? Will the commercial scale up be enough to do that? That will be another question for the patients.

Keith Stewart, MD, ChB, MBA: Very good.

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