Using CAR T Therapy in R/R Multiple Myeloma

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Keith Stewart, MD, ChB, MBA: Nina, let’s move on to the granddaddy of BCMA-targeted agents, which is CAR T therapy, with chimeric antigen receptor T cells. Let’s set the stage. Tell the audience where we’re at with CAR T therapy, particularly with respect to FDA approvals.

Nina Shah, MD: With BCMA and CAR T-cell therapy, there’s 1 product approved, which is IDE-CEL [idecabtagene vicleucel]. That’s 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 dose—which is going forward, the FDA-approved dose—the PFS was 12 months and 20 months if you’ve gotten a CR [complete response]. That’s the first approved product. There are other products coming down the line. We’re 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, it’s approved only for people who’ve had at least 4 lines of prior therapy?

Nina Shah, MD: Correct.

Keith Stewart, MD, ChB, MBA: Do you think that’s 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 you’re 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. It’s going to be hard for us to get there. You’re going to be using daratumumab–RVd [lenalidomide, bortezomib, dexamethasone] up front, and then you’re going to use carfilzomib second, selinexor, melphalan—I don’t know what’s going to happen. But there’s going to be a single-agent dexamethasone going onto the fourth line.

Keith Stewart, MD, ChB, MBA: You’re going to end up using 4 drugs, plus data, and rather than maintenance when we fail, you’re going to go to the CME [continuing medical education]. That’s 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 it’s up to date. You’re right. Christina, what about adverse effects? We’ve heard that these can be quite toxic therapies. What’s 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 don’t see a lot of the grade 3 and 4. It’s more manageable with the tocilizumab [Actemra] intervention. In neurotoxicity as well, to learn to mitigate, there’s an association between higher neurotoxicity with a high tumor burden. The study tried to bridge patients, to decrease the tumor burden, to minimize. That’s very important as well. In early intervention, it looks like there’s also a link between prior CRS and neurotoxicity. So early intervention with tocilizumab or steroids, and we’re learning how to use the CAR T-cell as well.

Keith Stewart, MD, ChB, MBA: Joe, today’s theme, as we’re 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. We’re not discussing the detail, but let’s 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. There’s a deliberate learning curve. Even within the KarMMa trial that Nina described, there was a learning curve. We’re becoming more aggressive in using, as Cristina said, the tocilizumab early up front, so it will become significantly safer. There’s 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. It’s still going to involve someone having their T cells collected, weeks to do manufacturing, etc, but it’s going to become considerably safer. It will be safer earlier in the disease course when people aren’t 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, it’s interesting. This triple-class refractory space is becoming quite congested. We have selinexor [Xpovio], we have belantamab mafodotin, we have melphalan flufenamide—the artist formerly known as Melflufen—and 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. We’re seeing response rates over 60%, 70%, and even—as we’re going to discuss in a moment—90%. 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, we’re still working through how to do that. But if they’re going to have access to a transplant-like center—they’re the ones that are basically doing CAR T—I’d be favor looking into CAR T-cell therapy after those 4 lines of prior therapy. We hope, with time, that we’ll 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 you’re probably missing a lot of people whom you could give CAR T cells to because, in general, it’s better tolerated than that. It’s the frail patient who can’t get through it, but don’t let age or anything else make that determination. It’s 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 don’t want to go into the hospital for whatever you’re going to do to me.” That takes CAR T cells away. You describe CRS to them, even though it’s mild in most patients, but they don’t 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. There’s a little more to this.

Keith Stewart, MD, ChB, MBA: Let me ask you the same exact question. A patient comes in who was referred…and 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 it’s 1 and done, and has a higher overall response rate and, at this time, a higher PFS. But that’s not always the case or isn’t always possible because there may be different factors that go into this. But if they’re coming to me, I’d 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.

Transcript Edited for Clarity