Joseph Mikhael, MD

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 Cristina, there are multiple CAR T [chimeric antigen receptor T-cell] products against BCMA in the pipeline, but the 1 that’s heading toward FDA approval the quickest is cilta-cel [ciltacabtagene autoleucel]. Do you want to tell us a little about that?

 Yeah. I have a new user, but he has different constructions. The persistency is probably superior to the other stuff. I was so surprised and sad, as money gave an update with longer follow-ups of patients in this trial. In the end, I was surprised that responses did that.

 Tell the audience what the results were.

 The responses were an overall response of 98%, I want to believe 90%, and the number of patients achieving a complete remission was about 60% with MRD [minimal residual disease] positivity. I don’t remember the exact numbers, but it was impressive and very rapid. Also, the durability, and the progression-free survival [PFS] with the longer follow-up, is close to 2 years with this type of CAR T cell. I was impressed because, before we were talking about how to choose CAR T cell vs 

 mafodotin, sometimes you can offer CAR T cell if you don’t have the time, right? You have the patient progressing rapidly, you have to collect lymphocytes to prepare—which takes some time—and you may not be able to stabilize the myeloma, so you have to go outside the shelter quickly. CAR T is moving a little earlier in clinical trial. I’m particularly interested in high-risk disease, and it looks as if this is effective. That means that the responses and the toxicity profile were also very friendly—the CRS, and the neurotoxicity, grade 1 and 2. So I liked the follow-up. I really did.

 Joe, were you impressed with that data? Was it exciting?

 It was hard not to be impressed with the data. I’m impressed with the data throughout, with all CAR T cells, but in particular, I emphasized 1 thing a little more. Nina mentioned it briefly. Keith, this notion of the 1 and done. I think of a patient I saw not that long ago who said he’s nearly 2 years post–CAR T and has been on a trial. He says, “Doc, I love you. But I’m glad I’m not seeing you as frequently.” That’s when you know that he’s doing as well as he’s feeling.

 Yeah. I love you too, Keith. That’s an interesting point. Now that day may come where we know these aren’t—right now at least—curative, where we may have to introduce some kind of maintenance therapy after CAR T. Maybe there’s a way to keep the T cells engaged. We’re looking at different mechanisms. But to me, that was striking. In this group of people, who we generally wouldn’t have expected to have a survival over 9 or 10 months, to have a PFS pushing 2 years. Even in the KarMMa study, early on we heard about the PFS of 9 months, but the overall survival was close to 20 months. It’s not as if when someone relapses after CAR T, it’s game over. We have other options for the patient thereafter. I’m very encouraged by the CAR T data, and I’d like to get our hands around some of the toxicities a little better. We’ll do that with time.

 Sagar, what’s your impression of this?

 The CAR T data are impressive. It’s a small phase 2 study, and to compare 1 small phase 2 study against another, and say 1 is better, is a little challenging. The patients weren’t the same.

 I was going to ask you that specific question. It’s unfair to cross compare, but why? They’re both 5 to 6 prior lines. One has double the PFS compared with the other one. Why is it unfair to compare them?

 Because if you look at the number of triple-class refractory patients, it’s not the same between the 2 trials. There were more patients in the KarMMa trial than there were in the CAR T 2 trial. And you don’t know about the delays from enrollment to getting drug or other situations that may have influenced who got the product. Remember, CAR T cells—Nina and Joe keep saying they’re 1 and done—are 1 and done until they aren’t. So far, every patient, unfortunately, has relapsed. So it’s 1 and done for a short period of time. There are intrinsic biases in who gets the drug because they could wait a long time for manufacturing, and screening, and other things. It’s hard to say 1 is better.

 Nina, there has been a strange phenomenon of some later neurotoxicity and HLH [hemophagocytic lymphohistiocytosis] is common, more so than we expected. What’s your experience with delayed toxicities if you will?

 CRS happens all the time. It’s between 80% and 95%, depending on the product, and it’s usually grade 1 or 2. Neurotoxicity has been a little more confusing. I believe it’s 18% with IDE-CEL [idecabtagene vicleucel], but 20% with cilta-cel [ciltacabtagene autoleucel]. That was not all ICANS [immune effector cell-associated neurotoxicity syndrome]. ICANS is the neurotoxicity you expect from CAR T cell. There’s a little confusion, and you’ll seem a little drunk, but about 12% of people in the cell-to-cell data had this strange neurotoxicity, which was like cognitive issues or peripheral neuropathy. One person did die from that. Reassuringly, at the ASCO [American Society of Clinical Oncology annual meeting] update this past year, Saad Usmani presented that nothing else had happened. There weren’t any additional weird neurotoxic events in any of the other participant programs. These were constant data, but they did suggest that the tumor burden is possibly associated with developing this adverse effect. I suspect that there may be some epitope binding with some neurology tissue, but we don’t know because there could have been some other things seen in the bispecific category as well. To your question about HLH, yes. There was this mass-like phenomenon that happened—and it happens with a small percentage, maybe a minority of patients—in a lot of these patients. Actually, it’s treatable by anakinra [Kineret] and may ultimately cause some prolonged cytopenias, but it’s manageable. I definitely wouldn’t say don’t get CAR T therapy because of that.

 I must say, in my personal experience, I may have been unlucky, but for the audience, who haven’t used CAR-T, peripheral neuropathy—like cranial or neural palsies—has Parkinson-like symptoms. Even lower motor weakness is something strange that happens occasionally. Be aware if your patient is going for CAR T therapy and they get sent back to your care if they start to develop neurological symptoms. It’s not common, but it’s reported for both products. Please get in touch with the treating center if you see those things happening. It’s a bit unclear if it’s because of too many CAR T cells in the circulation or if something is otherwise unrecognized.

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Experts discussed safety and efficacy data of cilta-cel for R/R MM from the CARTITUDE-1 and CARTITUDE-2 studies.

CARTITUDE Trials in Multiple Myeloma

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 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.

 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.

 If I understand it correctly, it’s approved only for people who’ve had at least 4 lines of prior therapy?

 Do you think that’s fair, or do you think the FDA was harsh on that company with that?

 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 

 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.

 Yeah. If the insurance company loves it. Correct.

 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?

 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.

 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?

 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.

 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?

 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.

 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?

 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.

 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?

 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.

 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?

 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.

Nina Shah, MD, and other experts discuss the role of CAR T-cell therapy in relapsed/refractory multiple myeloma.

Joseph Mikhael, MD

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