CARTITUDE-1 and CARTITUDE-2 Trials in Multiple Myeloma

Keith Stewart, MD, ChB, MBA: 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?

Cristina Gasparetto, MD: 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.

Keith Stewart, MD, ChB, MBA: Tell the audience what the results were.

Cristina Gasparetto, MD: 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 belantamab 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.

Keith Stewart, MD, ChB, MBA: Joe, were you impressed with that data? Was it exciting?

Joseph Mikhael, MD: 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.

Keith Stewart, MD, ChB, MBA: You don’t care about me, Joe.

Joseph Mikhael, MD: 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.

Keith Stewart, MD, ChB, MBA: Sagar, what’s your impression of this?

Sagar Lonial, MD, FACP: 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.

Keith Stewart, MD, ChB, MBA: 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?

Sagar Lonial, MD, FACP: 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.

Keith Stewart, MD, ChB, MBA: Is that true for both of them though?

Sagar Lonial, MD, FACP: Yes. That’s right.

Keith Stewart, MD, ChB, MBA: 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?

Nina Shah, MD: 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.

Keith Stewart, MD, ChB, MBA: 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.

Transcript Edited for Clarity