Ciltacabtagene Autoleucel and CARTITUDE Findings in Relapsed/Refractory Myeloma

A roundtable discussion, moderated by Thomas Martin, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center, focused on CAR T-cell therapy considerations in the treatment of multiple myeloma, including data on approved CAR-T options and a look at the pipeline. Dr. Martin was joined by a panel that included Sagar Lonial, MD, FACP, FACP; Peter Voorhees, MD; and Shambavi Richard, MD.

In the next segment of the roundtable series, the panel discusses the second FDA-approved CAR-T therapy for myeloma, ciltacabtagene autoleucel, including results from the CARTITUDE studies.

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Dr. Martin: We have a second product now, ciltacabtagene autoleucel (cilta-cel), and cilta-cel is actually a product that originally came from China. Very interesting, we had a patient at UCSF that actually went to China, and he was the first US patient to receive this chimeric antigen receptor (CAR) T-cell therapy. I tell him all the time, you are responsible for this to be a drug in the United States, because he went there with very refractory disease, triple-class refractory; we had nothing more to give him. He came back without all the extramedullary disease that he went there with, in complete remission, and we were just amazed. We were nervous when he went to China, and we were amazed when he came back. Dr. Richards, can you give us a little update of where we are with cilta-cel and the clinical development?

Dr. Richard: The Legend product and the CARTITUDE studies, I think, reset the bar with BCMA CAR T cells and just what to expect from patients who were so refractory and so advanced. CARTITUDE-1 was a phase Ib/II study to assess the safety and efficacy of cilta-cel. This is also a second-generation autologous BCMA-directed CAR-T product. But one difference, cilta-cel is different from ide-cel, in that the tumor binding domain actually targets two BCMA epitopes, and it was designed this way to confer an increased avidity. Patients eligible for this study were a very advanced group, again, similar to the KarMMa trials; [they] had to have three or more prior lines of therapy, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 antibodies or had to be double refractory to PI and IMiD or had to have progressive disease within 12 months of their last line of therapy.

So, 97 patients were enrolled and studied on this trial, with a median of six prior lines of therapy. [This was a] very advanced group: 88% were triple-class refractory, 42% were penta-refractory, and 99% were refractory to their last line of treatment. The responses happened quick, by the first month, and best responses was seen at less than three months; these responses tended to deepen over time. These were actually updated at the two-year mark post-last patient, actually on your paper, Tom, in the Journal of Clinical Oncology. The results again were outstanding. The overall response rate was 98% for all patients, [with] very deep responses: stringent complete response (CR) in about 83% of patients; 61 of these 97 patients were minimal residual disease (MRD)-evaluable, and 92% of them were actually negative. But even more impressively, these MRDs were sustained in 68% of patients at six months and in about 55% of patients at 12 months.

Also impressively, the median progression-free survival (PFS), overall survival, and duration of response has not been reached at this almost 28-month follow-up. The 27-month PFS rate is about 55%. But then when we tested patients with deeper responses, so PFS for stringent CR was 64% and then for those who had sustained MRD at six months, it was 73%. These were excellent results. Again, by the same token, when you look at two-year overall survival, it was 70% at 27 months. But then when looking at patients with sustained MRD for at least six months, this was well over 90%. Compared to standard-of-care approaches, where we expected median overall survival for triple-class refractory patients to be less than 12 months or penta-refractory patients to be less than six months, these were indeed impressive results.

Based on this, cilta-cel was approved by the FDA last year in February as a commercially approved CAR-T product. Interestingly again, there were some other differences when looking at cilta-cel in terms of correlatives for response. For one thing, not surprisingly, depth of response was important too, for the ultimate outcome in terms of progression-free survival. Patients who were in stringent CR or sustained MRD negativity had a longer PFS. Interestingly, also patients in the higher-risk groups, like the high-risk cytogenetic abnormalities or patients with baseline plasmacytomas, they did have good response rates, comparable response rates, but their PFS was a little bit less, as expected. Patients at high risk continue to be at high risk even with these very powerful tools in terms of high tumor burden or high-risk cytogenetics or baseline plasmacytomas.

But interestingly, no correlation was observed with these in terms of expansion of CAR T cells, exposure, persistence, or even BCMA expression on myeloma cells. That’s something interesting with this product that seems to be a little different. Other correlatives that we heard about recently was that in terms of baseline pro-inflammatory parameters that seem to also influence the progression-free survival, patients who came in with baseline high ferritins or C-reactive protein (CRPs) or IL-6 and other things, or even high baseline neutrophils, things that you think are somewhat in this pro-inflammatory milieu, these patients also seem to have a shorter progression-free survival as compared to the overall group.

Dr. Martin: Are there any clinical features in a particular patient that you’d say, okay, this is a great patient for cilta-cel?

Dr. Richard: Ultimately, I just want to get the best response for the longest time. I think it’s quite intuitively patients who just are in a better disease shape, just in terms of low tumor burden at the time of not progressing at the time of the CAR-T. All of these inflammatory markers are not really sizzling; they’re not high ferritins and high CRPs when they come in. Overall, the disease is behaving itself. Ultimately, they get through the CAR-T process most smoothly, not too many ruffles; the cytokine release syndrome is managed, not too much of the other neurotoxicity and things like that. They tend to just do better overall in terms of disease. But I guess we could say that with any goal of therapy.

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Continue on to watch the next roundtable segment.