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; Peter Voorhees, MD; and Shambavi Richard, MD.
In the next segment of the roundtable series, Drs. Voorhees and Martin discuss one of the FDA-approved CAR-T therapies for myeloma, idecabtagene vicleucel, including clinical trial and real-world data related to its safety and efficacy.
Dr. Martin: Now we have some therapeutics that are actually approved for use and in fact the two therapeutics that were first to be approved were both chimeric antigen receptor (CAR) T-cell therapeutics, both actually targeting BCMA. The first one came from the original studies using the CAR T cell that was noted as bb2121 and that eventually became our product known as idecabtagene vicleucel (ide-cel). Dr. Voorhees, can you give us a little update on what’s happening with ide-cel and how we got to the point we are right now?
Dr. Voorhees: As Tom mentioned, ide-cel is a BCMA-targeted CAR T-cell therapy. The phase I study was published in the New England Journal of Medicine back in 2019 by Noopur Raje, MD, and colleagues. What they did in this portion of the KarMMa studies is they looked at anywhere from 50 to 800×10-6 CAR T cells per patient. Patients received lymphodepletion chemotherapy with fludarabine and cyclophosphamide from days minus five through minus three. Then they underwent CAR T-cell infusion on day zero. What they found in this particular portion of the study is that dose mattered. Overall response rate was only 33% for those that got 50×10-6 CAR T cells, whereas those that received 450 to 800×10-6 CAR T cells had response rates of over 90%.
In this relatively small number of patients, median progression-free survival was close to 12 months, at 11.8. [It was] small numbers of patients, but there was a clear correlation with the number of cells that you got with regard to response. CAR T-cell expansion, whether that was measured by C-max or area under the curve, whether you got cytokine release syndrome or not, there was also a signal toward worse overall responses for those that had high-risk cytogenetics versus those who had standard-risk cytogenetics.
That led to the phase II portion of the KarMMa trial, which was also published in the New England Journal of Medicine two years later in 2021. Nikhil Munshi, MD, and colleagues published this data, and they took patients who had relapsed/refractory multiple myeloma. They had to have had at least three prior regimens, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. They had to be refractory to their last line of therapy. They had to have a good performance status at a creatinine clearance of 45 mL/min/1.73m2 or better. Patients received anywhere from 150 to 450×10-6 CAR T cells in the study. The vast majority of these patients were receiving either 300 or 450×10-6 and the lymphodepletion, and the timing of CAR T-cell infusion was the same as in the phase I trial.
What they found in this particular study is that the overall response rate was 73%, with a third of patients achieving at least a complete response. The median progression-free survival for the entire group was 8.8 months, but when you single out those that got 450×10-6 T cells, median progression-free survival was 12.1 months, and median duration of response was 10.7 months.
This, I think, is really an impressive dataset. That’s what led to regulatory approval of this particular regimen for patients with relapsed/refractory multiple myeloma. They also looked at markers, measures of response, and what they found here is that for those patients who had a low dose of cells, response tended to be negatively impacted by that, and patients who had revised International Staging System stage 3 disease going into CAR T-cell therapy also had inferior response rates. They saw very impressive responses in triple- and penta-refractory disease patients who had extramedullary disease as well. [It was] really nice data.
Dr. Martin: Awesome. In terms of the expression on BCMA on the surface of the plasma cells, do you think that is important, or is there any data that suggests we should start looking at that clinically?
Dr. Voorhees: Yeah, so far, no. In the initial phase I portion of the KarMMa trials, what they found was that whether you had more than 50% BCMA expression versus less, your responses were very good; now, they’re dichotomizing a continuous variable. Someone who has 5% expression versus 95% expression, maybe there’s a difference there. I think we need to study that more carefully. But the bottom line is that you can respond with a wide range of BCMA expression levels.
Dr. Martin: Excellent. Ide-cel was the first drug to be approved in this setting and has certainly been used clinically, and we do have some real-world experience. Doris Hansen, MD, has presented at multiple conferences the real-world experience, and it looks like it performs just as well as what you said. I think clinically we’re all seeing the same thing at our own centers, that it does work. It works in some of these patients who you wouldn’t expect to have any significant response for any other drug that we would’ve had access to, right?
Dr. Voorhees: Yeah, it’s pretty rare that real-world experience recapitulates what you see in phase I and phase II testing. The fact that the real-world experience was virtually identical with regard to progression-free survival is actually very reassuring. What we found in that particular real-world analysis is that prior exposure to BCMA-targeted therapies did negatively impact progression-free survival. There was also a signal toward inferior progression-free survival for those patients who had high-risk cytogenetic features.