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EBMT 2021 | Future of BCMA-targeting CAR-T for myeloma

Nikhil Munshi, MD, Dana-Farber Cancer Institute, Boston, MA, gives a summary of his talk on B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of multiple myeloma. Dr Munshi discusses results of the Phase II KarMMA study (NCT03361748) of idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma, which has shown promise in patients with advanced disease. Dr Munshi also outlines the use of ciltacabtagene autoleucel (cilta-cel) and shares his thoughts on the future of CAR-T for the treatment of myeloma. This interview took place during the 47th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) 2021.

Transcript (edited for clarity)

So, thank you very much for having me here. And I think this is one of the most important topics of this discussion at EBMT, mainly because of the impending approval of the first of many such products available. Now, BCMA is a great target in myeloma because it’s expressed only on myeloma cells and normal plasma cells. And because there is a growth connection between this molecule and myeloma cell survival...

So, thank you very much for having me here. And I think this is one of the most important topics of this discussion at EBMT, mainly because of the impending approval of the first of many such products available. Now, BCMA is a great target in myeloma because it’s expressed only on myeloma cells and normal plasma cells. And because there is a growth connection between this molecule and myeloma cell survival. So, with this characteristic, a number of products have been evaluated and the discussion in the EBMT was focused on the results with this.

The study that is most advanced and was published just very recently in New England Journal of Medicine comes from a Phase II study of idecabtagene vicleucel or ide-cel, a Phase II study in patients with relapsed/refractory myeloma. In patients with three or more lines of therapy and having exposure to all the three drugs, et cetera, patients where leukapheresis CAR-T cells were produced, takes around four weeks, and then before infusion patient received lymphodepletion. This is a standard for every CAR T-cell at the present time, lymphodepletion with fludarabine and Cytoxan.

And in this study, 128 patients were treated, and these were very advanced disease patients. On average, they had received 6 median lines of therapy, six years from treatment. One third to 40% patients had high-risk disease, et cetera. In this very advanced disease patients, overall response rate was 73%, with 33% achieving CR. But the target dose of 450 million cells, the response rate was 82%. Again, almost 40% achieving CR and significant proportion of CR patient, there was 70% also achieved an MRD negativity. So very, very deep responses. Also, PFS is 8.8 months. However, PFS is 20 months in patients who get a CR. Overall survival in this particular study was 19-plus month and it is still premature for final version.

Importantly, ide-cel has the same side effect that you’d expect with CAR T-cell, which is cytokine release syndrome in 90-plus percent patient. But majority grade 1 and 2. Only 6% were grade 3. Neurotoxicity, 18 to 20%. Again, grade 1 and 2, with a small 3% grade 3 toxicity. And cytopenia isn’t a concern. All are manageable toxicity, and the important news is that this is a very important component of our treatment in myeloma when this drug becomes available.

Another large study that has been presented has been a product called cilta-cel. And cilta-cel is another BCMA-targeting molecule. The two targeting epitopes is how it differs from ide-cel. And in the large Phase II study in 97 patients, the overall response rate was 96%, with 67% patients achieving stringent CR. Also, very deep MRD-negativity in the majority of the patients.

And toxicity profile is more or less similar. There is a cytokine release syndrome in almost all patients. Neurotoxicity is relatively limited. There is also a component of late neurotoxicity, but overall, very manageable. And so, this is another product which is expected to be approved hopefully by the end of the year.

And then there were a number of other studies which were presented in this session which suggest – there’s an orva-cel, bb21217, et cetera – and they just suggest, all of those studies put together, that even in advanced myeloma we get deep responses. We get very high level of responses, 70-90, 95% with CRs. And the toxicity is very similar with low-grade CRS and low-grade neurotoxicity.

So, great excitement, even in advanced patient. And an important component of the discussion was how to improve from this point on. So, these drugs are going to become available. How do we improve upon it? And there’s a great discussion about various newer methods of producing CAR-T cells that may have more memory component. We could have RNA CAR, changing the constitutions, CD4:CD8 ratio of the CAR-T cells. And then there is something called BAT CAR where we can modulate the CAR activity by injecting different tagged antibodies, et cetera.

And on the other hand, we have to improve the patient selection. Treat patients at the earlier time point with less disease burden and also use agents such as gamma-secretase to increase BCMA.

Very importantly, many new targets are coming up for CAR T-cell. GPRC5D is one of them. And so bottom-line message of this presentation and the current status is that there’s a great excitement for BCMA as target, which has provided deep responses. And in combination with various other agents and with various other strategies, we are looking to get long, durable, disease-free survival in these patients, and what I would call inching towards a cure.

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