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IMS 2025 | Genomic drivers of resistance to anti-BCMA immunotherapies in multiple myeloma
Francesco Maura, MD, Memorial Sloan Kettering Cancer Center, New York, NY, gives an overview of a study on genomic drivers of resistance to anti-BCMA immunotherapies in multiple myeloma. The study found genetic signatures associated with good and poor outcomes, and Dr Maura highlights that the resistance mechanisms differ between CAR T-cell therapies and bispecific antibodies. This interview took place at the 22nd International Myeloma Society (IMS) Annual Meeting in Toronto, Canada.
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Transcript
So in this study, performed in collaboration with Moffitt Cancer Center, University of Miami, University of Calgary, and Memorial Sloan Kettering, we assembled a cohort validation set and training set from patients treated with CAR-T. And to investigate why, despite the unprecedented responses, these patients relapsed after a variable period. So, to understand what drives this behavior, we interrogated whole genome sequencing and single-cell RNA from these patients...
So in this study, performed in collaboration with Moffitt Cancer Center, University of Miami, University of Calgary, and Memorial Sloan Kettering, we assembled a cohort validation set and training set from patients treated with CAR-T. And to investigate why, despite the unprecedented responses, these patients relapsed after a variable period. So, to understand what drives this behavior, we interrogated whole genome sequencing and single-cell RNA from these patients. And our findings can be summarized with two main aspects. So, we think there is a group of patients where the myeloma transforms or evolves into something more aggressive, more proliferative, that reduces the expression of this marker like BCMA, making them refractory, growing in extramedullary disease and promoting T-cell exhaustion. These genomic signatures of aggressiveness predict refractoriness to most of our immunotherapies. So while this is bad news, the characterization of these signatures can also eventually allow the development of new targets or new drugs to treat this high-risk or immune-refractory patient. On the other hand, we found signatures with good outcomes and that’s of course highlighted by the fact that some patients can achieve very long responses to remission if they have the right genomics. Finally, we also identified different mechanisms when the tumor progressed compared to the specific antibody. Why the specific antibody? The tumor progresses with mutations because it had to escape the continuous stimulation from the antibody. In the CAR-T, the selection is very short in time. And that doesn’t mean the tumor doesn’t have to hide and wait until the storm is passed to pop up again. So that’s why we don’t see mutations in the CAR-T. So I think these are important findings that need to be expanded, validated, but have potential clinical implications for how we want to select the right therapy and the best therapy for our patients.
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