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Oxford Myeloma Workshop 2025 | Genomic determinants of resistance to anti-BCMA CAR-T in patients with R/R myeloma
Kenneth Shain, MD, PhD, Moffitt Cancer Center, Tampa, FL, discusses work investigating the genomic determinants of resistance to anti-BCMA CAR-T therapies in patients with relapsed/refractory (R/R) multiple myeloma (MM). Dr Shain highlights the importance of identifying predictors of response to CAR-T therapy, which can help tailor treatment decisions and minimize unnecessary treatment in patients who may not respond well. He notes that genomic complexity, including features such as TP53 mutations and 1q21 gain, may serve as a predictive biomarker for response to CAR-T therapy and that further research is needed to fully understand these findings. This interview took place at the 5th Oxford Myeloma Workshop in Oxford, UK.
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Transcript (AI-generated)
Yeah, so it’s a great collaboration. So again, looking at the genomics of kind of response to CAR-T, to BCMA CAR-T therapy. And so we did there is again a collaboration with multiple institutions in the United States, both University of Miami as well as MSK and ourselves at Moffitt, looking at a group of patients who were treated with CAR-T that had a whole genome sequencing done on them...
Yeah, so it’s a great collaboration. So again, looking at the genomics of kind of response to CAR-T, to BCMA CAR-T therapy. And so we did there is again a collaboration with multiple institutions in the United States, both University of Miami as well as MSK and ourselves at Moffitt, looking at a group of patients who were treated with CAR-T that had a whole genome sequencing done on them. Again, trying to provide that kind of structural block of what does it look like in the context of genetically what these patients look like, and then what are predictors of response, right? Who’s going to do well with CAR-T or not do well with CAR-T? And if you can do that, it’s a huge gain because CAR-T isn’t the simplest. It’s fantastic therapy, but it’s not the simplest for patients to go through. So if we know who’s not going to respond up front, it’d be good to maybe not give them CAR-T and have them go through that process.
And what was really cool is we learned several things. I mean, one of the most important lessons I think was is from a perspective, not many patients lack the actual target of these CAR-T cells, BCMA, but it is a way if you don’t have the target, antigen loss of BCMA, you’re not going to respond to a targeted therapy to it. That’s kind of common sense. What kind of reinforces that that’s been shown by other folks.
I think one of the cool things we learned is that there is kind of this signal for genomic complexity. So we know that if you really have these features that go along with it that really you might not do very well, your disease might not respond very well or very long to CAR-T therapy and I think it’s gonna take a little bit more for us to figure out what that really means, but I think right now that’s kind of the biggest thing that we walked away from it with was really there are several things that kind of go into this genomic complexity score, certain things we can all think about, TP53 mutations and 1q21 amplification, but then also hyper-APOBEC, things like that. These are things we know, but if you put them all together, they really kind of highlight groups that might not do as well with CAR-T. Again, more to follow, hopefully, in the very near future.
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Disclosures
Sanofi: Consultancy; BMS: Consultancy, Research Funding; Glaxo Smith Kline: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Takeda: Consultancy; Karyopharm: Research Funding; Janssen: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Adaptive Biotech: Consultancy; Amgen: Research Funding; Karyopharm, Janssen, Adaptive Biotechnologies, GlaxoSmithKline, BMS, Sanofi, Regeneron: Honoraria.
