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IMS 2025 | Improving CAR T-cell responsiveness and overcoming resistance in multiple myeloma
Meral Beksac, MD, Istinye University Ankara Liv Hospital, Ankara, Turkey, discusses strategies to improve CAR T-cell responsiveness and overcome resistance in multiple myeloma. Dr Beksac suggests decreasing tumor burden before CAR-T, as well as adding drugs to improve CAR T-cell responsiveness. This interview took place at the 22nd International Myeloma Society (IMS) Annual Meeting in Toronto, Canada.
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Transcript
Depending on the different factors, CAR-T refractoriness may develop. And based on evidence and published data, we know that patients who have a very aggressive disease are prone to have less response after CAR-T. And these types of patients have multiple factors related to refractoriness and it may be related to the antigen and also the antigen profile of the cells and also in the microenvironment and the immune responsiveness of the patient...
Depending on the different factors, CAR-T refractoriness may develop. And based on evidence and published data, we know that patients who have a very aggressive disease are prone to have less response after CAR-T. And these types of patients have multiple factors related to refractoriness and it may be related to the antigen and also the antigen profile of the cells and also in the microenvironment and the immune responsiveness of the patient. To overcome this, it’s possible to decrease the tumor burden before going into the CAR-T production and also CAR-T therapy. And this way, it is possible to come back and return and circumvent the refractoriness of the aggressive disease. So this is one strategy. And the second strategy is when the CAR T-cells are introduced to the patient, they can have a short or longer lifespan. And it is possible to measure the persistence of CAR T-cells. In the case that the CAR T-cells are still there, but the target is missing or there’s a mutation, which is a rare situation, then it is time to change to another target. So the sequencing experience so far shows that to change from, let’s say, from BCMA to GPRC5D or FcRH5, these are the ways to overcome the antigen-related issues. But if the CAR T-cells are still persistent, but the immune responsiveness is not optimal, in that case, we can add drugs such as IMiDs, CELMoDs, immune checkpoint inhibitors. So these are the newer approaches to improve the CAR T-cell responsiveness and overcome resistance. And in some disorders, which is the other type, for instance, extramedullary disease, in that case, the penetrance of the CAR T-cells into the microenvironment in the extramedullary disease may not be optimal, or the cells in that microenvironment may be myelosuppressive and for this reason it’s not effective as it should be. And to overcome this the dual antigens either by bispecifics or bispecific CAR T-cells are the way to go to overcome refractoriness in this type of very difficult-to-treat myeloma subgroup.
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Disclosures
Janssen: Research Funding, Speakers Bureau; Menarini: Consultancy, Other: advisory; GSK: Research Funding; Sanofi: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Membership on an entity’s Board of Directors or advisory committees.
