SOHO 2023 | Considerations for mitigating CAR-T resistance in multiple myeloma

CAR-T cell resistance is a real phenomenon. We don’t, I would say that we don’t have a way really to mitigate the CAR-T cell resistance at the current time, other than probably most likely doing it in patients that have early relapse or, you know, earlier lines of therapy. I think with earlier lines of therapy, the T-cells are, you know, perhaps going to be less exhausted. And also the immunosuppressive cells, the Tregs, the Bregs, the MDSCs, I think will be less abundant in the bone marrow in patients that have earlier lines of therapy. What we don’t know, and what would be something that we’re all trying to figure out, is, are there therapies that we can give going into CAR-T cell therapy that potentially would prime the bone marrow to a better position so that patients actually will have a better response to CAR-T cell therapy. We also are noting that, you know, after CAR-T cell therapy, there is this clonal escape of cells that basically are BCMA negative. We now are starting to find a small percentage of patients that are actually BCMA negative. We’re also in the bispecific space, finding patients that actually have mutations in BCMA. And so that antigen on BCMA that the antibody is targeted against, there’s a mutation in that region and thus the antibody no longer binds. These are investigations that we need more of and we need to really figure figure it out. One of the things that might help also is to do combinations of therapies. And so maybe we actually need to do CAR-T cell therapy and do a short course of maintenance therapy. Maybe if we had a CELMoD and we can use that either before, during or after CAR-T cell therapy. Or we can do maintenance with a bispecific targeting a different antigen like talquetamab after a BCMA CAR-T cell therapy. These are strategies that we’ve all been thinking about and considering to try to mitigate problems with resistance. But it’s a real deal. And, you know, I think one of the biggest developments in the next one to five years will be figuring out that that issue and trying to actually make it so that CAR is actually, they last longer, and basically that we’re not developing this resistance to a certain target on the cell surface.