Multiple Myeloma Surviving T Cell Therapies Exhibits a CD45+ Immune Evasive Phenotype

Multiple myeloma (MM) is an incurable plasma cell malignancy where relapse is inevitable, even after the advent of transformative T cell redirecting therapies (TCRT) such as chimeric antigen receptor (CAR)-T cells and bispecific T cell engaging (TCE) antibodies. Identifying and characterizing MM cells that persist after these therapies is critical to improving outcomes. Here, we demonstrate that MM persisting through CAR-T and TCE treatments upregulate CD45 as part of a resistance-associated gene expression program. Bone marrow samples from MM patients were treated ex vivo with TCEs elranatamab and SAR442257, as well as anti-BCMA CAR-T and activated T cell alone. MM cells surviving were analyzed via flow cytometry, and the phenotypes observed were validated using samples from patients before and after clinical treatment with idecabtagene vicleucel CAR-T. Across all treatments, MM cells persisting after treatment with TCRT exhibited new surface expression of CD45. Imaging flow cytometry revealed CD45 expression in discrete focal patches on the MM cell surface. Mechanistic studies implicated secreted HSP70 as a key driver of this effect. Bulk-RNA-Seq revealed a concurrent increase of LAG-3 and IFNγ signaling mRNAs alongside CD45 mRNA. These findings were confirmed at the protein level, where PD-L1 upregulation was also observed. Our results suggest that selective pressure from TCRT drives the emergence of an immune evasion phenotype in MM, marked by CD45 upregulation and immune checkpoint activation. These findings highlight the potential for combining TCRT with checkpoint inhibitors to counteract resistance in relapsed or refractory MM.