Multiple Myeloma Cells Resistant to T-cell Therapies Exhibit a CD45+ Immunoevasive Phenotype.

Multiple myeloma is a plasma cell malignancy that is mostly incurable, even with recent advances in treatment such as B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells and bispecific T cell-engaging (TCE) antibodies. To better understand this treatment resistance, we examined multiple myeloma cells that persisted after these treatments and consistently observed CD45 upregulation as part of a resistance program. Bone marrow samples were treated ex vivo with BCMA CAR T cells, TCE antibodies (elranatamab, SAR442257), or activated T cells and analyzed via flow cytometry. CD45 upregulation was validated in patient samples before and after idecabtagene vicleucel therapy (anti-BCMA CAR T-cell therapy) and using an in vivo mouse model of disseminated multiple myeloma. Persisting multiple myeloma cells exhibited focal CD45 surface patches. Mechanistic studies implicated secreted HSP70, whereas bulk RNA sequencing revealed increased LAG-3, IFNγ signaling, and PD-L1 expression. These findings suggest that T cell-redirecting therapy (TCRT) drives an immunoevasive phenotype defined by CD45 upregulation and immune checkpoint activation, supporting combination strategies of TCRT with checkpoint inhibitors to overcome resistance in relapsed/refractory multiple myeloma.