Multiple Myeloma Cells Resistant to T-cell Therapies Exhibits a CD45+ Immune Evasive Phenotype

Multiple myeloma (MM) is plasma cell malignancy that is mostly incurable, even with recent advances in treatment such as BCMA-targeted chimeric antigen receptor (CAR) T cells and bispecific T cell–engaging antibodies (TCEs). To better understand this treatment resistance, we examined MM 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, TCEs (elranatamab, SAR442257), or activated T cells, and analyzed by flow cytometry. CD45 upregulation was validated in patient samples before and after idecabtagene vicleucel therapy (anti-BCMA CAR T-cell therapy), and by using in an in vivo mouse model of disseminated MM. Persisting MM cells exhibited focal CD45 surface patches. Mechanistic studies implicated secreted HSP70, while bulk RNA-sequencing revealed increased LAG-3, IFN-γ signaling, and PD-L1 expression. These findings suggest T cell–redirecting therapy (TCRT) drives an immuno-evasive phenotype defined by CD45 upregulation and immune checkpoint activation, supporting combination strategies of TCRT with checkpoint inhibitors to overcome resistance in relapsed/refractory MM.