Reconstitution of the multiple myeloma microenvironment following lymphodepletion with BCMA CAR-T therapy

<p>BCMA-targeted CAR-T therapy has shown potent treatment outcomes in treating multiple myeloma (MM), a disease characterized by malignant bone marrow (BM) plasma cells. However, the remodeling of MM microenvironment after CAR-T therapy remains poorly understood. Here, we report the reconstitution of MM microenvironment by obtaining single-cell transcriptomes for paired BM specimens (n = 14) from 7 MM patients before (<em>i.e.</em>, baseline, ''day −4'') and after (<em>i.e.</em>, ''day 28'') post-lymphodepleted BCMA CAR-T therapy. Our analysis revealed heterogeneity in driver gene expression among MM cells, even those harboring the same cytogenetic abnormalities. The best overall responses of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8⁺ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells (Tregs), enhanced CD8⁺ effector T cell cytotoxic activity, and elevated type 1 conventional dendritic cell (cDC1) antigen presentation ability. DC re-clustering inferred intramedullary-originated cDC3s with extramedullary migration. Cell-cell communication network analysis indicated BCMA CAR-T therapy mitigates BAFF/GALECTIN/MK pathway-mediated immunosuppression and activates MIF pathway-mediated anti-MM immunity. Our study sheds light on MM microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.</p>