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

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
(i.e., baseline, ''day −4'') and after (i.e.,
''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.