Cilta-cel salvages ide-cel failure in relapsed multiple myeloma by driving distinct immune responses.

Ide-cel and cilta-cel are the two FDA-approved anti-BCMA CAR T cell therapies for the treatment of relapsed/refractory multiple myeloma. Here, we studied a patient who was initially treated with ide-cel with progressive disease and subsequently treated with cilta-cel with a complete response. To elucidate the underlying mechanisms underpinning the distinct clinical outcomes, we conducted multimodal, cross-tissue, and longitudinal single-cell analyses. This enabled us to directly compare the specific cellular and molecular factors distinguishing these two CAR therapies including their cell phenotypes, post-infusion kinetics, and endogenous immune landscapes. We found that the ide-cel infusion product was dominated by CD4 CAR T cells, upregulated a terminal effector phenotype, and exhibited elevated activation signatures. Post-infusion, ide-cel CAR T cells failed to proliferate, sustain cytotoxicity, or migrate into the bone marrow, resulting in persistent myeloma cells and dysregulated monocytes and natural killer cells. In contrast, the cilta-cel infusion product exhibited a balanced ratio of CD4 and CD8 CAR T cells, upregulated a resident memory-like signature, and displayed signatures of IL-1 and IL-2 family cytokine signaling. Post-infusion, cilta-cel CAR T cells retained their resident memory-like profile, were durably retained in the peripheral blood, and successfully infiltrated the bone marrow, leading to effective tumor clearance and reestablishment of immune homeostasis. Our results present important clinical evidence that cilta-cel can serve as an effective salvage treatment following ide-cel failure. By providing a direct patient-matched comparison between two CAR therapies, our study uncovers important insights into both CAR T-cell intrinsic properties and immune environmental factors that contribute to effective BCMA CAR T-cell treatment.