A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma

Chimeric Antigen Receptor (CAR) T-cell therapies targeting B-cell maturation antigen (BCMA) have transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM). In this study, we present a real world cohort of 61 RRMM patients treated with idecabtagene vicleucel (Ide-cel, n=34) and ciltacabtagene autoleucel (Cilta-cel, n=27). Cilta-cel demonstrated superior complete response (CR) rates (CR: 78% vs. 38%, p < 0.001) and longer progression-free survival (PFS), with a distinct CAR-T expansion profile marked by increased CD4+CAR+/CD8+CAR+ ratio. To gain insights into immune dynamics encompassing CAR-T cell infusion with either product, we developed a longitudinal multi-omics single-cell atlas using 135 peripheral blood samples from 57 of the 61 patients. There was a strong association between CD4+ cytotoxic T cells and treatment with Cilta-cel, CR and CRS occurrence. Analysis of T cell receptor repertoires showed higher clonality in CD4 T cells in CR patients at all time points. CD8 T cells of non-CR patients showed transcriptomic changes in line with impaired effector function after CAR-T infusion. The BCMA expressing circulating plasma cells, B-cells and plasmacytoid dendritic cells were depleted after infusion in a response-dependent manner, with Cilta-cel leading to significantly slower B-cell recovery (p=0.03). Increased soluble BCMA reduction between day 0 and 30 was linked to stronger CAR-T expansion and higher CRP levels, suggesting an association of tumor debulking and systemic inflammation (p < 0.01, respectively). Our analyses provide a comprehensive resource for understanding longitudinal cellular kinetics in RRMM patients treated with BCMA-directed CAR-T cells.