BCMA CAR promoter choice drives a highly effective GZMK+ transcriptional program

Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are FDA-approved BCMA-directed CAR T cells for multiple myeloma. The increased efficacy of cilta-cel compared to ide-cel may be related to its unique nanobody binding domain, but the constructs also differ in their use of EF1α and MND promoters, respectively, to drive CAR expression. To elucidate the basis of cilta-cel’s superior efficacy, we analyzed CAR T cells from 87 patients (50 cilta-cel, 37 ide-cel) using flow cytometry and single-cell multi-omics. Cilta-cel showed a 10-fold higher peak expansion and greater persistence, driven by an inflammatory GZMK⁺ T cell subset marked by EOMES expression and motif accessibility, but not exhaustion profile. Animal modeling revealed that the EF1α promoter (cilta-cel) rather than binder recapitulated increased tumor control, enhanced expansion and GZMK transcriptional profile compared to the MND promoter (ide-cel). Cilta-cel’s efficacy is therefore linked to EF1α-driven GZMK⁺ transcriptional trajectory that supports both persistence and effector function.