The EF1α promoter of cilta-cel drives a highly effective GZMK+ transcriptional program.

Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are approved BCMA-directed chimeric antigen receptor (CAR) T cells approved for the treatment of multiple myeloma. Although the higher efficacy of cilta-cel compared to ide-cel may be related to its unique nanobody binding domain, 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 efficacy, we analyzed CAR T cells from 87 patients with multiple myeloma (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. In myeloma xenograft models, the EF1α promoter in cilta-cel, rather than binding domain, recapitulated increased tumor control, enhanced expansion, and GZMK transcriptional profile compared with the MND promoter (ide-cel). These findings suggest that the efficacy of cilta-cel is linked to an EF1α-driven GZMK⁺ transcriptional trajectory that supports both persistence and effector function.