Abstract 3980: Non-canonical CAR T cell states correlate with durable therapeutic responses in multiple myeloma patients

Abstract Background: Chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) have exhibited unprecedented efficacy with >70% initial response rate in patients with relapsed/refractory multiple myeloma (RRMM), which led to FDA approval of 2 CAR T products: ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel). However, long-term clinical outcomes vary markedly in RRMM patients. Prior studies have shown that specific states of CAR T cells, immature myeloma phenotype and hostile tumor microenvironment (TME) are associated with rapid relapse, but much remains to be elucidated regarding how CAR T cells evolve, persist and interact with host immunity over time in patients with distinct clinical outcomes. Methods: We acquired longitudinal bone marrow (BM) and peripheral blood mononuclear cells (PBMC) samples from 22 RRMM patients receiving 4 different anti-BCMA CAR T products, including cilta-cel (n=7), ide-cel (n=5), BB21217 (n=1) and orva-cel (n=9). The frequency and cell states of CAR and non-CAR T cells were assessed using flow cytometry and single-cell multi-omics (scRNA-seq). Results: At 1-month post-infusion, the frequency of CAR T cells in BM was significantly higher in durable responders (DR, PFS>12mo) than transient responders (TR, PFS<12mo) (p=0.04). Single-cell transcriptomic profiling further demonstrated CAR T cells in DR patients were significantly enriched in memory-like and proliferative states with less exhaustion phenotype. After 1 month, the frequency of persisting CAR T declined in all patients, but DR patients had significantly higher frequencies of CAR T cells than TR (p<0.0001). By 6 months, persisting CAR T cells in DR patients predominantly exhibited a non-canonical state (T persisters) possessing high expression levels of AP1 genes, NF-κB regulators, and effector cytokines as well as low level of exhaustion-related genes. By single-cell TCR tracking, these T persisters transitioned from multiple cell states at early timepoints. In DR patients, classical monocytes within the BM exhibited less immunosuppressive phenotype post CAR T infusion. Conclusions: Favorable clinical outcomes in RRMM patients are associated with greater expansion and persistence of CAR T. Durable responses are also associated with non-canonical CAR T cell states as well as a less immunosuppressive tumor microenvironment. These results provide insights into the determinants of durable clinical responses with anti-BCMA CAR T cells for RRMM. Citation Format: Kai Wu, Karen Law, Serena Kwek, Marcel Arias-Badia, Aram Lyu, Rachel Wolters, Averey Lea, Matthew Clark, Chang Liu, Ye Li, Ryan Owens, Lam Trieu, Alex Tran, Mark Bridge, Zenghua Fan, Alexander Cheung, Jeffrey Wolf, Andrew Portuguese, Jordan Gauthier, Thomas Martin, Justin Eyquem, Lawrence Fong. Non-canonical CAR T cell states correlate with durable therapeutic responses in multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3980.