Anti-BCMA CAR T-Cell Expansion and Its Association with Response and Toxicity in Multiple Myeloma

Background:

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cells have revolutionized the management of relapsed/refractory multiple myeloma (RRMM). However, data on CAR-T expansion and persistence and the association with response and toxicities are limited (Fischer et al., Leukemia 2024). We analyzed RRMM patients treated with standard of care CAR-T (idecabtagene vicleucel, ide-cel and ciltacabtagene autoleucel, cilta-cel) to assess the expansion and persistence of BCMA-targeted CAR T-cells and association with response and toxicities.

Methods:

Circulating CAR T-cells were assessed and quantified by flow cytometry. A PE fluorochrome labeled human BCMA/TNFRSF17 protein was used to detect BCMA-specific CAR T-cells. A total of 56 RRMM patients treated with ide-cel (n=30) or cilta-cel (n=26) were included in the analysis. Response was assessed by IMWG criteria and was categorized into complete response (CR), very good partial and partial response (VGPR/PR), stable disease (SD) and progressive disease (PD). Continuous variables were compared using a Mann-Whitney U-test, while time-to-event variables were compared using a Cox proportional hazard model. Median follow-up was calculated using the reverse Kaplan-Meier method.

Results:

Median age of our cohort was 67 years, 13% were Black, 25% were Hispanic, 36% had high-risk cytogenetics, 46% had extramedullary disease (EMD). Median prior lines of therapy were 5 and 48% were penta-refractory.

Median follow up was 19.7 (95% CI: 12.7, 26.3) months for ide-cel (n=30) and 7.2 (95% CI: 4.9, 19.0) months for cilta-cel (n=26). The median time-to-progression (TTP) was 8.5 (95% CI: 4.2, 21.9) months for ide-cel and 15.3 (95% CI: 4.5, 19.6) months for cilta-cel. The median time to reach the peak CAR-T expansion was 14 (95% CI: 7.3, 15) days for ide-cel, and 14.5 (95% CI: 14, 17.3) days for cilta-cel.

Within the ide-cel cohort, peak CAR-T expansion was higher amongst responders (PR or better) compared to patients with SD/PD based on response at 3 months (median 70.4/uL in responders vs 5.3 in non-responders; P<0.001) as well as at 6 months (157.4 vs 6.2/uL; P<0.001). The ide-cel peak levels were not significantly associated with TTP via Cox proportional hazards model (HR 0.99, P=0.107). We next assessed whether peak expansion was associated with toxicities. The peak ide-cel levels were not significantly different between patients who developed cytokine release syndrome (CRS) or not, P=0.933, nor in patients who developed immune effector cell-associated neurotoxicity syndrome (ICANS) or not, P=0.358.

Within the cilta-cel cohort, peak expansion was higher in responders compared to non-responders at 3 months (median 148.7/uL vs 65.9/uL) and 6 months (median 128.3/uL vs 89.7/uL), though these did not reach statistical significance (3 months: P=0.273; 6 months: P=0.65). Similar to the ide-cel cohort, peak expansion levels were not significantly associated with TTP (HR 0.99, P=0.59) as well as CRS (P=0.51) in the cilta-cel cohort. However, interestingly, the peak expansion was significantly higher for patients who developed ICANS (median 1269.2/uL) versus those who did not develop ICANS (median 99.7; P<0.001).

Conclusions:

We demonstrate that CAR kinetics are associated with response and toxicity and that these associations may differ among CAR-T products. In the ide-cel cohort, peak CAR-T expansion was associated with response at 3 and 6 months and no significant difference in toxicities. In the cilta-cel cohort, higher peak CAR-T levels were associated with ICANS development. Neither cohort demonstrated significant association between peak CAR expansion levels and TTP. Future studies are needed to confirm these findings in larger sample sizes.

Kennedy:Astellas: Consultancy. Smith:CVS Caremark: Consultancy; A28 Therapeutics: Current holder of stock options in a privately-held company. Shiraz:Kite Pharma-Gilead: Research Funding. Dahiya:Adaptive Biotechnologies: Consultancy; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Kite-Pharma-Gilead: Consultancy, Research Funding. Weng:Dren Bio: Other: Member of Data and Safety Monitoring Board . Muffly:Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Research Funding; Autolus: Consultancy; Vor: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Cargo Therapeutics: Consultancy; Astellas: Consultancy; Adaptive: Research Funding; Jasper: Research Funding. Mackall:Link Cell Therapies: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Mammoth: Consultancy, Current equity holder in private company; Ensoma: Consultancy; Lyell Immunopharma: Current equity holder in publicly-traded company, Research Funding; Immatics: Consultancy; Adaptimmune: Consultancy; Bristol Meyers Squibb: Consultancy; Cargo Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Miklos:Bristol Myers Squibb: Consultancy; Galapagos: Consultancy; Miltenyi: Consultancy, Research Funding; Novartis: Consultancy; Adaptive Biotechnologies: Research Funding; Allogene: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel Support, Research Funding; Janssen: Consultancy, Patents & Royalties; Juno Therapeutics: Consultancy; 2SeventyBio: Research Funding; Fosun Kite Biotechnology: Honoraria; Adicet: Research Funding. Mikkilineni:Legend Biotech: Consultancy, Other: advisory board at ASH December 2023; BiolineRx: Consultancy, Other: advisory board at ASH December 2023. Sidana:Oncopeptides: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Regeneron: Consultancy; Takeda: Consultancy; BiolineRx: Consultancy; Legend: Consultancy; BMS: Consultancy, Research Funding; Kite, A Gilead company: Consultancy; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Sanofi: Consultancy.