Impact of CAR T-Cell Persistence on Clinical Outcomes in Relapsed/Refractory Multiple Myeloma: Insights from the Phase 2 Fumanba-1 Study
Authors: Li Chunrui , Zou Dehui , Wang Di , Fang Baijun , Huang He , Li Jianyong , Chen Bing , Liu Jing , Zhang Xi , Dong Yujun , Hu Kai , Liu Peng , Mi Jianqing , Ding Kaiyang , Li Zhenyu , Dong Qie , Zhang Fuyuan , Hu Guang , Qiu Lu-Gui 
Published: December 2024

Background: The persistence of CAR T cells is a critical factor in their therapeutic efficacy, particularly in the treatment of hematologic malignancies such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and large B-cell lymphoma (LBCL). Notably, in multiple myeloma (MM) therapies targeting B-cell maturation antigen (BCMA), prolonged CAR T-cell persistence has been linked to better clinical outcomes. In the FUMANBA-1 study, we previously confirmed a positive correlation between Equecabtagene Autoleucel (Eque-cel) persistence and the maintenance of MRD negativity, which was reported at the 2023 ASH conference (Wang D et al. 2023 ASH oral 4584).

Objective: This study aims to analyze the relationship between CAR T-cell persistence and progression-free survival (PFS) as well as time to progression (TTP). Additionally, the study examines how the baseline level of soluble B-cell maturation antigen (sBCMA) influences these outcomes.

Methods: A retrospective analysis was performed to analyze the population receiving Eque-cel treatment in the FUMANBA-1 study. CAR T-cell persistence was monitored via digital droplet polymerase chain reaction (ddPCR). The sBCMA levels were measured using enzyme-linked immunosorbent assay (ELISA). Patients were categorized based on the efficacy to target ratio (VCN duration/baseline sBCMA), with further analysis on PFS and TTP differences between the groups. Univariate and multivariate analyses were conducted to identify factors influencing CAR T-cell persistence.

Results: During a median follow-up of 24.67 months, 107 patients in 14 centers were treated with Eque-cel. The median efficacy-to-target ratio, measured by the vector copy number (VCN) duration to baseline soluble B-cell maturation antigen (sBCMA), was 1.05 (Days*mL/ng). Patients were categorized into two groups: a high efficacy-to-target ratio group and a low ratio group . Those with a lower ratio had a significantly higher risk of disease progression, with a hazard ratio (HR) for PFS of 2.3 (95% CI: 1.27-4.14, p = 0.0045) and for TTP of 3.07 (95% CI: 1.51-6.24, p = 0.0011), both indicating a strong correlation between the efficacy-to-target ratio and disease progression risk.

At the data cutoff, the ongoing remission group showed a longer median VCN duration than those with progression or relapse (12.52 vs. 9.03 months, p = 0.71), though this was not statistically significant. Among baseline characteristics, including ECOG score, R-ISS and ISS disease stages, tumor BCMA expression, tumor burden, baseline sBCMA level, previous autologous stem cell transplantation (ASCT), triple-class exposure, bridging therapy, prior CAR-T treatment, and lymphodepleting conditioning, only previous ASCT (n = 30) was significantly associated with Eque-cel persistence (HR = 0.35, p = 0.004).

Post-infusion, patients with anti-drug antibodies (ADA) had a significantly higher risk of shorter VCN duration (HR = 5.79, p &lt; 0.0001). Notably, Cmax levels, whether above or below the median, did not significantly impact VCN duration (HR = 0.93, p = 0.78). Among the 107 patients, only 14 exhibited an aplastic neutrophil recovery phenotype, characterized by persistent neutrophil counts below 500/μl for 14 days or more. This phenotype did not significantly affect VCN duration compared to patients without this condition.

Conclusion: The efficacy-to-target ratio is a crucial determinant of clinical outcomes in patients treated with Eque-cel, underscoring the importance of CAR T-cell persistence. This ratio may serve as a biomarker for future treatment planning, highlighting the need for extended CAR T-cell persistence to achieve optimal disease control. While baseline characteristics like previous ASCT influence persistence, baseline sBCMA levels do not adversely affect the treatment efficacy of Eque-cel.