Safety and Efficacy of BCMA-Targeted CAR-T Therapy in Geriatric Patients with Multiple Myeloma

Introduction: Risks of B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR-T) therapy for patients with multiple myeloma (MM) include cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS), and infections. Geriatric patients with MM are at higher risk of infections (Blimark 2015), and pre-existing comorbidities may complicate CRS and ICANS in older patients. While progression-free survival (PFS) was similar in older vs younger patients in the KarMMa trial of idecabtagene vicleucel (Berdeja 2020), BCMA CAR-T outcomes in the geriatric setting - including the risks of prolonged cytopenias, hypogammaglobulinemia, and infections - have not yet been analyzed.

Methods: We analyzed all patients with MM who received any autologous BCMA CAR-T therapy from January 2017 - June 2022 at our institution. Key endpoints included CRS and ICANS incidence (American Society for Transplantation and Cellular Therapy criteria), days to absolute neutrophil count (ANC) recovery, incidence of hypogammaglobulinemia (IgG < 400 mg/dL), confirmed infections within 30 days of CAR-T infusion, response rates, time to measurable residual disease (MRD) negativity, PFS, and overall survival (OS). Characteristics were compared between older patients (age ≥70 at infusion) and younger patients using Fisher's & Kruskal-Wallis tests as appropriate. PFS and OS were compared using log-rank tests.

Results: Of 77 analyzed patients (age range 33-77), 19 (25%) were aged ≥70. Gender, weight, performance status, years since diagnosis, presence of extramedullary disease, bone marrow plasma cell burden, high-risk cytogenetics, prior lines of therapy, and triple-class refractory status were similar between older and younger patients. Despite similar weights, older patients had lower Cockcroft-Gault creatinine clearances (median 69.2 vs 92.5 mL/min, p<0.001) and were more likely to receive reduced-dose fludarabine as part of lymphodepletion (53% vs 17%, p<0.01). Rates of any-grade CRS (79% vs 79%), rates of any-grade ICANS (11% vs 10%), and median days to ANC recovery (14.0 vs 13.5) were similar between older and younger patients. Rates of baseline hypogammaglobulinemia were 32% in older patients vs 28% in younger patients (p=0.77), while post-infusion hypogammaglobulinemia occurred in 84% vs 71%, respectively (p=0.36). Six infections occurred before Day +30, all in the younger cohort: rhinovirus (n=2), Staphylococcus epidermidis (n=2), CMV reactivation (n=1), and COVID-19 (n=1). There were two deaths before Day +100, both due to progressive MM in younger patients. Overall response rates (84% vs 90%) were similar between older and younger patients. Median PFS (Figure 1A) was not reached (NR) in older patients (95% CI 10.6-NR) vs 13.1 months in younger patients (95% CI 9.4-33.1), with p=0.19. Median OS (Figure 1B) was NR in older patients (95% CI NR-NR) vs 30.0 months (95% CI 24.8-NR) in younger patients, with p=0.05. Two-year survival probabilities were 93% vs 66%, respectively.

Discussion: While limited by small sample size and unmeasured confounders, our retrospective analysis did not demonstrate significant increases in CAR-T toxicity among patients aged ≥70. Differences in rates of hypogammaglobulinemia between older and younger patients did not reach statistical significance. Fludarabine dose reductions during lymphodepletion (as expected with age-adjusted creatinine clearances) did not impair CAR-T efficacy among geriatric patients. Older patients paradoxically had a significantly better OS compared to younger patients, which may have been due to selection bias in favor of disproportionately healthy geriatric patients with regard to CAR-T candidacy. Overall, our data suggest that BCMA CAR-T is a safe and effective option for older patients with MM.

Lo:Oncopeptides: Consultancy; EUSA Pharma: Consultancy. Chung:Janssen: Research Funding; Cellectis: Research Funding; BMS/Celgene: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Caelum: Research Funding; Sanofi: Honoraria. Wong:Fortis: Research Funding; Caelum: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; GSK: Research Funding; Catalent Biologics: Consultancy; Patient Discovery: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Dren Bioscience: Consultancy. Wolf:Adaptive Biotechnologies: Consultancy. Martin:Legend Biotech: Consultancy; GlaxoSmithKline and Legend Biotech: Consultancy; Amgen, Johnson & Johnson / Janssen, Sanofi, and Seattle Genetics: Research Funding. Shah:Aztra Zeneca: Current Employment, Other: stock ownership; GSK, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite, Karyopharm, Oncopeptides,: Consultancy; AstraZeneca: Current Employment, Current equity holder in publicly-traded company; Celgene/BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar, Precision Biosciences: Research Funding. Banerjee:Curio Science: Honoraria; i3 Health: Consultancy; Pack Health: Research Funding; SparkCures: Consultancy; Sanofi: Consultancy; Guidepoint Global: Consultancy; Eradigm Consulting: Consultancy; Clinical Care Options: Honoraria.