Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Emerging Targeting Approaches of Cell Therapies for Hematologic Malignancies
Hematology Disease Topics & Pathways:
Research, Clinical trials, Adult, Clinical Research, Plasma Cell Disorders, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Treatment Considerations, Biological therapies, Lymphoid Malignancies, Study Population, Human, Measurable Residual Disease
Most pts with MM on current treatments will eventually relapse or fail to respond, including with B-cell maturation antigen (BCMA)-targeting therapies. Pts with RRMM have suboptimal survival rates, which worsen with each new line of treatment; thus, new therapy classes are needed. BMS-986393 is an autologous chimeric antigen receptor (CAR) T cell therapy targeting GPRC5D, a promising target for novel MM therapies. Initial data from a phase 1 study in pts with heavily pretreated RRMM suggested that a single infusion of BMS-986393 was efficacious with a favorable safety profile. At the recommended phase 2 dose (RP2D; 150 × 106 CAR T cells), the overall response rate (ORR) was 91%, and complete response rate (CRR) was 48% (Bal et al, ASH 2023). Here we report data after additional follow-up.
Methods
Pts had ≥ 3 prior anti-MM regimens including a proteasome inhibitor, an immunomodulatory agent, and anti-CD38 therapy, and autologous stem cell transplant (if eligible); prior BCMA-directed therapies (including CAR T) were allowed. After screening and leukapheresis (bridging therapy optional), pts received lymphodepleting chemotherapy followed by a single infusion of BMS-986393 (25–450 × 106 CAR T cells). The primary objective was safety.
Results
As of May 20, 2024, 84 pts had received BMS-986393, 26 at the RP2D. Median age was 63 years (range 39–80); 51% were male; 67% were White and 17% Black or African American. 42% had high‑risk cytogenetics (del[17p], t[4;14], and/or t[14;16]), 55% had 1q21 gain/amp, and 45% had extramedullary disease. Pts had received a median of 5 prior regimens (range 3–15); 49% had received prior BCMA‑targeted therapy, including BCMA-directed CAR T cell therapy in 38% of pts. 76% of pts had triple-refractory disease, and 35% had penta‑refractory MM.
Across all doses, treatment-related (TR) adverse events (AEs) occurred in 94% of pts; 71% had a grade (G) 3/4 TRAE, and there was 1 TRAE-related death (cytokine release syndrome [CRS]) in pts treated at 450 × 106. Overall, 69 pts (82%) had CRS (66 at G1/2); all but 1 (G5) resolved. Three pts had macrophage activation syndrome/hemophagocytic lymphohistiocytosis (all G3), none of these events occurred at the RP2D. TR neurologic AEs, including immune effector cell-associated neurotoxicity syndrome (ICANS) and other select neurotoxicities (dizziness, ataxia, neurotoxicity, dysarthria and/or nystagmus), were observed. ICANS occurred in 8 (10%) pts (2 at G3) and resolved in 7. Other select neurotoxicity occurred in 10 pts (12%); 5 (6%) at G3 (the rest G1/2); these appeared to be dose-related. On-target/off-tumor nail, skin and oral TRAEs occurred in 19%, 30%, and 31% pts, respectively. Five pts had TR weight loss (all G1/2), and treatment-emergent (TE) infections occurred in 42 (50%; 14 pts at G3/4).
After median follow-up of 14.6 months (range, 2.8–25.2 months) with 79 efficacy-evaluable pts, ORR was maintained at 87% (91% for the RP2D). Considering disease features, ORR was 84% for pts with high-risk cytogenetics (26/31), 87% for triple-class refractory disease (52/60), 79% for prior BCMA-targeting therapy (30/38), and 86% for extramedullary disease (31/36). Of pts with minimal residual disease (MRD) data and CR or better, 88% (22/25) were MRD‑negative (10−5 depth; at any time point within 3 months prior to achieving CR or better, until the time of progression or death). Of 69 responses, 33 (48%) were ongoing. Median PFS was 14.5 months (95% CI 11.8–20.8). Dose-dependent increases in cellular expansion occurred across dose levels, and all doses consistently reduced soluble BCMA levels.
Conclusions
After the longest recorded follow-up for a GPRC5D-targeted CAR T therapy, BMS-986393 showed a high rate of durable responses that deepened with time. High response rates occurred irrespective of disease characteristics, including in pts naïve and exposed to prior BCMA-targeted therapy, and with high-risk cytogenetics, triple-class refractory, and extra-medullary disease. Long-term safety data showed a manageable profile of on-target/off-tumor AEs and neurotoxicity, and that the risk of infections may be lower than some BCMA-targeted therapies. These data support BMS-986393 as a potential treatment for heavily pretreated RRMM, which is being investigated in the ongoing phase 2 QUINTESSENTIAL study (NCT06297226). The presentation will report updated data after ~ 18 months’ follow-up, including the first overall survival data.
Disclosures: Bal: Janssen: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; MJH Life Sciences: Honoraria; Beigene: Research Funding; Fate Therapeutics: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Nadeem: JNJ: Research Funding; Pfizer: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Berdeja: Janssen: Speakers Bureau; AstraZeneca, Bristol Myers Squibb, Caribou, Galapagos, Janssen, K36, Kite Pharma, Legend Biotech, Pfizer, Regeneron, Roche, Sanofi, Sebia, Takeda: Consultancy; 2 Seventy Bio, Abbvie, Amgen, BMS, C4 Therapeutics, Caribou Biosciences, CARsgen, Cartesian Therapeutics, Celularity, CRISPR Therapeutics, Fate Therapeutics, Genentech, GSK, Ichnos Sciences, Incyte, Janssen, Juno Therapeutics, K36 Therapeutics. Karyopharm: Research Funding. Rossi: Adaptive, BMS, Janssen, Karyopharm, JNJ, and Sanofi: Consultancy. Koçoğlu: Caelum: Other: research funding (to institution) from, Research Funding; Poseida: Other: research funding (to institution) from, Research Funding; Takeda: Other: research funding (to institution) from, Research Funding; GlaxoSmithKline: Other: research funding (to institution) from, Research Funding; Celgene/Bristol Myers Squibb: Other: research funding (to institution) from, Research Funding; Janssen: Other: research funding (to institution) from, Research Funding; Arcellx: Research Funding. Martin: Poseida: Research Funding; Sanofi: Research Funding; BMS: Research Funding; GSK, Pfizer, Roche: Honoraria; Janssen: Research Funding. Costa: Adaptive biotechnoligies: Honoraria; Sanofi: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Caribou: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Chen: BMS: Current Employment. Sarkis: Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Ziyad: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kao: BMS: Current Employment, Current equity holder in publicly-traded company. Kaeding: BMS: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Immunome, Inc: Current Employment, Current equity holder in publicly-traded company. Burgess: BMS: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months.