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364 Clinical Activity of BMS-986393 (CC-95266), a G Protein–Coupled Receptor Class C Group 5 Member D (GPRC5D)–Targeted Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma (MM): First Results from a Phase 1, Multicenter, Open-Label Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: CAR T in Multiple Myeloma and T-cell Therapies After Allo-HCT
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, Plasma Cell Disorders, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 10, 2022: 4:45 PM

Susan Bal, MD1*, M. Hakan Kocoglu, MD2, Omar Nadeem, MD3, Myo Htut, MD4, Tara Gregory, MD5*, Larry D. Anderson Jr., MD, PhD6, Luciano J. Megala Costa, MD, PhD1, Tonia J. Buchholz, MS, PhD7*, Safiyyah Ziyad, PhD7*, Meng Li, PhD7*, Yanping Chen, PhD7*, Allison J. Kaeding, MD7*, Michael R. Burgess, MD, PhD7*, Kristen Hege, MD7 and Jesus Berdeja, MD8

1University of Alabama at Birmingham, Birmingham, AL
2University of Maryland, Baltimore, MD
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4City of Hope Comprehensive Cancer Center, Duarte, CA
5Colorado Blood Cancer Institute, Sarah Cannon Cancer Network, Denver, CO
6Cellular Therapy and Hematologic Malignancies Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX
7Bristol Myers Squibb, Princeton, NJ
8Sarah Cannon Research Institute, Nashville, TN

Introduction: CAR T cell therapies targeting B‑cell maturation antigen (BCMA) have resulted in unprecedented depth and duration of response in R/R MM. However, relapses are frequent, and the development of novel approaches is critical. GPRC5D, an orphan receptor expressed on MM cells with limited expression in other tissues, has emerged as a promising therapeutic target for MM. MCARH109, a GPRC5D-directed CAR T cell therapy, demonstrated promising initial safety and efficacy in patients (pts) with R/R MM (Mailankody S et al. Blood. 2021), warranting further study of this CAR T target. We present interim results from the dose-escalation part (Part A) of CC‑95266‑MM‑001 (NCT04674813), a phase 1, first‑in-human, multicenter, open-label, dose-finding study evaluating BMS-986393 (CC‑95266), a GPRC5D-targeted autologous CAR T cell therapy, in pts with R/R MM.

Methods: Part A includes pts with ≥ 3 prior lines of therapy containing a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and, unless ineligible, a stem cell transplant. Prior BCMA-directed and CAR T cell therapies are allowed. The study follows a modified toxicity probability interval design with ≥ 3 pts per dose level. After screening and leukapheresis, pts received bridging therapy if needed, then lymphodepleting chemotherapy (fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2 daily for 3 days) followed by a single infusion of BMS-986393. Primary objectives are to determine the safety, tolerability, and maximum tolerated dose (MTD) and/or recommended phase 2 dose of BMS-986393.

Results: As of May 24, 2022, 21 pts enrolled and 17 pts received BMS-986393 at doses of 25 (n = 5), 75 (n = 9), and 150 (n = 3) × 106 CAR T cells. Among treated pts, 8 (47%) pts had high-risk cytogenetics (del[17p], t[4;14], and/or t[14;16]) and 8 (47%) pts had extramedullary plasmacytomas. Seven (41%) pts received prior BCMA-targeted therapies, including 6 (35%) pts treated with BCMA-directed CAR T cell therapy (Table). Four (24%) pts had penta-refractory MM.

Grade 3/4 treatment-emergent adverse events related to BMS-986393 (TRAEs) were reported in 11/17 (65%) pts; of these, the most frequent were neutropenia (41%) and thrombocytopenia (35%). TRAEs consistent with on-target, off-tumor activity affecting the skin (18%) and nails (12%), as well as dysgeusia/dysphagia (12%) were reported, all grade 1. Dose-limiting toxicities of prolonged (out to day 42) neutropenia and/or thrombocytopenia were reported in 2 pts; MTD has not been exceeded. Cytokine release syndrome (CRS) was reported in 11/17 (65%) pts, all grade 1/2 (median onset, day 3 [range, 2–4]; median duration, 2 days). Immune effector cell–associated neurotoxicity syndrome (ICANS)–type neurotoxicity was reported in 2/17 (12%) pts, both grade 1 (duration, 1–3 days), and was reversible with steroid treatment (Table).

Responses were reported in 12 of 14 pts evaluable for initial (1‑month) clinical response (overall response rate, 86%), including in 4/6 and 3/5 pts treated with prior BCMA‑directed and BCMA-directed CAR T cell therapies, respectively. Median duration of response has not been reached for any dose level, with median follow-up of 4.0 months (range, 1.0–13.1; Table). At the time of analysis, 15/17 (88%) pts remained in follow-up; 2 (12%) pts discontinued due to progressive disease.

In preliminary pharmacodynamic analyses, greater reductions in soluble BCMA levels were associated with increasing dose from 25 to 75 × 106 CAR T cells, and all 3 pts with complete response (CR) at the 25 × 106 CAR T-cell dose level were minimal residual disease (MRD)–negative (10−5 depth) at month 3, with follow-up ongoing.

Preliminary cellular pharmacokinetic analyses demonstrated a dose-dependent increase in BMS-986393 exposure (Table).

Conclusions: At all tested dose levels, BMS-986393 demonstrated a favorable safety profile; both CRS and neurotoxicity were low-grade, and neurotoxicity was infrequent and short-lived. Dose escalation is ongoing; MTD has not been exceeded. Preliminary efficacy appeared promising; antitumor responses were observed, including pts with CR who were MRD-negative at month 3. These initial data support GPRC5D-directed CAR T cell therapy with BMS-986393 as a new treatment paradigm in R/R MM. Selection of the dose(s) for expansion in Part B is underway, and updated data will be presented.

Disclosures: Bal: Adaptive Biotechnologies: Consultancy, Research Funding. Nadeem: Takeda: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GPCR Therapeutics: 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. Anderson: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Megala Costa: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding; Genentech: Research Funding. Buchholz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ziyad: Bristol Myers Squibb: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Li: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kaeding: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Burgess: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hege: Graphite Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties: Multiple. Berdeja: Legend Biotech: Consultancy; Kite Pharma: Consultancy; AbbVie: Research Funding; Sanofi: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Acetylon: Research Funding; Amgen: Research Funding; C4 Therapeutics: Research Funding; CARsgen: Research Funding; Cartesian Therapeutics: Research Funding; Celularity: Research Funding; EMD Sorono: Research Funding; Fate Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Ichnos Sciences: Research Funding; 2Seventy bio: Research Funding; Zentalis: Research Funding; Teva: Research Funding; Poseida: Research Funding; Novartis: Research Funding; Lilly: Research Funding; Karyopharm: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; SecuraBio: Consultancy.

*signifies non-member of ASH