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566 Results from the First Phase 1 Clinical Study of the B-Cell Maturation Antigen (BCMA) Nex T Chimeric Antigen Receptor (CAR) T Cell Therapy CC-98633/BMS-986354 in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Novel Drugs and Optimized Approaches in Myeloma
Hematology Disease Topics & Pathways:
Biological therapies, Therapies, Immunotherapy
Sunday, December 11, 2022: 12:15 PM

Luciano J. Megala Costa, MD, PhD1, Shaji K Kumar, MD2, Shebli Atrash, MD3*, Michaela Liedtke, MD4, Gurbakhash Kaur, MD5, Benjamin A. Derman, MD6, P. Leif Bergsagel, MD7, Sham Mailankody, MBBS 8, Philip L. McCarthy, MD9, Josiana Limones10*, Yanping Chen, PhD10*, Sharmila Das10*, Jerill Thorpe, BS10*, Jonathan Cacciatore10*, Garnet Navarro10*, Ashley K Koegel10*, Michael R. Burgess, MD, PhD10*, Kristen Hege, MD10 and Shambavi Richard, MD11

1University of Alabama at Birmingham Hospital, Vestavia, AL
2Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
3Atrium Health Levine Cancer Institute, Charlotte, NC
4Department of Medicine, Divisions of Oncology and Hematology, Stanford University, Stanford, CA
5Division of Hematologic Malignancies and Cellular Therapy, Dept of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX
6Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
7Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ
8Memorial Sloan Kettering Cancer Center, New York, NY
9Roswell Park Comprehensive Cancer Center, Buffalo, NY
10Bristol Myers Squibb, Princeton, NJ
11Mount Sinai Health System, New York, NY

Introduction: CC‑98633/BMS-986354 is a next-generation CAR T-cell product that contains the same fully human BCMA-targeted CAR construct as orvacabtagene autoleucel (orva-cel; Harrington K et al. Blood. 2017) and is manufactured using the NEX-T process. The NEX-T process was designed to shorten manufacturing time and improve the potency and phenotypic attributes of the CAR T-cell drug product with the aim of enhancing depth and durability of response. In vivo studies have shown that BMS-986354 is a less differentiated CAR T-cell product with improved potency and tumor control vs orva-cel. Here, we present phase 1 clinical data from the ongoing CC-98633-MM-001 trial (NCT04394650).

Methods: This is a multicenter, phase 1 trial investigating BMS-986354 in pts with RRMM who received ≥ 3 prior regimens, including an autologous stem cell transplant, proteasome inhibitor, immunomodulatory drugs, and an anti-CD38 monoclonal antibody. Following leukapheresis, patient T cells were purified and engineered with reduced ex vivo expansion and manufacturing time of 5 or 6 days. Pts received a single BMS-986354 infusion 2–7 days after lymphodepleting chemotherapy (3 days fludarabine [30 mg/m2] and cyclophosphamide [300 mg/m2]).

Results: As of May 12, 2022, 66 pts have been enrolled, 55 have been treated with BMS-986354, and 54 were evaluable for disease response. In the dose-escalation phase (Part A), pts were treated with 20 × 106 (dose level [DL] 1, n = 7), 40 × 106 (DL2, n = 24), or 80 × 106 (DL3, n = 11) CAR+ T cells; DL2 was selected for dose expansion (Part B), and an additional 13 pts were treated. Enrolled pts had a median age of 62.5 years (range, 43–75). Median time from diagnosis was 6.2 years (range, 0.7–24.6) with a median of 5 prior regimens (range, 3–13). During dose escalation, no pts had dose-limiting toxicities (DLTs) at DL1, 4 had DLTs at DL2 (prolonged neutropenia and thrombocytopenia [n=1], prolonged neutropenia [n = 2], decreased fibrinogen [n = 1]), and 3 had DLTs at DL3 (prolonged neutropenia [n = 2], prolonged thrombocytopenia [n = 1]); all DLs were tolerable per prespecified criteria.

Cytokine release syndrome (CRS) occurred in 80.0% of all treated pts, with most experiencing grade 1 (63.6%) or grade 2 (14.5%); only 1 pt experienced ≥ grade 3 (grade 4) CRS. Median onset was day 4 (range, 2–8), median duration was 4 days (range, 1–8), and common treatments included tocilizumab (n = 38), steroids (n = 25), and anakinra (n = 9). Neurotoxicity occurred in 6 (10.9%) pts (grade 1, n = 5; grade 4, n = 1); all events resolved after a median of 2.5 days (range, 2–21). No neurotoxicity events had an onset beyond day 9. Overall, with a median follow-up of 4.9 months, the objective response rate was 98.1%, with 57.4% of pts achieving a very good partial response or better, 29.6% achieving complete response or better, and 76.4% of responses ongoing.

Compared with orva-cel, BMS-986354 drug product is less differentiated, composed primarily of naive-like and central memory CAR T cells with fewer effector and terminally differentiated CAR T cells. Following CAR stimulation, BMS-986354 led to higher antigen-specific cytokine (interferon-gamma, tumor necrosis factor alpha, and interleukin-2) production than orva-cel (Figure).

Pharmacokinetic analysis of transgene levels using droplet-digital polymerase chain reaction demonstrated robust cellular expansion across all DLs (geometric mean maximum concentration [Cmax] of 8.67 × 104 gag copies/µg, area under the curve 0 to 28 days [AUC0–28] of 85 × 104 days × gag copies/µg, median time to Cmax of 14 days at DL2). Flow cytometry analysis during dose escalation showed that similar Cmax and AUC0–28 were reached with a > 11-fold lower dose of BMS-986354 than orva-cel, demonstrating increased proliferative capacity for BMS-986354 (geometric mean Cmax of 399 cells/µL, AUC0–28 of 3674 days × cells/µL at DL2 vs Cmax of 328 cells/µL, AUC0–28 of 3890 days × cells/µL at 450 × 106 cells).

Conclusions: BMS-986354, a NEX-T investigational BCMA-targeted CAR T-cell product, is a less differentiated, more potent cellular drug product than orva-cel and can be manufactured with a more rapid processing time. At low doses, BMS-986354 demonstrated a favorable safety profile and promising efficacy, including deep and durable responses in pts with heavily pretreated RRMM. The study continues to enroll patients in the dose-expansion phase. Updated safety, efficacy, and translational data will be presented.

Disclosures: Megala Costa: Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genentech: Research Funding. Kumar: Roche: Research Funding; Novartis,: Research Funding; Merck,: Research Funding; MedImmune/Astra Zeneca,: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE,: Research Funding; Adaptive,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee. Atrash: Jansen oncology: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Research Funding; GSK consultancy: Honoraria, Research Funding; Bristol Myers Squib: Research Funding; Sanofi: Research Funding. Liedtke: Adaptive: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Allogene: Research Funding; Caelum: Research Funding; Gilead: Research Funding; GSK: 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; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Natera: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seagen Inc.: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaur: UT Southwestern: Consultancy, Current Employment. Derman: COTA healthcare: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Janssen: Consultancy. Bergsagel: Novartis: Consultancy; Pfizer: Consultancy; GSK: Consultancy; Janssen: Consultancy; Oncopeptides: Consultancy. Mailankody: Evicore: Consultancy; Janssen Oncology: Consultancy, Research Funding; BioAscend: Consultancy; Optum Oncology: Consultancy; Allogene Therapeutics: Research Funding; Takeda Oncology: Research Funding; Juno Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Fate Therapeutics: Research Funding; Plexus Communication: Honoraria; OncLive: Honoraria; Physician Education Resource: Honoraria; Legend Biotech: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment. McCarthy: Bluebird Bio: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria; Janssen Global Services, LLC: Consultancy, Honoraria; Sanofi: Consultancy; Fate Therapeutics: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Takeda Pharmaceuticals America, Inc.: Consultancy, Honoraria; Partner Therapeutics, Inc.: Consultancy, Honoraria; Axios: Consultancy, Honoraria; Magenta Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Starton Therapeutics: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bristol Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Limones: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; PRA Health Sciences: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Das: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Deciphera Pharmaceuticals Inc./Beacon Hill: Ended employment in the past 24 months. Thorpe: Bristol Myers Squibb: Current Employment; Iovance: Current equity holder in publicly-traded company; Moderna: Divested equity in a private or publicly-traded company in the past 24 months. Cacciatore: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Organon: Current equity holder in publicly-traded company. Navarro: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Koegel: 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. 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. Richard: C4 Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH