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247 Genomic Determinants of Resistance to Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) Therapies in Patients with Relapsed/Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Genomic and Epigenomic Insights into Myeloma Outcomes
Hematology Disease Topics & Pathways:
Research, Translational Research, Bispecific Antibody Therapy, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Genomics, Treatment Considerations, Biological therapies, Biological Processes
Saturday, December 7, 2024: 2:00 PM

Francesco Maura, MD1, Ciara Louise Freeman, PhD, MSc, FRCPC, MRCP2, Holly Lee3*, Kylee H Maclachlan, PhD, BSc, FRACP, FRCPA4, Michael Durante, MD, PhD5*, Bachisio Ziccheddu1*, Meghan Menges2*, Benjamin Diamond, M.D.1*, Marios Papadimitriou1*, Ariosto Siqueira Silva, PhD2*, Praneeth Reddy Sudalagunta, PhD2*, Noemie Leblay, PhD3*, Sungwoo Ahn, PhD6*, Ethan Fuller7*, Edward Briercheck7*, Phaedra Agius2*, Doris K. Hansen, MD2, Xiaofei Song, PhD8*, Xiaohong Zhao, MD, PhD2*, Mark B. Meads, PhD2*, Jamie Teer2*, Ross S Firestone, MD, PhD4, Juan-Jose Garces, PhD4*, Tomas Jelinek9, Rachid Baz, MD2, Melissa Alsina, MD2*, Anusuyam Ramasubramanian7*, Eric Smith, MD, PhD7, Sergio Giralt, MD4, Sham Mailankody, MD, MBBS10, Paola Neri, MD, PhD3, Saad Z. Usmani, MD11, Frederick Locke, MD12, Nizar J. Bahlis, MD3, Ola Landgren1 and Kenneth H. Shain, MD, PhD2

1University of Miami, Miami
2Moffitt Cancer Center, Tampa, FL
3Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
4Memorial Sloan Kettering Cancer Center, New York
5Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
6Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
7Dana Farber Cancer Institute, Boston
8Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
9Department of Hematooncology, University Hospital Ostrava, Ostrava, Ostrava-Mesto, Czech Republic
10Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
11Memorial Sloan Kettering Cancer Center, New York, NY
12Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL

The introduction of chimeric antigen receptor T cells (CART) and bispecific T-cell engagers (TCE) has revolutionized the treatment landscape in patients with relapsed/ refractory multiple myeloma (RRMM). However, despite impressive responses reported to date, the mechanisms responsible for resistance or treatment failure remain inadequately determined.

To investigate the genomic mechanisms involved in primary refractoriness and resistance to anti-BCMA immunotherapies we interrogated 122 whole genomes (WGS; 80X median coverage) and 10 whole exomes (WES) generated from a total of 96 patients treated with either CART (n=74) or T-cell engagers (TCE, n=22). 74 and 13 patients had samples collected before treatment with CART (idecel n=58; ciltacel n=16) and TCE, respectively.

Patients treated with CART had a median progression-free survival (PFS) of 394 days, with 19 (25%) patients progressing within the first 100 days (i.e. refractory). The presence of pre-treatment extramedullary disease (EMD, 12%) and prior anti-BCMA exposure (20%) was associated with inferior progression free survival (PFS) (both p<0.0001). The MyCARe score high-risk patients (n=3, 4%) in this cohort had poor outcomes ; however, it failed to discriminate between low (n=21, 37.5%) and intermediate risk (n=32, 57%) (p=0.10).

Loss of TNFRSF17 was observed in 5/96 (5%) patients, 4 of whom were treated with CART. Of these, 3 had previously been exposed to anti-BCMA therapies, such as belantamab mafodotin (n=2), and these genomic events were present before CART treatment, causing complete refractoriness to CART. Interestingly, all patients with biallelic loss of BCMA were also noted to have CYLD or TRAF3 biallelic loss, key regulator of NFkB signaling. We hypothesize that as BCMA is a driver of NFkB activation in MM cells and that only in the presence of genomic alterations involving NFkB, can this absence of BCMA be tolerated by the tumor cell, promoting resistance to CART.

Next, we investigated what other alternations in pre-CART samples associate with inferior PFS and treatment refractory disease. Among known high-risk features 1q gain was significantly associated with inferior PFS. In investigating a large catalogue of driver genes, we identified multiple genomic drivers involved in resistance and primary refractoriness to anti-BCMA CAR-T. These drivers can be categorized into five major groups: one associated with favorable PFS and four associated with unfavorable PFS. The favorable group included patients with RPL10 mutations (84% patients in remission at 1 year). The second group included loss of genes involved in genomic instability and complexity such as RPL5, TP53, CDKN2C and presence of hyper-APOBEC. The third group included genes involved in the NFkB signaling (CYLD, TRAF3, NFKB2, MAP3K14). The fourth group included loss of function events involving transcription factors and regulators (e.g. SP140, KMT2C, DIS3). The last group had genomic events known to be involved in plasma cell differentiation (e.g. IKFZ3, CD38, XBP1, TNFRSF17).

Overall, patients with genomic events from any two of the unfavorable groups (n=32) had significantly worse outcomes compared with the other patients (median PFS 75 vs 763 days, p<0.0001), accounting for 84% of all refractory patients. By employing a Cox proportional-hazards model, we demonstrated that these genomic features independently and more accurately predict refractoriness to anti-BCMA CAR-T therapy [p<0.0001; Hazard ratio (HR): 5.5497] compared to traditional risk scores like EMD (p=0.59, HR: 0.5945) and MyCARe (p=0.03, HR: 0.1694).

Comparing WGS data from samples collected at the time of progression after CART (n=12) and post-TCE (n=9) patients, only one BCMA mutation (P33S) was observed after CART, and its impact on CART binding was not confirmed in functional studies. This is different from TCE where these mutations and antigen escape account for >50% of relapse (5/9; Lee et al. Nat Med 2023). Furthermore, it supports the hypothesis that the high prevalence of BCMA mutations seen post-TCE is a consequence of continuous selective pressure by TCE-based therapies.

Overall, these data suggest that comprehensive genomic profiling can accurately predict clinical outcomes in MM patients treated with anti-BCMA CART outperforming current clinical predictors of risk and potentially serving as tool to select different treatment strategies.

Disclosures: Maura: Sanofi: Consultancy, Honoraria; Medidata: Consultancy, Honoraria. Freeman: Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Incyte: Consultancy; Amgen: Consultancy; ONK therapeutics: Consultancy. Siqueira Silva: ABBVIE: Research Funding; KARYOPHARM: Research Funding. Sudalagunta: FORUS Therapeutics: Honoraria. Hansen: BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy. Jelinek: GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Baz: Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Alsina: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith: ImmuneBridge: Consultancy; Sana Biotech: Consultancy; Bristol Myers Squibb: Other: Scientific Advisory Board, Patents & Royalties: Licensed patents; ArsenalBio: Consultancy; Legend Biotech: Consultancy; Overland Pharmaceuticals: Consultancy; Blackstone Life Sciences: Consultancy; Eureka Therapeutics: Consultancy; Chroma Medicine: Consultancy; Clade Therapeutics: Consultancy; Predicta Biosciences: Current equity holder in private company, Other: Scientific Advisory Board; Chimeric Therapeutics: Other: Scientific Advisory Board; Sanofi: Other: Scientific Advisory Board, Patents & Royalties: Licensed patents, Research Funding. Mailankody: BMS, J&J, GSK, Springworks Therapeutics: Research Funding. Neri: Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Usmani: Array Biopharma: Research Funding; SeaGen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Oncopeptides: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; TeneoBio: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Gracell: Consultancy; SecuraBio: Consultancy; SkylineDX: Consultancy, Research Funding; Pfizer: Consultancy; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding. Locke: Society for Immunotherapy of Cancer: Honoraria; Legend Biotech: Consultancy; Gerson Lehrman Group (GLG): Consultancy; Imedex: Honoraria; Kite, a Gilead Company: Consultancy, Other: institutional, travel, accomodation, expenses, Research Funding; Cowen: Consultancy; A2: Consultancy; Allogene: Consultancy, Research Funding; Iovance: Consultancy; Pfizer: Consultancy; BioPharma Communications CARE Education: Honoraria; Clinical Care Options Oncology: Honoraria; EcoR1: Consultancy; Janssen: Consultancy; American Society of Hematology: Honoraria, Other: travel, accomodation, expenses; 2SeventyBio: Other: Institutional, Research Funding; National Cancer Institute: Other: Institutional, Research Funding; Aptitude Health: Honoraria; Communications CARE Education: Honoraria; Moffitt Cancer Center: Patents & Royalties; Allogene: Other: Institutional, Research Funding; CERo Therapeutics: Research Funding; Caribou: Consultancy; Calibr: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy; Umoja: Consultancy; Novartis: Consultancy, Research Funding; Sana: Consultancy; Leukemia and Lymphoma Society Scholar in Clinical Research: Other: Institutional, Research Funding. Bahlis: AbbVie, Amgen, BMS, Celgene, Janssen, GSK, Genentech, Karyopharm, Kyte, Novartis, Pfizer, Roche, Sanofi, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer, Janssen: Research Funding. Landgren: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees. Shain: Takeda: Consultancy; BMS: Consultancy, Research Funding; Karyopharm, Janssen, Adaptive Biotechnologies, GlaxoSmithKline, BMS, Sanofi, and Regeneron: Honoraria; Amgen: Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Sanofi: Consultancy; Adaptive Biotech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Glaxo Smith Kline: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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