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248 Genomic Complexity Correlates with the Degree of Marrow Independence of Malignant Plasma Cells in the Context of Extramedullary Disease

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, Genomics, Biological Processes
Saturday, December 7, 2024: 2:15 PM

Kylee H Maclachlan, PhD, BSc, FRACP, FRCPA1, Juan-Jose Garces, PhD2*, Tala Shekarkhand, MS3*, Sridevi Rajeeve, MD1*, Hamza Sloan Hashmi, MD3*, Hani Hassoun, MD3, Malin Hultcrantz, MD3, Neha Korde, MD3, Carlyn Rose Tan, MD1, Sham Mailankody, MD, MBBS3, Anish Simhal, PhD4*, David J. Chung, MD, PhD5, Gunjan L. Shah, MD6, Michael Scordo, MD7, Sergio Giralt, MD8, Alexandra Maria Poos, PhD9*, Lukas John, MD10*, Yanming Zhang, MD11, Robert Cimera, MS12*, Maria E. Arcila, M.D.13*, Juan E Arango Ossa14*, Umesh Bhanot, MD15*, Mala Jain, MD16*, Tala Merghoub, MD17*, Heather J. Landau, MD6, Alexander M. Lesokhin, MD1, Saad Z. Usmani, MD3, Niels Weinhold, PhD18*, Francesco Maura, MD19 and Urvi A. Shah, MD3

1Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2Memorial Sloan Kettering Cancer Center, New York
3Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
4Medical Physics Department, Memorial Sloan Kettering Cancer Center, New York
5Transplant and Cellular Therapy Services, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
6Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
7Transplant and Cellular Therapy Services, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY
8Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, NY
9Heidelberg Myeloma Center, Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
10Heidelberg Myeloma Center, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
11Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
12Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY
13Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
14Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
15Pathology Department, Memorial Sloan Kettering Cancer Center, New York
16Department of Pathology, Weill Cornell Medical Center, New York
17Memorial Sloan Kettering Cancer Center, New York, NY
18Heidelberg Myeloma Center, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
19University of Miami, Coral Gables, FL

Background: Growth of multiple myeloma (MM) beyond the bone marrow (BM) represents clinically aggressive disease and is associated with inferior therapy response. We hypothesize that genomic changes underlie the increasing BM independence seen from focal intra-medullary lesions (IMD) to para-medullary (PMD) and extra-medullary disease (EMD). To address this hypothesis, we have analyzed the largest sequencing cohort of IMD/PMD/EMD to date, comparing with paired BM samples where available.

Methods: Genomic assessment of all available IMD/PMD/EMD from Memorial Sloan Kettering Cancer Center (MSK) and the University of Heidelberg (DKFZ) were included. IMD was defined by MRI appearance, PMD by local extension through bone and EMD as non-contiguous with bone. Comprehensive genomic characterization combined SNP-array, extended targeted sequencing (MSK-IMPACT-Heme), whole exome (WES) and whole genome sequencing (WGS). New data was combined with our published pre-therapy BM WGS (Maura Nat Can 2023), PMD/EMD WGS from autopsy (Landau Nat Comm 2020) and spatially distinct WES (Rasche Nat Comm 2022).

In total, 84 IMD, 105 PMD and 55 EMD samples were assessed; 128 pre-therapy and 126 post-therapy. 134 patients had paired BM samples (113 coincident and 26 distant in time), with 12 patients having > 1 PMD/EMD biopsy. Including our previously published data, the cohort comprised 444 samples from 271 patients; 125 WGS, 66 WES, 145 MSK-IMPACT-Heme and 25 SNP-array. Analyses included GISTIC for significant copy number aberrations (CNA), dndscv for positively selected mutational drivers and mmsig for mutational signatures.

Results: Compared to paired BM and the independent control set of BM samples, PMD and EMD had considerably more CNA, while IMD was more similar to BM. Significant CNAs in PMD/EMD included gains affecting 1q, 8q (MYC), 20p and 20q, with focal gains at 1q21, 6p25 and 18q21. Deletions frequently affected 4p, 8p and 17p (TP53), and numerous focal deletions were detailed. While there was only a trend to difference in 1p/1q between BM and IMD, gain/amp1q was observed in 38% BM, 56% PMD, 78% of EMD overall, and in 83% of post-therapy EMD samples.

Prevalent mutations in PMD/EMD involved KRAS, NRAS and TP53, with KRAS being enriched in PMD (38%), while EMD was enriched for NRAS (40%) and TP53 (33%). PMD/EMD were also enriched for loss-of-function mutations (p=0.007). In contrast, there was no significant difference in any of KRAS/NRAS/BRAF or TP53 between BM and IMD. Dndscv analysis revealed multiple genes positively selected as driver events in PMD/EMD, including epigenetic modifiers (KMT2A, KMT2C, TET2, SMARCA4), immune response (PRMD1, LTB), proliferation (STAT3, NF1, BTG1), adhesion (FAT1), and DNA-damage response (TP53, ATM, BRCA2).

Paired BM-PMD/EMD showed 2 patterns; some had increased mutational burden in PMD/EMD, while others had retained mutations but increased CNA. Within those with > 1 PMD/EMD sample, diverging clones were defined by a variety of mutations (including KRAS, TP53, STAT3, IGF1R, DNMT3A), CNA affecting multiple chromosomes (including 8q; MYC, 17p; TP53), noncanonical translocations, and CNA consistent with chromothripsis.

In the WGS data, we note spatial divergence in mutational signature contribution and emergence of complex structural variants. Several patients with prior melphalan exposure have SBS99 evident in several biopsies, consistent with single cell expansion from MM cells surviving transplant and subsequently seeding in multiple sites.

Conclusions: PMD and EMD demonstrate multiple features of genomic complexity when compared with BM-based myeloma, which include emerging copy number aberrations, mutational burden and complex structural variants. EMD are more complex in general than PMD, while IMD shows only trends to increased genomic aberration compared with BM. Ongoing analyses include an expansion in WGS samples, and correlation of genomic features with clinical response to therapy.

Disclosures: Shekarkhand: Roche-Genentech: Consultancy. Hashmi: Amgen: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy. Hassoun: Janssen, Takeda: Research Funding. Hultcrantz: Abbvie, GlaxoSmithKline, SpringWorks Therapeutics, Daiichi Sankyo, Cosette Pharmaceuticals: Research Funding; Curio Science LLC, Intellisphere LLC, Janssen, Bristol Myers Squibb, and GlaxoSmithKline: Consultancy, Honoraria. Korde: Janssen: Membership on an entity's Board of Directors or advisory committees; Remedy Health 8/2022: Other: part of (Patient Power); CCO, OncLive, and Intellisphere: Consultancy; Amgen, Janssen, Epizyme, and AbbVie: Research Funding. Tan: Janssen: Honoraria, Research Funding; Takeda: Research Funding; Sanofi: Honoraria. Mailankody: BMS, J&J, GSK, Springworks Therapeutics: Research Funding. Shah: Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Scordo: Medscape: Honoraria; Amgen: Research Funding; Miltenyi Biotec: Consultancy; Sanofi: Research Funding; Angiocrine Biosciences, Inc.: Research Funding; IDEOlogy: Honoraria; Kite - A Gilead Company: Consultancy; MJH Life Sciences (Cancer Network): Honoraria; Omeros Corporation: Consultancy, Research Funding. Landau: Nexcella, Janssen, Alexion, Protego, Prothena: Research Funding; Abbvie, Immix Biopharma, Legend Biotech, Alexion, Prothena: Consultancy. Lesokhin: Arcellx: Consultancy, Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; F. Hoffmann-La Roche Ltd, Janssen, SVB Leerink: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Serametrix, Inc.: Patents & Royalties. Usmani: Sanofi: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Array Biopharma: Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Gracell: Consultancy; GSK: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; TeneoBio: Consultancy; SecuraBio: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; EdoPharma: Consultancy; Gilead: Research Funding; Pfizer: Consultancy; SeaGen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding. Weinhold: BMS/Celgene: Research Funding; GlaxoSmithKline (GSK): Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; The Binding Site: Research Funding. Maura: Sanofi: Consultancy, Honoraria; Medidata: Consultancy, Honoraria. Shah: Sanofi: Honoraria; Bristol Myers Squibb: Research Funding; Janssen: Honoraria, Research Funding.

*signifies non-member of ASH