Abstract A018: Functional chemo-genomic screening identifies novel combination therapies to treat RAS-driven multiple myeloma

Abstract Therapeutic resistance in multiple myeloma (MM) is driven by extensive genetic heterogeneity and clonal evolution, creating an urgent need for rational combination therapies that target conserved vulnerabilities. Oncogenic alterations in KRAS, NRAS, or FGFR3 occur in over half of MM cases; however, RAS-targeted strategies remain limited. To systematically identify actionable dependencies and multi-agent therapeutic opportunities in RAS-dependent MM, we integrated whole-genome CRISPR screens with high-throughput combinatorial chemogenomic profiling across MM cell lines. We evaluated the clinical-stage tri-complex pan-RAS inhibitor RMC-6236 against the MIPE 6.0 library of nearly 3000 small molecules in various stages of clinical development. Combinatorial screening identified strong synergy with both established and experimental anti-MM agents, including SWI/SNF inhibitor FHD-286 as a top synergistic partner. RMC-6236 demonstrated consistent low-nanomolar activity across over 50 genetically diverse MM cell lines, with enhanced sensitivity in RAS- and FGFR3-dependent lines. Phosphoproteomic profiling demonstrated robust suppression of MAPK and mTORC1 signaling, and proximity ligation assays (PLA) validated disruption of RAS interactions with MEK, mTOR, and SLC3A2. Mechanistically, co-targeting RAS signaling and chromatin remodeling complexes enhanced apoptosis and enforced G1 cell-cycle arrest. In vivo validation using KRAS- and NRAS-driven MM xenografts demonstrated rapid tumor regression and sustained growth inhibition under a clinically tractable induction–maintenance dosing regimen, with no treatment-related mortality or significant toxicity. Together, these findings support clinical development of RMC-6236 and FHD-286 in biomarker selected MM populations and define a therapeutic strategy for targeting oncogenic signaling in epigenetically vulnerable malignancies. Citation Format: Omar S. Al-Odat, Arnold Bolomsky, Michele Ceribelli, Lin Zhang, Constantine S. Mitsiades, Craig J. Thomas, Ryan M. Young. Functional chemo-genomic screening identifies novel combination therapies to treat RAS-driven multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A018.