Abstract 5002: Multi-omics insights into the role of clonal hematopoiesis in multiple myeloma

Abstract Multiple myeloma (MM) is a cancer involving the abnormal proliferation of malignant plasma cells in the bone marrow (BM). Clonal hematopoiesis (CH), a condition involving the clonal expansion of blood cells due to somatic mutations, is commonly observed with aging. However, its precise role in the pathogenesis of MM remains unclear. This study hypothesizes that CH influences MM cells and the microenvironment through paracrine mechanisms, thereby contributing to disease progression and treatment resistance. Using UK Biobank data, somatic CH variants were called, excluding those with a variant allele frequency (VAF) < 0.02, and analyzed them against ICD-10 codes. Hazard ratios (HR) were computed through Cox proportional regression, adjusting for covariates. Single-cell multi-omics (scDNA) sequencing was performed on BM aspirates from two MM patients, followed by cell type annotation and CH mutation subtyping using the MissionBio Mosaic pipeline. Exosomes were extracted from BM samples of 30 MM patients, and exosome small RNA sequencing was conducted. Differential expression of miRNAs was identified, and a computational tool was used to predict and integrate the target genes and pathways regulated by the differentially expressed miRNAs. Single-cell RNA (scRNA) sequencing was performed on BM sample from 12 MM patients, with data analyzed using the Seurat pipeline. Proteomics analysis using UK Biobank data was performed on a cohort of 190 MM patients identified based on ICD-10 codes. Differentially expressed protein and pathway analyses were conducted using OlinkAnalyze R package. Survival analysis conducted using the UK Biobank cohort revealed that the presence of CH was significantly correlated with MM diagnosis (HR: 1.64, CI: 1.35-2, P < 0.001), and CH in MM impacted EFS (HR: 1.61, CI: 1.25-2.1, P < 0.001). The results of the scDNA analysis revealed that approximately 88% of CH-mutated cells were distributed within myeloid cells, suggesting potential indirect effects on MM through paracrine interactions. Exosomal miRNA analysis of 30 MM patients revealed a significant reduction in miRNAs targeting the MAPK and JAK-STAT pathways (KEGG, P < 0.005), indicating dysregulation of oncogenic and inflammatory signaling in individuals with CH. scRNA analysis identified the activation of inflammatory pathways in CD14+ monocytes of individuals with TET2 and DNMT3A mutations, including the MAPK pathway (GOBP, adjP < 0.05) and cytokine interactions (KEGG, adjP < 0.05). Proteomics analysis using Olink data from 190 MM patients in the UK Biobank further validated the activation of inflammatory and oncogenic pathways, including MAPK pathway (GOBP, adjP < 0.05), STAT pathway, and cytokine-cytokine receptor interactions (KEGG, adjP < 0.05), in CH-positive MM cases. These findings highlight the potential for CH mutations, particularly in TET2 and DNMT3A, to exacerbate MM progression through inflammatory paracrine mechanisms. Citation Format: Jeongmin Park, Ja Min Byun, Dong-Yeop Shin, Junshik Hong, Sung-Soo Yoon, Siddhartha Jaiswal, Youngil Koh. Multi-omics insights into the role of clonal hematopoiesis in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5002.