Abstract Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a trait characterized by the accumulation of somatic mutations in hematopoietic stem cells in certain adults. It has been observed that the presence of CHIP can have significant implications for the development and prognosis of various blood cancers. Multiple myeloma (MM), a cancer involving the abnormal proliferation of malignant plasma cells in the bone marrow, is one such condition. Exosomes, a type of extracellular vesicles, play a role in cell communication by carrying information between cells. Analysis of UK Biobank data confirmed the poor prognosis of multiple myeloma patients with CHIP and identified a potential of paracrine effect on plasma cancer cells. To gain deeper insights into this paracrine effect on plasma cells, we attempted to analyze cell-to-cell interaction, such as the expression of miRNAs in exosomes, through exosome RNA sequencing. In our research, exosomes were extracted from bone marrow samples of 30 multiple myeloma patients, and exosome RNA sequencing was performed. Differential expression of miRNAs was identified. A total of 14 down-regulated miRNAs were identified based on adjusted p value < 0.05, log2 fold change < -1. We found that hsa-let-7f-5p, hsa-let-7a-5p, and hsa-miR-148a-3p, which are mainly miRNAs targeting MAP kinase, were significantly down-regulated in the CHIP cases. A computational tool was used to predict and integrate the target genes and pathways regulated by these DE miRNAs. The results suggested that certain inflammatory and oncogenic pathways including the MAPK signaling pathways, were not effectively suppressed in cases with CHIP (KEGG, p < 0.005). In addition, the chemokine signaling pathway and cytokine-cytokine receptor interaction (KEGG, p < 0.005) related to the paracrine effect, integrins in angiogenesis (PID, p < 0.005) related to poor prognosis and metastasis of cancer were also not adequately inhibited in the CHIP cases. Using UK Biobank data, we called somatic CHIP variants excluding those with VAF < 0.02 and analyzed them against ICD-10 codes. Hazard ratios (HR) were computed through Cox proportional regression with covariates. CHIP presence significantly correlated with MM diagnosis (HR: 1.64, CI: 1.35-2, p < 0.001), notably in TET2 mutation carriers (HR: 2.35, CI: 1.63-3.4, p < 0.001). TET2 mutations intensified MGUS to MM progression (HR: 5.0, CI: 2.27-11.0, p < 0.001). CHIP in MM impacted EFS (HR: 1.61, CI: 1.25-2.1, p < 0.001), with TET2 mutation carriers facing higher hazards (HR: 1.66, CI: 1.05-2.6, p = 0.031). CHIP, especially TET2 mutations, significantly contribute to adverse MM outcomes and MGUS to MM evolution. Our findings provide insight into how CHIP influences the tumorigenesis and cancer progression of MM. Citation Format: Jeongmin Park, GangPyo Ryu, Daniel Nachun, Maggie Maurer, Siddhartha Jaiswal, Dong-Yeop Shin, Ja Min Byun, Junshik Hong, Youngil Koh, Sung-Soo Yoon. Understanding the impact of clonal hematopoiesis on multiple myeloma: Insights from exosomal RNA analysis and survival analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2277.