Pathogenic and Clinical Implications of the 2-Way Interplay Between Clonal Hematopoiesis of Indeterminate Potential and Multiple Myeloma

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon. CHIP is prevalent in multiple myeloma (MM) patients, and several lines of investigations suggest it might be relevant for MM pathogenesis and clinical course. Phylogenetic studies indicate that CHIP and MM do not share a clonal origin. CHIP does not consistently affect survival in MM. However, CHIP has been associated with increased treatment-related toxicities. Recent single-cell RNA sequencing data suggest that CHIP is associated with a more inflammatory and immunosuppressive tumor microenvironment (TME), characterized by dysfunctional myeloid and T cells. Furthermore, growing evidence highlights how anti-MM therapies such as alkylators and immunomodulatory drugs can favor the expansion of pre-existing mutant clones. Collectively, these data suggest a bidirectional interplay in which CHIP, acting as a modifier of the TME, may amplify inflammation driven by MM plasma cells and therapy, ultimately affecting MM progression and therapeutic response, while treatment pressure may reshape CHIP clonal architecture. Understanding CHIP dynamics in the context of MM treatment is therefore crucial to optimize therapeutic strategies, anticipate toxicities, and guide tailored approaches. This review summarizes current evidence supporting a translational and clinical impact of CHIP in MM.