Clonal Hematopoiesis Impacts Frailty of Newly Diagnosed Multiple Myeloma Patients: A Retrospective Multicentric Analysis

Somatic mutations of hematopoietic cells in peripheral blood of normal individuals refers to clonal hematopoiesis of indeterminate potential (CHIP) and is associated with a 0.5–1% risk of progression to hematological malignancies and cardiovascular diseases. CHIP has been reported also in Multiple Myeloma (MM) patients but its biological relevance remains still to be elucidated. Here, high-depth targeted sequencing on peripheral blood derived from 76 NDMM patients revealed CHIP in 46% of them with a variant allele frequency (VAF) between ~1% and 34%: the most frequently mutated gene was DNMT3A followed by TET2 . A more aggressive disease features were observed among CHIP carriers, which also exhibited more high-risk (ISS and R-ISS 3) stages than controls. Longitudinal analyses at diagnosis and during follow-up showed slight increase of VAFs (p=0.058) for epigenetic ( DNMT3A, TET2 , and ASXL1 ) and DNA repair ( TP53 ) genes (p=0.0123); a more stable frequency was observed among other genes, thus suggesting different temporal dynamics of CH clones. Adverse clinical outcomes, in term of overall and progression-free survivals, were observed among CHIP carriers, who also exhibited immune T-cells weakening and enhanced frailty status that predicted the greater risk of toxicity and consequent shorter event-free survival of this group. Finally, a correlogram analysis identified platelets count as biomarker for higher VAF among CHIP carriers, regardless of specific variant. Overall, our study, by highlighting specific biological and clinical features, paves the way for designing tailored strategies among MM patients carrying CHIP.