CLINICAL IMPACT AND PREVALENCE OF CLONAL HEMATOPOIESIS IN MULTIPLE MYELOMA PATIENTS: RETROSPECTIVE MULTICENTRIC ANALYSIS

The charge of somatic mutations to hematopoietic cells in peripheral blood refers to hematopoiesis of indeterminate potential (CHIP) and is associated with a 0.5 1% risk of progression to hematological malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). CHIP clones have also been reported in Multiple Myeloma (MM) patients, but its biological relevance remains to be elucidated. We performed high-depth targeted sequencing on peripheral blood (PB) derived from 76 NDMM patients, observing CHIP in 46% of the entire cohort with a variant allele frequency (VAF) between approximately 1% and 34%. The most frequently mutated gene was DNMT3A, followed by TET2. A more aggressive disease characterized by lower hemoglobin and higher beta2-microglobulin, 24-hour protein urine, and creatinine levels was observed in CHIP carriers, who additionally exhibited more high-risk (ISS and R-ISS 3) stages. An analysis focused on CD138-negative cells derived from bone marrow aspirates showed high correlation (Pearson R=0.97, p<0.0001) with peripheral blood mononuclear cells, suggesting correlation between these two sources. Longitudinal analyses in a subset of patients confirmed a slight increment in mutational burden during follow-up, mainly in epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (TP53) (p=0.0123); stable frequency affected all others, suggesting different temporal dynamics of CHIP clones. Adverse clinical outcomes, in terms of overall and progression-free survival, were observed among CHIP carriers, who also exhibited shorter event-free survival. Finally, a specific mathematical model pinpoints platelet count as a surrogate biomarker for higher VAF rates among CHIP carriers. Overall, our study highlights specific biological and frailty characteristics, paving the way for designing tailored strategies for CHIP carriers among MM patients.