Circulating plasma cells (polyclonal and monoclonal) as markers of an aggressive multiple myeloma phenotype

Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells (PCs) in the bone marrow (BM). The pathogenesis of MM is complex and multifactorial, with significant heterogeneity among patients, making risk stratification and disease monitoring difficult. In this study, the potential role of circulating plasma cells (CPCs), including polyclonal CPCs, as innovative biomarkers, was evaluated in 108 MM patients. Using next generation flow, CPCs in peripheral blood (PB) were analyzed, finding their presence in 92% of cases (monoclonal CPCs 77%, polyclonal CPCs 15%), with a median of 0.02% (range 0.002-9%). CPCs were significantly correlated with adverse clinical parameters and tumor burden ( p < 0.05), indicating an association with a more aggressive phenotype even in the presence of polyclonal PCs. Notably, high CPCs-patients had mutations limited to KRAS , while patients with a low number of CPCs carried preferentially NRAS mutations. Lastly, comparisons between PCs phenotypes in BM and PB showed significant heterogeneity, such as variations in the expression of markers like CD56 and CD138, suggesting the potential migratory predisposition. Overall, the presence of both monoclonal and polyclonal CPCs, together with evidence of immunophenotypic and molecular heterogeneity, suggests that CPCs may reflect clinically relevant aspects of tumor dissemination and disease evolution.