The miR4261/PAMM axis in multiple myeloma promotes bone resorption

Myeloma bone disease (MBD) affects ~80% of multiple myeloma (MM) patients and remains a major cause of morbidity despite anti-resorptive therapies. Here we identify a previously unrecognized exosome-mediated mechanism by which MM cells directly promote osteoclastogenesis. Tumor-derived exosomal miR-4261 is transferred to monocyte precursors, directly targets and represses PAMM (PRXL2A/FAM213A)—an antioxidant protein that negatively regulates osteoclast differentiation—and thereby accelerates osteoclast formation and bone resorption. In two independent MM cohorts, serum exosomal miR-4261 was significantly elevated in patients with MBD, whereas PAMM expression was reduced; low PAMM strongly correlated with hypercalcaemia. PAMM knockdown recapitulated the pro-osteoclastogenic effects of miR-4261, and RNA-seq/GSEA revealed selective downregulation of negative regulators of osteoclast differentiation (including TNFAIP6, CCL3, and TLR3). These findings establish the miR-4261/PAMM axis as a novel driver of myeloma-induced bone destruction and suggest serum exosomal miR-4261 as a promising liquid-biopsy biomarker and therapeutic target in MBD.