scRNA analysis of multiple myeloma, extramedullary diease and solitary plasma cytomas.

Extramedullary multiple myeloma non-contiguous to bone (EMD) represents an aggressive, often late stage, treatment-resistant manifestation of plasma cell neoplasia characterized by dissemination beyond the bone marrow. Despite prior reports implicating proliferative and adhesion-related alterations in plasma cells in the EMD, the cellular architecture and transcriptional organization underlying this transition remain incompletely defined. To define the cellular and transcriptional programs underlying this transition, we performed single-cell RNA sequencing on clonal plasma cells (CPCs) from EMD lesions (n=8), solitary plasmacytomas (SPM; n=4), and bone marrow aspirates (BMA; n=4), analyzing 128,908 clonal plasma cells. We identified eight conserved PC states across the three disease entities spanning quiescent, proliferative, extracellular matrix-interacting, and migratory phenotypes. We demonstrate that CPCs in EMD are characterized by generalized proliferative rewiring, pervasive EMT-like transcriptional plasticity with metabolic adaptations, and a non-canonical IL-6/STAT3/VEGF signaling axis consistent with niche-independent survival. Comparative analysis with solitary plasmacytomas suggest that these features are unique to EMD CPCs and not just reflective of the extramedullary localization. A parsimonious 11-gene EMD signature robustly distinguished EMD from SPM and BMA, was externally validated and demonstrated independent prognostic utility in a dataset with newly diagnosed MM. These findings establish EMD cells to harbor a MYC-driven high-amplitude proliferative rewiring, stress-adapted and niche independent growth with potentially distinct therapeutic vulnerabilities.