Gene expression-based dissemination score predicts early spread and poor outcomes in multiple myeloma.

Multiple myeloma progresses from bone marrow-confined disease to systemic forms through processes linked to loss of adhesion and EMT-related programs. We analyzed baseline plasma cell RNA-seq, microarray, and single-cell datasets to derive and validate a dissemination score. In the newly diagnosed MMRF CoMMpass cohort (n = 754), differential expression analyses of circulating plasma cells (n = 592) and PET-CT-confirmed plasmacytomas (n = 118), integrated with 1114 EMTome genes, identified 1357 dissemination-associated genes. Elastic Net Cox regression derived a 30-gene Dissemination Score (DS) that stratified overall survival (54.5 vs 102.5 mo; C-index 0.71) and improved prognostic performance when added to UAMS70 and EMC92 in bootstrap analyses. DS was associated with Adverse stromal interaction (ASI) and stratified high-risk ASI interactions. In an independent Mayo Clinic cohort (n = 133), DS reproduced prognostic discrimination (52.1 vs 113.6 mo, p < 0.01) and predicted earlier dissemination events (2.1 vs 6.8 yrs, p < 0.01). In GSE117156, circulating plasma cells showed consistently higher DS than marrow plasma cells across MGUS, SMM, MM, and AL, with progressive DS increase from controls to MM. In GSE106218, CD138⁺ extramedullary plasma cells had higher DS than marrow plasma cells (p < 0.01). Collectively, DS quantifies dissemination biology.