Timing and Pattern of Extraosseous Dissemination Are Key Determinants of Survival in Multiple Myeloma

ABSTRACT Extraosseous (EO) involvement in multiple myeloma (MM) is a critical marker of systemic clonal escape, but its spatial and temporal dynamics are largely omitted from current risk models like R2‐ISS. In this cohort of 543 patients with longitudinal follow‐up between 2010 and 2025, whole‐body (WB) imaging including WB‐MRI ± FDG‐PET/CT was used to characterize EO disease. EO status was modeled as a time‐varying covariate in multivariable Cox proportional hazards models including clinical, biological, and genetic covariates to assess impact on overall survival (OS). EO disease was identified in 24.6% of cases ( n = 134). We identified a distinct prognostic hierarchy for OS based on the timing and pattern of dissemination: compared to marrow‐confined disease, prognosis was increasingly worse for primary paraskeletal (PS) lesions present at diagnosis (HR = 2.22), secondary PS (HR = 3.33), and reaching an ultra‐high‐risk for secondary extramedullary disease (EMD) (HR = 8.14). Patients with initial PS lesions faced a 2.6‐fold increased risk of evolving into secondary EMD ( p = 0.002). While lesion volume and anatomical localization of EO lacked prognostic value, secondary EMD, R2‐ISS stage IV, number of lines of treatment and TP53 mutation at time of EO diagnosis independently predicted lower post‐EO survival. Thus, EO involvement defines an aggressive phenotype in which prognosis is driven by the timing and dissemination pattern rather than EO tumor burden. WB imaging accurately identifies patients transitioning into these high‐risk groups. Integrating timing and spatial EO features into future risk frameworks is essential for better prognostication, as the adverse impact of EO disease persists even after adjusting for R2‐ISS and cytogenetic status.