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

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.