Extracellular Vesicle IL5RA and BCMA in Serum Enable Non-Invasive Risk Stratification of Multiple Myeloma

Background/Objectives: Multiple myeloma (MM) is an incurable plasma cell neoplasm in which diagnosis and prognostication rely on invasive bone marrow examinations that may not capture biological heterogeneity across different disease sites. There is a clinical need for non-invasive biomarkers that can accurately predict treatment outcomes. Methods: We performed a global proteomic profiling of bone marrow-derived extracellular vesicles (EVs) from nine MM patients and ten controls. A total of 8839 proteins were identified, of which 14 met predefined selection criteria. These candidates were quantified in serum-derived EVs using targeted proteomic analysis. Prognostic relevance of selected proteins was evaluated in newly diagnosed MM (NDMM) patients treated with daratumumab-containing frontline regimens (n = 26) and healthy individuals (n = 60). Progression-free survival (PFS) was analyzed using univariable and multivariable models. Results: IL5RA (p = 0.003) and BCMA (p < 0.001) were significantly elevated in serum EVs from MM patients compared with controls. Higher serum EV-IL5RA and EV-BCMA were associated with a trend toward shorter PFS. Combined assessment of these biomarkers enabled clear stratification of MM patients into three prognostic groups, including a cohort with markedly inferior outcomes, with a 20-month PFS of 0 (p = 0.001). In multivariable analysis, the combined serum EV-IL5RA and EV-BCMA signature suggests an independent prognostic potential (HR = 38.49 [95% CI, 1.51–47.79], p = 0.015). Conclusions: Serum EV-IL5RA and EV-BCMA are novel non-invasive biomarkers, measurable through routine blood testing, with strong potential to improve risk stratification in NDMM patients in the era of daratumumab-based frontline therapy.