Integrating an updated high-risk multiple myeloma classification into clinical practice and clinical trial epidemiology

INTRODUCTION: Numerous risk staging systems exist for newly diagnosed multiple myeloma (NDMM), from older models which rely purely on markers of 'tumor burden' to modern scores which incorporate tumor genetics. While the 2025 IMS-IMWG high-risk criteria, based on specific cytogenetic analyses and the β2-microglobulin titer, represent a major push to harmonize NDMM risk stratification, multiple barriers to successful, comprehensive implementation in standard practice remain. There also exists substantial heterogeneity in how therapeutic trials quantify risk. AREAS COVERED: We herein summarize the novel 2025 IMS-IMWG criteria. We then provide a brief overview of the current state of NDMM risk stratification in standard practice, as well as the variability in 'high-risk' disease definitions in NDMM trials. Finally, we discuss ways in which such variation in 'high-risk' definition is being addressed. EXPERT OPINION: Attempts to improve prognostication and potentially demonstrate outcome prediction in NDMM have been confounded by variable performance of risk stratification in standard clinical practice and substantial heterogeneity of 'high-risk' definitions in clinical trials. If implemented comprehensively, the 2025 IMS-IMWG criteria will allow for apples-to-apples comparison across trials via meta-analysis and thus harmonize risk assessment in myeloma, setting the stage for investigation of risk-adapted treatment deescalation and intensification.