Validation of the 2025 IMS/IMWG risk classification in patients with newly diagnosed multiple myeloma treated with quadruplets and autologous stem cell transplant.

Despite the improvement in outcomes of patients with newly diagnosed multiple myeloma (NDMM) with quadruplet therapy (QUAD) and autologous stem cell transplantation (ASCT), outcomes are heterogeneous. The International Myeloma Society (IMS) and International Myeloma Working Group (IMWG) published new consensus high-risk (new-HiR) criteria which combine cytogenetic abnormalities, next-generation sequencing data, β2 microglobulin and renal function developed in a population treated prior to the introduction of QUADs. We utilized a cohort of NDMM patients treated with QUAD + ASCT with a median follow-up of 41.5 months to validate the IMS/IMWG high-risk criteria and compared the performance of the old-HiR, based on the presence of t(4;14), t(14;16) or del(17p) versus new-HiR criteria. Among the 310 patients, 89 (29%) were classified as new-HiR. Patients with new-HiR NDMM had substantially worse progression-free survival (PFS) (hazard ratio [HR] 4.17, 95% confidence interval [CI] 2.58-6.73; p < 0.001) and overall survival (OS) (HR 5.13, 95% CI 2.44-10.80, p < 0.001). The new IMS/IMWG criteria better fit a predictive model for PFS and OS than the old criteria. The new criteria were able to identify misclassified patients under the old criteria. The 2025 IMWG/IMS criteria outperform legacy risk classification systems in the identification of patients at high risk for early progression and death despite modern therapy.