Application of the New IMWG/IMS High-Risk Classification for Multiple Myeloma: Analysis of a Large Real-World...

Multiple myeloma (MM) is a biologically heterogeneous plasma cell malignancy in which prognosis is strongly influenced by cytogenetic abnormalities. Recent updates from the International Myeloma Working Group (IMWG), along with the European Hematology Association (EHA) and European Myeloma Network (EMN), have refined the definition of high-risk (HR) disease by integrating TP53 alterations, chromosome 1 abnormalities, and specific combinations of cytogenetic lesions. However, validation of these criteria in real-world patient populations remains limited. We conducted a retrospective, single-center study including 738 patients diagnosed with MM between 2017 and 2025, of whom 408 had available fluorescence in situ hybridization (FISH) data at diagnosis. Patients were reclassified according to the latest IMWG/IMS high-risk criteria proposed in international literature. Cytogenetic abnormalities, treatment patterns, and clinical outcomes, including overall survival (OS), progression-free survival (PFS), response rates, and relapse, were analyzed. Survival was estimated using the Kaplan-Meier method. A total of 103 patients (25%) were reclassified as high-risk according to IMWG/IMS high-risk criteria. Cytogenetic HR abnormalities were identified in 17.2% of cases, with del(17p) being the most frequent (14.7%). Median OS and PFS in HR patients were 52.4 months and 16 months, respectively, compared with 68.4 months and 28 months in standard-risk patients (log-rank test p values of 0.0197 and 0.0004, respectively). Although overall response rates were high (83% in HR vs. 91% in standard-risk), relapse remained frequent in HR patients. Outcomes varied significantly according to cytogenetic complexity. Isolated del(17p) was associated with improved survival compared with cases harboring additional abnormalities, while double-hit and triple-hit profiles demonstrated inferior outcomes. The presence of chromosome 1 abnormalities, particularly in combination with IGH translocations, further worsened prognosis. Among HR patients, 44% underwent autologous stem cell transplantation (ASCT), including 10 cases of TANDEM ASCT. No survival benefit was observed for TANDEM compared with single ASCT, with median OS of 52.9 vs. 78.3 months, respectively (log-rank test p values of 0.2516). Our real-world analysis supports the prognostic relevance of the updated IMS/IMWG high-risk criteria in MM. Cytogenetic complexity, rather than individual abnormalities alone, is a key determinant of outcome. Despite high response rates achieved with modern therapies, survival remains inferior in HR patients. TANDEM ASCT did not confer additional benefit in this cohort, supporting a more individualized approach to treatment intensification.