e19538 Background: High-risk multiple myeloma is associated with poor outcomes and inferior survival. Cytogenetic abnormalities are a key determinant of high-risk disease and were defined by the International Myeloma Working Group (IMWG) in 2015, including del(17p), t(4;14), and t(14;16) by fluorescence in situ hybridization (FISH). In 2025, the IMWG refined this classification to include variants of 1p loss, 1q gain/amplification, TP53 mutation, and defined high-risk IgH translocation only in setting of other high-risk cytogenetics; in addition to categorizing β2-microglobulin ≥ 5.5 alone as high risk. This updated IMWG definition is intended to improve identification of patients with truly high-risk disease who may benefit from aggressive treatment. Here, we report our real-world application of the 2025 criteria to evaluate whether it better predicts survival. Methods: We conducted a retrospective review of patients who underwent standard-of-care autologous stem cell transplantation (ASCT) at our institution between January 2012 and August 2025, the start date corresponding to the expansion of our institutional myeloma FISH panel to include cytogenetic abnormalities in 2015 IMWG model. Baseline cytogenetic risk was classified using both the 2015 and 2025 definitions to evaluate changes in risk categorization. Overall survival (OS) was measured from the time of diagnosis. Results: In our cohort of 436 patients, median age at diagnosis was 61 years, and 59.6% were male. Extramedullary disease or plasma cell leukemia was present in 6.9%. Using 2015 criteria, 24.1% were classified as high risk compared with 31.2% using the 2025 criteria. Overall, 12.6% of patients were reclassified, with significantly more upstaged from low to high risk than downstaged (9.9% vs 2.8%; p<0.01). All but one patient was upstaged due to 1p loss or elevated β2-microglobulin ≥ 5.5 mg/L. At a median follow-up of 5.1 years (SD +/- 3.1 years), median OS was not reached for either high- or low-risk groups using the 2015 criteria, with 5-year OS of 67% and 77%, respectively. In contrast, using the 2025 criteria, median OS was 9.6 years for high-risk patients, and the median OS was not reached for low-risk patients. Corresponding 5-year OS estimates for 2025 classification were of 66% and 78% for high-risk and low-risk, respectively. Median OS of downstaged patients was not reached, while that of upstaged group was 8.9 years. On univariate analysis, 2025 high-risk status (HR 1.52, p=0.02), extramedullary disease/plasma cell leukemia (HR 2.46, p<0.01), and age at diagnosis (HR 1.05, p<0.01) predicted poor OS. Conclusions: Our study illustrates that the 2025 IMWG criteria tend to predict outcomes and identify high-risk multiple myeloma patients at a greater capacity than the prior 2015 criteria. Our analysis shows validity of the 2025 IMWG multiple myeloma criteria in a real-world cohort, although continued refinement will be needed.
Chopra et al. (Thu,) studied this question.