Validation of the new IMS/IMWG consensus genomic staging (CGS) of high-risk multiple myeloma (HRMM) in a contemporary cohort of 1209 patients.

Due to its high clinical and biological complexity, multiple myeloma (MM) is a malignancy of heterogeneous prognoses and outcomes. The International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) formulated a consensus genomic staging (CGS) of high-risk MM (HRMM), aiming to refine and homogenize the classification of high-risk disease. We evaluated the new HRMM criteria in a cohort of 1209 consecutive newly diagnosed MM patients with complete CGS data (except TP53 mutations), treated in a single center with contemporary regimens, including triplets and quadruplets, between 2010 and 2024. Based on CGS criteria, 25.2% of our cohort's patients were classified as HRMM. High-risk status was associated with significantly inferior outcomes: median overall survival (OS) was 44 months for HRMM versus 93 months for standard-risk (SR) patients (hazard ratio [HR] 1.81; P < 0.001), corresponding to 5-year OS rates of 40% versus 61%. Similarly, median progression-free survival was 21.3 months for HRMM versus 36 months for SR (HR 1.64; P < 0.001). The presence of ≥2 high-risk features identified an ultra-high-risk group (4.4% of patients) with a threefold increased risk of death, compared to SR patients. CGS remained prognostic irrespective of renal dysfunction, stratifying patients with sCr > 1.2 mg/dL (HR 1.71; P < 0.001) and retained prognostic significance across different age groups, transplant eligibility, and treatment eras (pre- and post-2020). The IMS/IMWG CGS effectively stratified patients in a large cohort treated at a tertiary academic center, identifying a substantially high-risk population with poor outcomes despite modern therapies. This validation supports its deployment in clinical practice and research to enhance the precision of risk-adapted management.