High-risk genomic consensus validation for patients with newly diagnosed multiple myeloma using next-generation sequencing.

The prognostic heterogeneity of multiple myeloma is mainly driven by genomic features of myeloma cells. The International Myeloma Society (IMS) / International Myeloma Working Group (IMWG) recently proposed a high-risk (HR) genomic model in order to have a consensus definition of genomic risk. We performed NGS panel in 6528 new diagnosed myeloma patients (NDMM) and 1583 patients at first relapse, between 2019 and 2024. We observed that 22.4% of patients at diagnosis and 36.7% at first relapse were HR according to the Consensus Genomic Staging (CGS). Clinical data were available for 2695 patients at diagnosis. After a median follow-up of 35 months, the median PFS was 30 months for HR NDMM patients, vs 51 months for standard-risk (SR) (p<0.0001). HR cytogenetic criteria from the Revised-ISS score were not able to discriminate patients in HR nor SR IMS/IMWG genomic subgroups. Looking at each criteria independently, we found that the presence of del(17p), TP53 mutation, biallelic del(1p32), or the combination of intermediate risk cytogenetics (gain 1q, del(1p32), t(4;14), t(14;16), t(14;20)) significantly reduces the PFS compared with standard-risk patients. Moreover, patients cumulating several criteria had an even worse prognosis. Among SR patients according to the genomic definition with normal creatinine, median PFS of those with high beta2-microglobulin was not significantly different from patients with normal beta2-microglobulin level. This study validates the IMS/IMWG genomic definition of high-risk myeloma in a large cohort of patients diagnosed from 2019.