IMS-IMWG 2025 consensus genomic staging predicts outcomes with daratumumab-based quadruplet regimens for NDMM

The International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG) recently published a new consensus genomic staging (CGS) for defining high-risk (HR) newly diagnosed multiple myeloma (NDMM), intended to provide consistency in clinical trial reporting and for use in designing enrichment clinical trials focused on the HR subset. The HR definition is the first to include TP53 mutations and considers the co-occurrence of immunoglobulin H translocations with chromosome 1 aberrations. Given that limited data from the anti-CD38 monoclonal antibody-based quadruplet induction regimens were available for consensus consideration, here, we demonstrate that the new HR definition also predicts clinical outcomes in this setting. The patient population comprised 503 patients with NDMM treated with daratumumab-based quadruplet induction therapy at Memorial Sloan Kettering Cancer Center, with a median follow-up time of 2.2 years (maximum, 7.9 years). The CGS criteria defined 31% of NDMM cases as HR, better delineating patients at intermediate risk by preexisting prognostic scores. The CGS did not predict early minimal residual disease (MRD) status, with MRD negativity occurring at the same rate in patients with HR and standard-risk (SR) NDMM. However, the CGS did predict progression-free survival (PFS), with a median of 2.6 years in HR compared with not reached in SR (P< .0001). CGS risk remained predictive of PFS even in the setting of MRD negativity after autologous stem cell transplantation. We conclude that although the IMS-IMWG CGS is ideal for standardizing NDMM trial design, any MRD-guided trial design should also consider genomic risk.