IMWG Consensus Risk Criteria Predicts Survival in Daratumumab Quadruplet Therapy

Updated risk criteria based on the International Myeloma Working Group (IMWG) guidelines can help predict survival outcomes for patients with newly diagnosed multiple myeloma (NDMM) receiving daratumumab (Darzalex; Johnson & Johnson) quadruplet therapy, according to data presented at the 2025 International Myeloma Society (IMS) Annual Meeting in Toronto, Canada.

In 2024, the IMS and the IMWG released an updated consensus definition for high-risk (HR) NDMM. This new framework incorporates TP53 mutations and the co-occurrence of immunoglobulin heavy chain (IgH) translocations with chromosome 1 abnormalities—features increasingly recognized as strong predictors of adverse outcomes.

However, adoption has been slow, as many treatment centers continue to rely on fluorescence in situ hybridization (FISH) rather than next-generation sequencing (NGS), and routine assessment of TP53 mutations remains limited. Researchers from the Memorial Sloan Kettering Cancer Center applied this updated risk classification to daratumumab quadruplet regimens, offering the first real-world glimpse into how genomic risk classification translates into outcomes with induction therapy.

The study included 506 patients with NDMM who were treated with daratumumab, lenalidomide (Revlimid; Bristol Myers Squibb), dexamethasone plus bortezomib (Velcade; Takeda Pharmaceutical Company; DVRd) or carfilzomib (Kyprolis; Amgen; DKRd). Patients presented with high-risk features—identified using FISH, SNP-array, and MSK-IMPACT-Heme targeted sequencing—including 14% with del17p/TP53mut, 11% with IgH translocation + del1p/gain1q, 7% with del1p + gain1q, and 6% with B2M greater than 5.5 mg/dL + creatinine less than 1.2 mg/dL. Notably, of patients with ISS 3 (19%), 57 were no longer considered high-risk when considering creatinine levels.

Genomic data were available for 96% of patients, enabling detailed stratification by the consensus risk model. Approximately one-third (33%) met high-risk criteria, substantially more than when classified by prior scoring systems such as the International Staging System (ISS, 19%), Revised ISS (8%), or R2-ISS (7%). This broader classification highlighted patients considered intermediate risk under older models but who carried significant genomic vulnerabilities.

The researchers used Fisher exact test and Kaplan-Meier estimates to measure minimal residual disease (MRD) status and event-free survival (EFS). EFS was defined as disease progression or therapy modification due to suboptimal response, and MRD was assessed after 4 to 6 treatment cycles. Of the population, 150 received DKRd and 356 were treated with DVRd, of whom 40% and 30% were high-risk, respectively.

Outcomes differed by genomic risk status. While MRD negativity rates after induction did not vary between HR and standard-risk patients, survival outcomes diverged over time. One- and 2-year EFS were 81% and 70% in the HR group, compared with 94% and 90% in standard risk. Patients with overlapping high-risk designations by both ISS and consensus criteria fared worst, reinforcing the cumulative effect of multiple adverse genomic features.

No differences in EFS or overall survival (OS) were observed between DVRd and DKRd regimens, though high-risk patients made up a greater proportion of the DKRd group, likely reflecting physician choice in higher-risk settings.

The findings suggest that daratumumab-based quadruplet induction mitigates the impact of individual high-risk features, but patients harboring multiple abnormalities continue to experience inferior survival. Crucially, the new IMWG/IMS consensus definition provided more accurate risk prediction than legacy staging systems, particularly in the context of modern therapy.

Application of the 2024 IMWG/IMS consensus criteria in a real-world MSKCC cohort confirmed their value in predicting survival among NDMM patients receiving daratumumab-based quadruplet induction.

REFERENCES

Maclachlan K, Tan C, Shekarkhand T, et al. The new IMS/IMWG consensus risk definition predicts outcomes with daratumumab-based quadruplet regimens for multiple myeloma. 2025 International Myeloma Society Annual Meeting. September 17, 2025, to September 20, 2025. Toronto, Canada. Abstract PA-181