(PA-181) The New IMS / IMWG Consensus Risk Definition Predicts Outcomes with Daratumumab-based Quadruplet Regimens for Multiple Myeloma

In 2024, the IMS and IMWG presented a new consensus risk definition for newly diagnosed myeloma (NDMM), including TP53 mutations and the co-occurrence of IgH translocations with chromosome 1 aberrations. However, as most centers assess NDMM using FISH rather than NGS, TP53 mutation status is not yet routinely available. Here, we apply the consensus definition to patients treated with daratumumab-based quadruplet induction (dara-quads) at MSKCC.

Methods: We assessed all patients treated with daratumumab-revlimid-dexamethasone plus bortezomib (DVRd) or carfilzomib (DKRd), with at least 3 months of follow-up data available. Genomic information included FISH, SNP-array and MSK-IMPACT-Heme targeted sequencing. MRD-status was compared by Fisher exact test. Survival analysis used Kaplan-Meier estimates, with event-free survival (EFS) including progression and therapy change for suboptimal response.

Results:

506 patients were treated with DKRd (n=150) or DVRd (n=356). Median follow-up was 1.8 years (y, IQR 0.9-3.0, max 7.5y), with 484/506 (96%) having genomic data available.

The distribution of individual high-risk (HR) features was 14% with del17p/TP53mut, 11% with IgH translocation + del1p/gain1q, 7% with del1p + gain1q, and 6% with B2M >5.5mg/dL + creatinine < 1.2 mg/dL. Interestingly, of 86/461 (19%) with ISS III, 57 were no longer HR if considering creatinine level. Overall, 33% were defined as HR by at least one consensus criteria, higher than when defining by ISS (19%), R-ISS (8%) or R2-ISS (7%), thereby better delineating patients at intermediate risk by other prognostic scores.

EFS and OS did not differ between DVRd and DKRd, with HR patients comprising 30% of DVRd-treated, and 40% of DKRd-treated, possibly reflecting physician preference in this real-world cohort. MRD-status after 4-6 cycles did not differ by risk (p=0.4), however 1y- and 2y-EFS in HR were 81% and 70% respectively, compared with 94% and 90% in standard risk (SR). Of note, patients who were HR by ISS but not by the new definition had shorter EFS compared with SR, while those HR by both ISS and the consensus definition had even shorter EFS.

EFS based on each of t(4;14), t(14;16), and gain1q were significant at a univariate level (p< 0.005), however, these risk factors mainly occurred in combination, and none retained significance when excluding patients harboring multiple risk factors.

Conclusions: Dara-quad induction overcomes individual prognostic features in NDMM, however the cumulative impact of HR features remains adverse. Consensus HR status did not predict early MRD status but did predict EFS, suggesting that any MRD-directed approaches should also consider genomic risk. Given that the new IMWG / IMS risk criteria accurately predict survival in the setting of dara-quads, they are a good basis for harmonizing NDMM clinical trial inclusion and stratification. Future trials may benefit from considering risk definition by IMWG / IMS consensus criteria together with HR by ISS staging.