New IMS/IMWG risk criteria by next-generation sequencing (NGS): Analysis of daratumumab benefit in both high- and standard-risk patients (pts) in the PERSEUS study.

Abstract

7505 Background: IMS/IMWG recently proposed novel Consensus Genomic Staging (CGS) high-risk criteria for newly diagnosed multiple myeloma (NDMM), including genetic alterations not identifiable by fluorescence in situ hybridization (FISH) but by NGS (eg, TP53 mutations). PERSEUS/EMN017 (NCT03710603) evaluated the addition of daratumumab to VRd induction/consolidation and to R maintenance (DVRd arm) vs VRd+R (VRd arm) in transplant-eligible (TE) pts. PERSEUS previously reported that DVRd significantly improved progression-free survival (PFS) regardless of cytogenetic risk as defined by previous criteria. Methods: 709 pts with NDMM were randomized 1:1 to DVRd vs VRd. Unique molecular assay (UMA)-NGS target panel was used on DNA extracted from CD138+ bone marrow (BM) cells. Of 664 pts from whom BM was collected, 434 patient DNA samples were available for NGS testing. Per the new IMS/IMWG CGS criteria, high risk was defined post-hoc by the presence of del17p/ TP53 mutations; t(4;14) or t(14;16) or t(14;20) with additional amp1q or del1p; amp1q and del1p; biallelic del1p; and high β2 microglobulin with normal renal function. Classic FISH high risk was defined per-protocol by the presence of del17p, t(14;16), and/or t(4;14). Minimal residual disease negativity (MRD neg) was assessed by NGS (Adaptive) in pts with complete response or better. Results: Of 434 pts evaluated, 152 (35%) were high risk by CGS. The most common genetic lesions were del17p/ TP53 (n=59, 14%), IgH translocation with amp1q/del1p (12%), and del1p with amp1q (9%); 2% had biallelic focal del1p. Using CGS criteria, 17% of pts were reclassified from standard risk to high risk; additionally, 4% of pts previously classified as high risk were reclassified as standard risk. DVRd was associated with increased MRD neg rates at 10 -6 compared to VRd in both CGS standard-risk (67% vs 39%, P =0.0001) and high-risk pts (56% vs 26%, P =0.0003). Sustained MRD neg (10 -6 ) rates for ≥12 months (+/-1 mo) were higher with DVRd vs VRd for both CGS standard-risk (57% vs 24%; P <0.0001) and high-risk pts (41% vs 19%; P <0.0001), and pts who achieved sustained MRD negativity (10 -6 ) had superior PFS outcomes versus those who did not, regardless of CGS risk status ( P <0.0001). DVRd led to improved PFS in both CGS standard-risk (HR 0.38, 95% CI 0.20–0.73; P =0.001) and high-risk pts (HR 0.54, 95% CI 0.31–0.95; P =0.039), adjusting for ISS, lactate dehydrogenase, and age (>65 years). Conclusions: DVRd improved MRD negativity and PFS over VRd in both the new IMS/IMWG CGS high-risk and standard-risk subgroups. UMA-NGS panel successfully stratified risk according to CGS criteria, identifying nearly twice as many high-risk pts in the PERSEUS study. These data further support DVRd induction/consolidation and DR maintenance as standard of care for TE-NDMM, regardless of cytogenetic risk. Clinical trial information: NCT03710603 .