Daratumumab + bortezomib, lenalidomide, and dexamethasone (DVRd) vs VRd in transplant-ineligible (TIE)/transplant-deferred (TD) newly diagnosed multiple myeloma (NDMM): Phase 3 CEPHEUS trial cytogenetic subgroup analysis.

Abstract

7529 Background: In CEPHEUS, DVRd significantly improved overall MRD negativity (MRD neg + ≥CR) and sustained MRD neg rates and PFS in patients (pts) with TIE/TD NDMM. In this post hoc analysis, we report outcomes in cytogenetic risk subgroups. Methods: Pts with TIE/TD NDMM were randomized 1:1 to DVRd or VRd. High-risk (HiR) cytogenetic abnormalities (HRCAs) were assessed by FISH. HiR was ≥1 of: del(17p); t(4;14); t(14;16). Revised HiR (R-HiR) was ≥1 of above or gain (3 copies) or amp(1q) (≥4 copies). Standard risk (SR) was 0 HRCAs; revised SR (R-SR) was 0 revised HRCAs. Additional risk groups included: gain or amp(1q) + other HRCAs; 1 and ≥2 revised HRCAs. We assessed overall MRD neg rate, sustained MRD neg, ≥CR rate, and PFS. We reported all MRD neg rates at 10 -5 unless noted. Results: Of 395 randomized pts (DVRd, n=197; VRd, n=198), 298 had SR (DVRd, n=149; VRd, n=149) and 52 HiR (DVRd, n=25; VRd, n=27). 184 pts had R-SR (DVRd, n=94; VRd, n=90) and 167 R-HiR (DVRd, n=83; VRd, n=84). At median 58.7-month (mo) follow-up, overall MRD neg rate was higher with DVRd vs VRd in SR (64% vs 38%; P <0.0001) and R-SR pts (68% vs 38%; P <0.0001). Rates by treatment (tx) arm in HiR (48% vs 56%; P =0.7816) and R-HiR pts (55% vs 45%; P =0.2169) were comparable. DVRd improved ≥1-year (y) sustained MRD neg rate vs VRd in SR (51% vs 26%; P <0.0001) and R-SR pts (54% vs 24%; P <0.0001). Sustained MRD neg rates by tx arm were comparable in HiR (40% vs 37%; P =1.0000) and R-HiR pts (43% vs 30%; P =0.0782). PFS was improved with DVRd vs VRd in SR and R-SR pts and was comparable by tx arm in HiR and R-HiR pts (Table), including in MRD neg pts (R-SR: hazard ratio [HR]=0.63 [95% CI, 0.26–1.52]; P =0.3003; R-HiR: HR=0.71 [95% CI, 0.32–1.58]; P =0.3995). Remaining outcomes, including rates of ≥CR, ≥2-y sustained MRD neg, and overall and ≥1-y sustained MRD neg at 10 -6 , were improved with DVRd in SR and R-SR pts and comparable by tx arm in HiR and R-HiR pts. Conclusions: In CEPHEUS, DVRd consistently improved the key response outcomes of MRD neg and PFS in (R-)SR pts. In HiR pts, MRD and PFS outcomes trended lower in both tx arms vs those in SR pts. Here, DVRd mostly improved PFS outcomes vs VRd; however, pt numbers were small, with the study underpowered for HiR pts. These data support use of DVRd for TIE/TD NDMM regardless of cytogenetic risk status. Clinical trial information: NCT03652064 . DVRd VRd n mPFS, mo n mPFS, mo HR (95% CI); P -value HiR a 25 39.8 27 31.7 0.88 (0.42–1.84); 0.7387 R-HiR 83 NE 84 45.6 0.73 (0.46–1.15); 0.1739 SR a 149 NE 149 60.6 0.61 (0.41–0.91); 0.0136 R-SR 94 NE 90 60.6 0.54 (0.32–0.91); 0.0189 Gain(1q) + other HRCAs 43 60.3 48 42.2 0.80 (0.45–1.43); 0.4496 Amp(1q) + other HRCAs 31 NE 20 NE 0.97 (0.38–2.47); 0.9525 1 revised HRCA 66 NE 72 47.2 0.63 (0.37–1.09); 0.0938 ≥2 revised HRCA 17 22.7 12 29.7 1.01 (0.42–2.44); 0.9868 a Unknown cytogenetic risk: DVRd, n=23; VRd, n=22. mPFS, median PFS; NE, not estimable.