OA - 63: Daratumumab + Bortezomib/Lenalidomide/Dexamethasone in Patients With Transplant-ineligible or Transplant-deferred Newly Diagnosed Multiple Myeloma: Results of the Phase 3 CEPHEUS Study

Introduction: Daratumumab (DARA) has improved overall survival (OS) in 3 frontline regimens and was the first anti-CD38 monoclonal antibody approved in newly diagnosed multiple myeloma (NDMM). For transplant-ineligible (TIE) NDMM, the MAIA regimen (DARA + lenalidomide/dexamethasone [D-Rd]) is a standard of care (SOC), with a median OS of 7.5y. For transplant-eligible NDMM, the PERSEUS regimen (subcutaneous DARA [DARA SC] + bortezomib/lenalidomide/dexamethasone [D-VRd] then D-R maintenance) has shown significant progression-free survival (PFS) benefit vs SOC.



The CEPHEUS study evaluated the addition of DARA SC to VRd vs VRd in NDMM patients (pts) who are TIE or for whom transplant was not planned as initial therapy (transplant deferred). Here we report for the first time the results of the CEPHEUS study.


Methods: Pts were aged ³18y with TIE or transplant-deferred NDMM. All pts received eight 21-day cycles of VRd, followed by 28-day cycles of Rd until progressive disease (PD). Patients randomized to D-VRd received DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) given QW in Cycles 1-2, Q3W in Cycles 3-8, and Q4W in Cycles 9+ until PD. The primary endpoint was overall minimal residual disease (MRD)-negativity (neg) rate (10^–5), among pts achieving complete response or better (³CR). Secondary endpoints included ³CR rate, PFS, and sustained MRD-neg rate (³12 months [mo]).


Results: 395 pts were randomized 1:1 (D-VRd, n=197; VRd, n=198). Median age was 70 (range, 31-80) y; 28.1% had ISS stage III disease; 13.2% had high-risk cytogenetics (t[4;14], t[14;16], or del[17p]). At a median follow-up of 58.7 mo, the overall MRD-neg rate was 60.9% for D-VRd vs 39.4% for VRd (OR, 2.37; 95% CI, 1.58-3.55; P < 0.0001). PFS was significantly improved with D-VRd vs VRd (HR, 0.57; 95% CI, 0.41-0.79; P=0.0005). Median PFS was not reached for D-VRd vs 52.6 mo for VRd; estimated 54-mo PFS rates were 68.1% vs 49.5%. ³CR rate was 81.2% with D-VRd vs 61.6% with VRd (P < 0.0001) and sustained MRD-neg rate was 48.7% vs 26.3% (P < 0.0001). OS trended in favor of D-VRd (HR, 0.85; 95% CI, 0.58-1.24); HR was 0.69 (95% CI, 0.45-1.05) in a sensitivity analysis censoring deaths due to COVID-19. Median treatment duration was 22 months longer for D-VRd (56.3 mo) vs VRd (34.3 mo). Addition of DARA did not affect relative dose intensity of VRd. TEAEs were consistent with known safety profiles for DARA and VRd. Grade 5 TEAE rates adjusted for treatment exposure were comparable for D-VRd and VRd (0.39 vs 0.31 per 100 pt-mo).

Conclusions: In pts with TIE or transplant-deferred NDMM, DARA SC + VRd significantly improved PFS vs VRd, reducing the risk of progression or death by 43%. D-VRd significantly increased overall MRD negativity, ³CR rate, and sustained MRD negativity. These data, coupled with PERSEUS, demonstrate the consistent benefit of DARA + VRd vs VRd, and support DARA quadruplet therapy, with or without transplant, as a new SOC for NDMM.