Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Alone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma or for Whom Transplant Is Not Planned As Initial Therapy: Analysis of Minimal Residual Disease in the Cepheus Trial
Authors: Zweegman Sonja , Facon Thierry , Hungria Vania , Bahlis Nizar J. , Venner Christopher P. , Braunstein Marc , Pour Luděk , Marti Tutusaus Josep , Basu Supratik , Cohen Yael C. , Matsumoto Morio , Suzuki Kenshi , Hulin Cyrille , Grosicki Sebastian , Legiec Wojciech Maciej , Beksac Meral , Maiolino Angelo , Takamatsu Hiroyuki , Perrot Aurore , Turgut Mehmet , Liu Weiping , Wang Jianping , Chastain Katherine , Vermeulen Jessica , Krevvata Maria , Lopez-Masi Lorena , Carey Jodi , Rowe Melissa , Carson Robin , Usmani Saad Z. 
Published: December 2024

Introduction: The achievement of minimal residual disease (MRD) negativity is associated with longer-term survival outcomes and has evolved into a strong prognostic clinical endpoint in MM. In the phase 3 CEPHEUS study, DARA in combination with VRd (D-VRd) significantly increased depth of response, including rates of overall MRD negativity, complete response or better (≥CR), and sustained MRD negativity (versus VRd) in patients with transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) or for whom transplant was not intended as initial therapy (transplant deferred). These deep responses translated into a significantly superior progression-free survival (PFS) for D-VRd versus VRd (HR, 0.57; 95% CI, 0.41-0.79; P=0.0005). Here we report an expanded analysis of MRD outcomes from the CEPHEUS study.
Methods: CEPHEUS is a multicenter, open-label, randomized, phase 3 study that included eligible patients with NDMM with no intent for transplant based upon age (≥70 yrs), the presence of comorbid conditions likely to hinder transplant or high-dose chemotherapy tolerance, or had deferred first-line transplant. Patients were stratified by International Staging System disease stage and age/transplant eligibility (&lt;70 yrs ineligible, &lt;70 yrs and transplant deferred, ≥70 yrs) and randomized 1:1 to D-VRd or VRd. All patients received eight 21-day cycles of VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-14; d: 20 mg PO/IV Days 1, 2, 4, 5, 8, 9, 11, 12), followed by 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg PO/IV Days 1, 8, 15, 22). Patients in the D-VRd group also received subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) weekly in Cycles 1-2, every 3 weeks in Cycles 3-8, and every 4 weeks in Cycles 9+. Treatment continued until progressive disease or unacceptable toxicity. The primary endpoint was MRD-negativity rate (10-5). MRD was evaluated via next-generation sequencing (clonoSEQ®) using bone marrow aspirate samples obtained at baseline, at the time of suspected complete response, and at 12, 18, 24, 30, and 36 months after the first dose and annually thereafter in patients with complete response.
Results: A total of 395 patients (D-VRd, n=197; VRd, n=198) were randomized between December 11, 2018 and October 7, 2019. At a median follow-up of 58.7 months, overall MRD-negativity rates were significantly higher with D-VRd versus VRd at both 10-5 (60.9% vs 39.4%; OR, 2.37; 95% CI, 1.58-3.55; P&lt;0.0001) and 10-6 (46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P=0.0001) sensitivity thresholds. Prespecified subgroup analyses showed a consistent MRD benefit with D-VRd across the majority of subgroups, except for patients with high cytogenetic risk. Rates of sustained MRD negativity (≥12 months) were also higher with D-VRd versus VRd at both 10-5 (48.7% vs 26.3%; OR, 2.63; 95% CI, 1.73-4.00; P&lt;0.0001) and 10-6 (32.0% vs 15.7%; OR, 2.52; 95% CI, 1.55-4.11; P=0.0001), with continued benefit of sustained MRD negativity observed with D-VRd for 2 yrs (10-5: 38.6% vs 21.2%; 10-6: 24.9% vs 12.6%) and 3 yrs (10-5: 27.4% vs 13.6%) versus VRd. D-VRd improved landmark MRD-negativity rates and cumulative MRD negativity at all prespecified assessment timepoints (12/18/24/30/36/48/60 months) at both 10-5 and 10-6 depths compared to VRd. PFS trended higher with D-VRd versus VRd in patients with MRD-negative (10-5: HR, 0.61; 95% CI, 0.35-1.06; 10-6: HR, 0.66; 95% CI, 0.31-1.41) and MRD-positive status (10-5: HR, 0.82; 95% CI, 0.54-1.24; 10-6: HR, 0.74; 95% CI, 0.51-1.06). The estimated 54-mo PFS rates were 81.0% for D-VRd versus 69.5% for VRd in MRD-negative (10-5) patients and 46% versus 33.7% for MRD-positive patients.
Conclusion: D-VRd resulted in significantly higher rates of overall and sustained MRD negativity at both 10-5 and 10-6 sensitivity thresholds versus VRd at all timepoints in TIE and transplant-deferred patients with NDMM. This deeper response translated into significant improvements in overall PFS in the D-VRd group. Of patients who achieved MRD-negativity (10-5) with D-VRd, &gt;80% were alive and progression-free at 54 months. These data further support the use of D-VRd as a new standard of care for patients with NDMM that are TIE or for whom transplant is deferred.