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 (<70 yrs ineligible, <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<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<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, >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.

Disclosures

Zweegman:BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Hungria:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer and Regeneron: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bahlis:Pfizer, Janssen: Research Funding; AbbVie, Amgen, BMS, Celgene, Janssen, GSK, Genentech, Karyopharm, Kyte, Novartis, Pfizer, Roche, Sanofi, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Janssen, BMS, GSK, Sanofi, Pfizer, Abbvie, Forus: Honoraria. Braunstein:AstraZeneca, Abbvie, Bristol Myers Squibb, CTI Biopharma, Epizyme, Guidepoint, Janssen (speaker), Lava Therapeutics, Sanofi, Seagen: Membership on an entity's Board of Directors or advisory committees; Janssen, Bristol Myers Squibb, Prothena: Research Funding; Pfizer/ICON: Other: Independent review committee. Marti Tutusaus:BMS, Medison Pharma, Pfizer, Roche: Consultancy. Cohen:Amgen, BMS, GSK, JNJ, Medison, Pfizer, Roche, Sanofi Aventis, Takeda: Consultancy; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Matsumoto:Janssen, Ono, Takeda, Sanofi, Nippon Kayaku, SymBio: Honoraria; Janssen, BMS, GSK, Pfizer: Research Funding. Suzuki:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; SRL: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; BMS: Honoraria, Research Funding; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Ono: Honoraria. Beksac:BMS, Takeda, Janssen, Menarini, Amgen, GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, Janssen, Takeda, Sanofi: Speakers Bureau. Maiolino:Bristol Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Takamatsu:Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Ono: Honoraria; Janssen: Honoraria; SRL: Consultancy; Adaptive Biotechnologies: Consultancy. Perrot:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Menarini Stemline: Honoraria; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Liu:Janssen: Current Employment, Current holder of stock options in a privately-held company. Wang:Janssen: Current Employment, Current holder of stock options in a privately-held company. Chastain:Janssen: Current Employment, Current holder of stock options in a privately-held company. Vermeulen:Janssen: Current Employment, Current holder of stock options in a privately-held company. Krevvata:Janssen: Current Employment, Current holder of stock options in a privately-held company. Lopez-Masi:Janssen: Current Employment, Current holder of stock options in a privately-held company. Carey:Janssen: Current Employment, Current holder of stock options in a privately-held company. Rowe:Janssen: Current Employment, Current holder of stock options in a privately-held company. Carson:Janssen: Current Employment, Current holder of stock options in a privately-held company. Usmani:Abbvie: Consultancy, Research Funding; Gracell: Consultancy; Merck: Research Funding; GSK: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; TeneoBio: Consultancy; Amgen: Consultancy, Research Funding; SeaGen: Consultancy, Research Funding; Array Biopharma: Research Funding; SkylineDX: Consultancy, Research Funding; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; SecuraBio: Consultancy; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; EdoPharma: Consultancy; Pharmacyclics: Research Funding; Oncopeptides: Consultancy; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding.

Off Label Disclosure:

Daratumumab is currently approved in combination with lenalidomide and dexamethasone for the treatment of patients with transplant-ineligible newly diagnosed multiple myeloma, but it is not yet approved in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of patients with transplant-ineligible newly diagnosed multiple myeloma.

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2024
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