Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved across multiple lines of therapy for patients with multiple myeloma. In the primary analysis of the phase 3 ALCYONE study (median follow-up, 16.5 months), a significant progression-free survival (PFS) benefit was achieved with D-VMP versus VMP alone (median not reached vs 18.1 months; hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P <0.001) in transplant-ineligible patients with NDMM, with no increase in overall toxicity (Mateos MV, N Engl J Med 2018). With longer follow-up (median follow-up, 40.1 months), D-VMP significantly prolonged overall survival (OS) compared to VMP alone (median not reached in either arm; HR, 0.60; 95% CI, 0.46-0.80; P = 0.0003). The rate of minimal residual disease (MRD) negativity was also higher with D-VMP versus VMP (28% versus 7%; P <0.0001; Mateos MV, Lancet 2020). Here, we present an updated analysis of ALCYONE after a median follow-up of 74.7 months.

Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplant were randomized 1:1 to receive VMP ± DARA. Randomization was stratified by International Staging System disease stage (I vs II vs III), region (Europe vs other), and age (<75 vs ≥75 years). All patients received up to nine 6-week cycles of VMP (V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; M: 9 mg/m2 PO on Days 1-4 of Cycles 1-9; P: 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg IV given once weekly in Cycle 1, once every 3 weeks in Cycles 2-9, and once every 4 weeks in Cycles 10+ until disease progression). OS, MRD-negativity rate (10-5 sensitivity: clonoSEQ® version 2.0), and safety were secondary endpoints.

Results: In total, 706 patients were randomized (D-VMP, n = 350; VMP, n = 356). Baseline characteristics were well balanced between treatment arms. After a median follow-up of 74.7 months, a 37% reduction in the risk of death was observed with D-VMP versus VMP; median OS was 82.7 months with D-VMP versus 53.6 months with VMP (HR, 0.63; 95% CI, 0.51-0.78; P <0.0001). The estimated 72-month OS rate was 55.8% with D-VMP versus 39.2% with VMP (Figure A). The observed OS benefit of D-VMP versus VMP alone was generally consistent across pre-specified patient subgroups (Figure B). The MRD-negativity rate was higher for D-VMP versus VMP (28.3% vs 7.0%; P <0.0001), as was the rate of sustained MRD negativity lasting ≥12 months (14.0% vs 2.8%; P <0.0001).

The most common (occurring in ≥30% of patients in either arm) any grade treatment-emergent adverse events (TEAEs; D-VMP/VMP) were neutropenia (50.6%/52.5%), thrombocytopenia (50.0%/53.7%), anemia (32.4%/37.0%), upper respiratory tract infection (30.9%/14.1%), and peripheral sensory neuropathy (28.9%/34.5%). Grade 3/4 TEAEs occurred in 82.9% of D-VMP patients and 77.4% of VMP patients, with the most common (occurring in ≥15% of patients in either arm) being neutropenia (D-VMP/VMP; 40.2%/39.0%), thrombocytopenia (34.7%/37.9%), anemia (18.2%/19.8%), and pneumonia (15.6%/4.5%). Grade 3/4 infection rates were 29.8%/15.0%.

Conclusions: In this updated analysis of ALCYONE, the addition of DARA to VMP continued to prolong OS versus VMP alone in transplant-ineligible patients with NDMM; median OS was reached in both arms for the first time after a median follow-up of >6 years. D-VMP also achieved a 4-fold higher MRD-negativity rate and a 5-fold higher ≥12-month sustained MRD-negativity rate versus VMP alone. No new safety concerns were observed with longer follow-up. Our results continue to support the use of D-VMP in transplant-ineligible patients with NDMM. Updated OS results based on extended follow-up will be presented at the meeting.

Figure 1
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Mateos:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: 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. San-Miguel:Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Takeda, Regeneron, Roche, Sanofi, and SecuraBio: Consultancy, Other: Advisory Board. Cavo:AbbVie, Amgen, Bristol Myers Squibb/Celgene, Pfizer, GlaxoSmithKline, Sanofi, Roche, Takeda: Consultancy, Honoraria; Janssen: Honoraria, Speakers Bureau. Bladé Creixenti:Janssen, Calegen/BMS,Amgen, Takeda, Oncopeptides: Honoraria. Suzuki:Amgen, Takeda, and Bristol Myers Squibb: Consultancy; Takeda, ONO, Amgen, Novartis, Sanofi, Bristol Myers Squibb, AbbVie, and Janssen: Honoraria; Bristol Myers Squibb: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Knop:Bristol-Myers Squibb; Celgene; AMGEN; Sanofi; Molecular Partners; Jansssen: Consultancy, Honoraria. Doyen:Janssen-Cilag: Honoraria. Lucio:Janssen: Consultancy. Liberati:AbbVie: Research Funding; Beigene: Research Funding; BMS: Research Funding; Celegene: Research Funding; DR REDDY'S LABORATORIES SPA: Research Funding; Janssen: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Secura Bio: Research Funding; Takeda: Research Funding; Verastem: Research Funding; PSI: Research Funding; iQVIA: Research Funding; LOXO: Research Funding; MEI-PHARMA: Research Funding; EPZIME: Research Funding. Campbell:Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene (BMS): Research Funding; CSL Behring: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Yoon:Amgen: Consultancy; Novartis: Consultancy; Kyowa Kirin: Research Funding; Astellas Pharma: Consultancy; Tikaros: Consultancy; Yuhan Pharmaceutical: Research Funding; Roche-Genetech: Research Funding; Chugai Pharmaceutical: Consultancy; Takeda: Consultancy; Janssen Pharmaceutical: Consultancy; Celgene: Consultancy. Garg:Janssen, Takeda, Navartis, Amgen, BMS, GSK: Consultancy, Honoraria; Janssen, Amgen, Takeda, Novartis: Consultancy, Other: Ad Board; Janssen, Amgen: Consultancy, Speakers Bureau. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Krevvata:Janssen R& D, Johnson and Johnson: Current Employment. Carson:Janssen: Current Employment. Borgsten:Janssen: Current Employment. Dimopoulos:Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria.

Author notes

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Asterisk with author names denotes non-ASH members.

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2022
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