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859 Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Overall Survival in Alcyone

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Improving the Outcomes of Newly Diagnosed Multiple Myeloma
Hematology Disease Topics & Pathways:
Diseases, antibodies, Adult, Biological, multiple myeloma, Therapies, Study Population, Plasma Cell Disorders, Lymphoid Malignancies
Monday, December 9, 2019: 4:30 PM
Hall E2, Level 2 (Orange County Convention Center)

Maria-Victoria Mateos1, Michele Cavo2*, Joan Bladé, MD, PhD3, Meletios A. Dimopoulos, MD4, Kenshi Suzuki, MD, PhD5, Andrzej Jakubowiak, MD, PhD6, Stefan Knop7*, Chantal Doyen, MD8, Paulo Lucio, MD, PhD9*, Zsolt Nagy, MD, PhD10*, Ludek Pour, MD11*, Mark Cook, MBChB, PhD12, Sebastian Grosicki, MD, PhD13, Andre H Crepaldi, MD14*, Anna Marina Liberati15, Philip Campbell, MBBS, FRACP, FRCPA16, Tatiana Shelekhova17*, Sung-Soo Yoon, MD, PhD18, Genadi Iosava, MD19*, Tomoaki Fujisaki, MD, PhD20*, Mamta Garg, MD, FRCP, FRCPath21*, Maria Krevvata, PhD22*, Jianping Wang23*, Anupa Kudva, MD23*, Jon Ukropec, PhD24, Susan Wroblewski, PhD22*, Rachel Kobos, MD23 and Jesus San-Miguel, MD, PhD25

1University Hospital of Salamanca/IBSAL, Salamanca, Spain
2Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
3Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
4National and Kapodistrian University of Athens, Athens, Greece
5Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
6University of Chicago Medical Center, Chicago, IL
7Würzburg University Medical Center, Würzburg, Germany
8Université catholique de Louvain, CHU UCL Namur, Yvoir, Belgium
9Champalimaud Centre for the Unknown, Lisbon, Portugal
10Semmelweis Egyetem, Budapest, Hungary
11University Hospital Brno, Brno, Czech Republic
12University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom
13Department of Cancer Prevention, School of Public Health, Silesian Medical University, Katowice, Poland
14Clinica de Tratamento E, Cuiaba, Brazil
15Azienda Ospedaliera "Santa Maria", Terni, Italy
16Andrew Love Cancer Centre, Geelong, Australia
17Clinic of Professional Pathology, Saratov, RUS
18Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of (South)
19LTD “Medinvent” Institute of Health, Tbilisi, Georgia
20Matsuyama Red Cross Hospital, Matsuyama, Japan
21Leicester Royal Infirmary, Leicester, United Kingdom
22Janssen Research & Development, LLC, Spring House, PA
23Janssen Research & Development, LLC, Raritan, NJ
24Janssen Global Medical Affairs, Horsham, PA
25Clínica Universidad de Navarra-CIMA, IDISNA, CIBERONC, Pamplona, Spain

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The addition of DARA to standard-of-care regimens in phase 3 studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response or better, and induced a ≥3-fold increase in minimal residual disease (MRD)–negativity rates versus standard of care alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) and relapsed/refractory 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 (median not reached vs 18.1 months; hazard ratio [HR], 0.50; P <0.001) was observed with the addition of DARA to bortezomib/melphalan/prednisone (D-VMP) in patients with transplant-ineligible NDMM, without an increase in overall toxicity (Mateos MV, et al. N Engl J Med. 2018;378[6]:518-528). D-VMP continued to demonstrate a significant PFS benefit versus VMP alone after 1 year of additional follow-up, including in patients ≥75 years of age (Dimopoulos MA, et al. Blood. 2018;132[Suppl 1]:156). After a median follow-up of 27.8 months, D-VMP reduced the risk of disease progression or death by 57% versus VMP alone, with a 24-month PFS rate of 63% in the D-VMP group and 36% in the VMP group. This PFS benefit was observed regardless of patient age and was maintained during the subsequent line of therapy in patients with transplant-ineligible NDMM. Here, we present >36 months of follow-up from ALCYONE, including analysis of overall survival (OS) from a prespecified interim analysis.

Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age (≥65 years) or comorbidities were randomized 1:1 to receive up to nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously 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; melphalan 9 mg/m2 orally and prednisone 60 mg/m2 orally on Days 1-4 of Cycles 1-9) with or without DARA (16 mg/kg intravenously once weekly for Cycle 1, once every 3 weeks for Cycles 2-9, and once every 4 weeks for Cycles 10+ until disease progression). The primary endpoint was PFS. Secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, MRD-negativity rate (10–5 threshold), PFS on subsequent line of therapy (PFS2), OS, and safety.

Results: A total of 706 patients were enrolled in this study (D-VMP: n = 350; VMP: n = 356). Patient baseline characteristics were well balanced between treatment arms. The median (range) age was 71 (40-93) years, and 29.9% of patients were ≥75 years of age. 518 (84.1%) and 98 (15.9%) of 616 patients evaluated had standard and high (del17p, t[14;16], and/or t[4;14] positive) cytogenetic risk, respectively, as assessed via local fluorescence in-situ hybridization/karyotyping. Median PFS was 36.4 months with D-VMP versus 19.3 months with VMP after a median follow-up of 40.08 months (HR, 0.42; 95% confidence interval [CI], 0.34-0.51; P <0.0001; Figure A). Median PFS2 was not reached with D-VMP versus 42.3 months with VMP (HR, 0.55; 95% CI, 0.43-0.71; P <0.0001). The estimated 36-month OS rate was 78% with D-VMP versus 68% with VMP, with a significant benefit for OS observed for D-VMP versus VMP alone (HR, 0.60; 95% CI, 0.46-0.80; P = 0.0003; Figure B); median OS was not reached in either group and follow-up is ongoing. Additional efficacy data, including MRD negativity, and updated safety data will be presented at the meeting.

Conclusions: For the first time, we demonstrate that the addition of DARA to VMP prolongs OS in patients with transplant-ineligible NDMM, with a 40% reduction in the risk of death versus VMP alone after a median follow-up of 40 months. D-VMP continued to demonstrate a significant PFS benefit, which was also maintained during the subsequent line of therapy. These findings, together with the phase 3 MAIA study (DARA plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone), continue to support the addition of DARA to frontline treatment regimens in patients with transplant-ineligible NDMM.

Disclosures: Mateos: Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria. Cavo: Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau. Bladé: Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Dimopoulos: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Sanofi Oncology: Research Funding; Genesis Pharma: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Suzuki: Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Jakubowiak: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Lucio: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Nagy: Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cook: Celgene, Jannsen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squibb, GlycoMimetics, Seattle Genetics and Sanofi: Honoraria. Liberati: Janssen: Honoraria; Bristol & Mayer: Honoraria; Celgene: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Campbell: Janssen: Honoraria, Research Funding, Speakers Bureau. Garg: Novartis, Janssen: Research Funding; Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria. Krevvata: Janssen: Employment. Wang: Janssen: Employment. Kudva: Janssen: Employment, Equity Ownership. Ukropec: Janssen: Employment, Equity Ownership. Wroblewski: Janssen: Employment, Equity Ownership. Kobos: Janssen: Employment. San-Miguel: Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

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