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4561 Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of the Phase 3 Alcyone Study

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, adult, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Study Population, Human, Minimal Residual Disease
Monday, December 12, 2022, 6:00 PM-8:00 PM

Maria-Victoria Mateos, MD1, Jesús San-Miguel, MD, PhD2, Michele Cavo, MD3*, Joan Bladé Creixenti, MD, PhD4, Kenshi Suzuki5, Andrzej Jakubowiak, MD, PhD6, Stefan Knop7*, Chantal Doyen, MD8, Paulo Lucio, MD, PhD9*, Zsolt Nagy, MD, PhD10*, Ludek Pour, MD, Prof, PhD11*, Sebastian Grosicki, MD, PhD12, Andre H Crepaldi, MD13*, Anna Marina Liberati14, Philip Campbell, MB, ChB15*, Tatiana Shelekhova16*, Sung-Soo Yoon, MD, PhD17, Genadi Iosava, MD18*, Tomoaki Fujisaki19*, Mamta Garg, MD, FRCP, FRCPath20*, Huiling Pei, PhD21*, Maria Krevvata22*, Robin Carson22, Fredrik Borgsten23* and Meletios A. Dimopoulos, MD24

1University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain
2Clínica Universidad de Navarra, CCUN, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC, Pamplona, Spain
3Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
4Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
5Department of Hematology, Japanese Red Cross Medical Center, Department of Hematology, Tokyo, Japan
6University of Chicago Medical Center, Chicago, IL
7Nuremberg General Hospital, Department of Hematology, Oncology and Stem Cell Transplantation, Paracelsus Medical School, Nuremberg, Germany
8Université Catholique de Louvain, CHU UCL Namur, Yvoir, Belgium
9Champalimaud Centre for the Unknown, Lisbon, Portugal
10Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Na, Hungary
11University Hospital Brno, Brno, Czech Republic
12Department of Hematology and Cancer Prevention in Chorzów, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, Katowice, Poland
13Clinica de Tratamento E, Cuiaba, Brazil
14Università degli studi di Perugia, Azienda Ospedaliera Santa Maria, Terni, Italy
15Andrew Love Cancer Centre, University Hospital Geelong, Geelong, Australia
16Clinic of Professional Pathology, Saratov, RUS
17Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of (South)
18Medinvest-Institute of Hematology, Tbilisi, Georgia
19Matsuyama Red Cross Hospital, Matsuyama, Japan
20Haematology Department, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
21Janssen Research & Development, LLC, Titusville, NJ
22Janssen Research & Development, LLC, Spring House, PA
23Janssen Research & Development, LLC, Raritan, NJ
24National and Kapodistrian University of Athens, Athens, Greece

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.

Disclosures: 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; Celgene: Consultancy; Janssen Pharmaceutical: Consultancy; Tikaros: Consultancy; Yuhan Pharmaceutical: Research Funding; Roche-Genetech: Research Funding; Chugai Pharmaceutical: Consultancy; Takeda: 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.

*signifies non-member of ASH