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LBA-2 Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA)

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
antibodies, Biological, multiple myeloma, Diseases, Therapies, Plasma Cell Disorders, Lymphoid Malignancies
Tuesday, December 4, 2018, 7:30 AM-9:15 AM
Hall AB (San Diego Convention Center)

Thierry Facon1*, Shaji K. Kumar, MD2, Torben Plesner, MD, DSc3, Robert Z. Orlowski, MD, PhD4*, Philippe Moreau5*, Nizar Bahlis, MD6, Supratik Basu, MBBS, MD, FRCP, FRCPath7*, Hareth Nahi, MD, PhD8*, Cyrille Hulin, MD9*, Hang Quach, MD, FRACP, FRCPA, MBBS10, Hartmut Goldschmidt, MD11, Michael O’Dwyer12*, Aurore Perrot13*, Christopher P. Venner, MD, FRCPC14, Katja Weisel, MD15*, Joseph R. Mace16*, Tahamtan Ahmadi17*, Christopher Chiu, PhD18, Jianping Wang19*, Rian Van Rampelbergh20*, Clarissa M. Uhlar18*, Rachel Kobos, MD19, Ming Qi, MD, PhD18 and Saad Z. Usmani, MD21

1Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France
2Department of Hematology, Mayo Clinic, Rochester, MN
3Vejle Hospital and University of Southern Denmark, Vejle, Denmark
4Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX
5Hematology, University Hospital Hôtel-Dieu, Nantes, France
6University of Calgary, Arnie Charbonneau Cancer Institute, Calgary, AB, Canada
7Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom
8Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm, Sweden
9Department of Hematology, Hospital Haut Leveque, University Hospital, Pessac, France
10St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
11University Hospital Heidelberg and National Center of Tumor Diseases (NCT), Heidelberg, Germany
12Dept. of Medicine/Haematology, NUI, Galway, Ireland
13Hematology Department, University Hospital, Vandoeuvre Les Nancy, France
14Division of Medical Oncology University of Alberta, Edmonton, AB, Canada
15Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II, Tuebingen, Germany
16Florida Cancer Specialists & Research Institute, St. Petersburg, FL
17Genmab US, Inc., Princeton, NJ
18Janssen Research & Development, LLC, Spring House, PA
19Janssen Research & Development, LLC, Raritan, NJ
20Janssen Research & Development, Beerse, Belgium
21Levine Cancer Institute/Atrium Health, Charlotte, NC

Introduction

Lenalidomide-based therapies are a standard of care for patients with newly diagnosed, transplant-ineligible MM. Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody which has single-agent activity in heavily pretreated MM patients. As previously reported in 3 phase 3 studies, the addition of DARA to standards of care in both relapsed refractory (D-Rd, DARA plus bortezomib and dexamethasone [D-Vd]) or transplant-ineligible NDMM (DARA plus bortezomib, melphalan, and prednisone [D-VMP]) resulted in a ≥50% reduction in the risk of disease progression or death (Palumbo A, et al. N Engl J Med 2016;375:754-766; Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331; Mateos MV, et al. N Engl J Med 2018;378:518-528). Of these, the POLLUX study with D-Rd showed the greatest benefit with a 63% reduction in risk of disease progression or death in patients with MM who had at least one prior line of therapy. Based on the efficacy and tolerable safety profile of D-Rd, we conducted a phase 3 study (MAIA) to evaluate D-Rd vs Rd in transplant-ineligible NDMM. Here we report the prespecified interim analysis of the MAIA study.

Methods

Patients ineligible for high-dose chemotherapy with autologous stem cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to Rd ± DARA. Stratification was based on International Staging System stage (ISS [I, II, III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of treatment with Rd ± DARA. R: 25 mg (oral) QD on Days 1‑21; d: 40 mg (oral) on Days 1, 8, 15 and 22. In the D-Rd arm, DARA was given at 16 mg/kg (intravenously) QW for Cycles 1‑2, Q2W for Cycles 3-6, and Q4W thereafter. In both arms, patients were treated until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), minimal residual disease (MRD)‑negativity rate (10-5 sensitivity, clonoSEQ® version 2.0), and safety.

Results

This international study randomized 737 patients (368 to D-Rd; 369 to Rd) from 14 countries. Key baseline characteristics were well balanced between the two arms. The median (range) age was 73 (45-90) years with 44% of patients ≥75 years, and 52% were male. Two thirds of patients had ECOG scores ≥1: ECOG score 0, 34%; 1, 50%; ≥2, 17%. Overall, 27%, 43%, and 29% were ISS stage I, II, and III, respectively. Of 642 patients evaluable for FISH/karyotyping analysis, 86% and 14% were standard and high cytogenetic risk, respectively. The prespecified interim analysis occurred after 239 PFS events on 24 September 2018 with a median follow up of 28 months. For the primary endpoint, the hazard ratio was 0.55 (95% CI, 0.43 to 0.72; P <0.0001), representing a 45% reduction in the risk of progression or death in patients treated with D-Rd (Figure). The median PFS for the Rd arm was 31.9 months and not reached for the D-Rd arm. Adding DARA to Rd resulted in deeper responses with a complete response (CR) or better rate of 47.6% in the D-Rd arm compared with 24.7% in the Rd arm (odds ratio [OR] 2.75, 95% CI, 2.01 to 3.76; P <0.0001). The very good partial response (VGPR) or better rate was 79.3% in the D-Rd arm compared with 53.1% in the Rd arm (OR 3.4, 95% CI, 2.45 to 4.72; P <0.0001). A total of 19% of patients have died and the HR for OS was 0.78 (95% CI, 0.56 to 1.1); follow-up is ongoing. Higher rates (5% or more difference) of grade 3/4 pneumonia, neutropenia, and leukopenia were observed in the D-Rd arm. The safety profile is consistent with previously reported DARA studies. The complete topline data set will be presented with additional efficacy endpoints, including MRD negativity rate.

Conclusion

The addition of DARA to Rd in patients with transplant-ineligible NDMM significantly reduced the risk of progression or death by 45%. There are no new safety signals using DARA plus Rd in NDMM. These data together with the phase 3 ALCYONE study (D-VMP vs VMP) support the addition of DARA to standard of care combinations in patients with NDMM ineligible for transplant.

Disclosures: Facon: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kumar: KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Celgene: Other: Independent Response Assessment Comittee; Janssen: Consultancy. Orlowski: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioTheryX: Research Funding; Spectrum Pharma: Research Funding. Moreau: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hulin: Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt: Adaptive Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria. O’Dwyer: Janssen: Consultancy. Perrot: Janssen: Consultancy, Equity Ownership, Honoraria. Venner: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Weisel: Celgene: Consultancy; Angeb: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding; Bristol Myers SquibbMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ahmadi: Genmab: Employment, Equity Ownership. Chiu: Janssen Research & Development, LLC: Employment, Equity Ownership. Wang: Janssen Research & Development, LLC: Employment. Van Rampelbergh: Janssen: Employment. Uhlar: Janssen: Employment. Kobos: Janssen Research & Development: Employment. Qi: Janssen Research & Development, LLC: Employment. Usmani: Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.