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2 Initial Phase 3 Results Of The First (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) In Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible For Stem Cell Transplantation (SCT)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: Plenary Session
Sunday, December 8, 2013: 2:55 PM
Hall F (Ernest N. Morial Convention Center)

Thierry Facon, MD1, Meletios A. Dimopoulos2, Angela Dispenzieri, M.D.3, John V. Catalano, MD4, Andrew Belch, MD5, Cyrille Hulin, MD6*, Michele Cavo, MD7*, Antonello Pinto, MD8*, Katja Weisel, MD9*, Heinz Ludwig, Univ. Prof. Dr.10, Nizar J. Bahlis, MD11, Anne Banos, MD12*, Mourad Tiab, MD13*, Michel Delforge, MD, PhD14, James D Cavenagh, MD15, Catarina Geraldes, MD16*, Je-Jung Lee, MD, PhD17*, Christine I. Chen, MD, MEd, FRCPC18, Albert Oriol, MD19*, Javier De La Rubia20*, Lugui Qiu, MD21, Darrell J. White, MD22, Daniel Binder, MD23, Kenneth C. Anderson24, Philippe Moreau, MD, PhD25*, Michel Attal26, Robert Knight, MD27*, Guang Chen, PhD27*, Jason Van Oostendorp27*, Christian J. Jacques, MD27, Annette Ervin-Haynes27 and Lofti Benboubker, MD28*

1Service des Maladies du Sang, Hopital Claude Huriez, CHRU Lille, Lille, France
2Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
3Mayo Clinic Cancer Center, Rochester, MN
4Frankston Hospital, Monash University, Frankston, Australia
5University of Alberta and Cross Cancer Institute, Edmonton, AB, Canada
6Service d’Hématologie, CHU Nancy – Brabois, Vandoeuvre, France
7Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
8Oncoematologia, Istituto Nazionale Tumori Fondazione, Napoli, Italy
9Dept. of Hematology, Oncology and Immunology, University of Tuebingen, Tuebingen, Germany
10Department of Medicine I, Wilhelminen Cancer Research Institute, Wilhelminenhospital, Vienna, Austria
11University of Calgary, Calgary, AB, Canada
12Centre Hospitalier de la Côte Basque, Bayonne, France
13Departemental Medecine Interne Les Oudairies, Centre Hospitalier, La Roche sur Yon, France
14University Hospital Leuven, Leuven, Belgium
15St Bartholomew's Hospital, London, United Kingdom
16Clinical Hematology Department, Coimbra University Hospitals, Coimbra, Portugal
17Internal Medicine, Hwasun Chonnam National University Hospital, Hwasun-goon, South Korea
18Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada
19Hospital Germans Trias i Pujol, Barcelona, Spain
20Hematology, Hospital Universitario La Fe, Valencia, Spain
21State Key Lab of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin, China
22Queen Elizabeth II Health Sciences Ctr., Halifax, NS, Canada
23Kantonsspital Winterthur, Winterthur, Switzerland
24Dana-Farber Cancer Institute, Boston, MA
25Service d'Hematologie, CHU, Nantes, France
26Hématologie Clinique, CHU Purpan, Toulouse, France
27Celgene Corporation, Summit, NJ
28University Hospital Tours, Tours, France

Background:  Melphalan, prednisone and thalidomide (MPT) is a standard therapy for NDMM recognized worldwide based on a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) vs. MP (Facon Lancet 2007; Fayers Blood 2011; NCCN 2013). The combination of lenalidomide and low-dose dexamethasone (Rd) increased OS with fewer adverse events (AEs) than treatment with lenalidomide and high-dose dexamethasone in NDMM pts (ECOG E4A03) (Rajkumar Lancet Oncol 2010). The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of Rd versus MPT in transplant-ineligible NDMM pts.

Methods:  NDMM pts either ≥ 65 years of age, or not candidates for SCT were randomized to one of three arms:  Rd in 28-day cycles until disease progression (Arm A), Rd in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Assessments by International Myeloma Working Group criteria were done after each cycle. Pts with renal impairment were enrolled; however, pts on dialysis were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age. Dose adjustments were permitted for AEs. All pts were required to receive anti-thrombotic prophylaxis. Stratification factors included age, International Stage System, and country. The primary endpoint was a comparison of PFS in Arm A vs. Arm C. Secondary endpoints included OS, overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL).  A preplanned additional analysis included time from randomization to second progression event or death (PFS2). The final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A vs. Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events) are presented in this abstract. Comparisons of PFS and all secondary endpoints, including OS for all three arms, will be presented at the meeting.

Results:A total of 1,623 pts were randomized 1:1:1 in three arms. As of today, 121 pts continue to receive lenalidomide on study (Arm A). The median age was 73 (40.0–92.0) years; 35% pts were aged ≥ 75 years; and 41% of pts had ISS stage 3 disease. After a median follow-up of 37 months, the trial met its primary endpoint (PFS), demonstrating a 28% reduction in risk of progression or death (HR=0.72; p= 0.00006). The preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A vs. Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p<0.0096) was not crossed. All other secondary endpoints consistently showed improvement in favor of Arm A vs. Arm C; ORR (PR or better) 75% vs. 62% (p < 0.00001), DOR (HR=0.63; p<0.00001), and PFS2 (HR=0.78, p=0.0051). Relevant Grade 3/4 adverse events in Arm A vs. Arm C were neutropenia (28% vs. 45%), thrombocytopenia (8% vs. 11%), febrile neutropenia (1% vs. 3%), infection (29% vs. 17%), neuropathy (5% vs.15%), and deep-vein thrombosis (5% vs. 3%). The incidence of secondary primary malignancies (SPM) was evaluated. Hematologic malignancies were 0.4% in Arm A vs. 2.2% in Arm C; the overall incidence of solid tumors was identical (2.8%).

Conclusion: Continuous treatment with the all oral doublet Rd significantly improved the primary endpoint of PFS compared with the standard triplet, MPT. All secondary endpoints support the clinical benefit of continuous Rd treatment. The safety profile of Rd was manageable, with reduced hematologic SPM compared to MPT.

Disclosures: Facon: Celgene: Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau . Off Label Use: Lenalidomide as treatment for NDMM. Dimopoulos: Celgene, Orthobiotech: Honoraria . Dispenzieri: Celgene, Millenium, Jansenn, Pfizer: Research Funding . Catalano: Celgene, Roche: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding . Hulin: Janssen: Honoraria ; Celgene: Honoraria . Cavo: Celgene, Janssen, Millennium, Onyx, Brystol Myers Squibb: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees . Pinto: Mundipharma: Consultancy , Honoraria ; Roche: Honoraria ; Celgene: Consultancy , Honoraria . Weisel: Janssen: Consultancy , Honoraria ; Celgene: Consultancy , Honoraria , Research Funding . Ludwig: Celgene: Honoraria , Research Funding , Speakers Bureau . Bahlis: Celgene: Consultancy , Honoraria . Delforge: Celgene: Honoraria . Chen: Celgene: Consultancy , Research Funding ; Lundbeck: Consultancy ; Johnson & Johnson: Consultancy , Research Funding ; Roche: Honoraria ; GlaxoSmithKline: Research Funding . Oriol: Celgen: Consultancy . White: Celgene: Honoraria , Research Funding . Binder: Celgene: Research Funding . Anderson: Acetylon, OncoPep: Equity Ownership ; Celgene, Onyx, Sanofi Aventis, Gileod: Consultancy . Moreau: Celgene Corporation: Honoraria , Speakers Bureau . Attal: Janssen: Lectures , Membership on an entity’s Board of Directors or advisory committees , Other: Lectures ; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees , Other: Lectures . Knight: Celgene: Employment , Equity Ownership . Chen: Celgene: Employment . Van Oostendorp: Celgene: Employment . Jacques: Celgene: Employment . Ervin-Haynes: Celgene: Employment , Patents & Royalties . Benboubker: Celgene: Consultancy .

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