title: Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.
abstract: BACKGROUND
  Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
  
  
  METHODS
  In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866.
  
  
  RESULTS
  Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]).
  
  
  CONCLUSIONS
  For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option.
  
  
  BACKGROUND
  Onyx Pharmaceuticals, Inc., an Amgen subsidiary.
authors.affiliation: School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: mdimop@med.uoa.gr.
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
authors.affiliation: University of Nantes, Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: University of Turin, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.affiliation: Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Douglas
authors.initials: D
authors.lastname: Joshua
authors.affiliation: University Hospital Brno, Brno, Czech Republic.
authors.forename: Ludek
authors.initials: L
authors.lastname: Pour
authors.affiliation: University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
authors.forename: Roman
authors.initials: R
authors.lastname: Hájek
authors.affiliation: CHRU Lille Hôpital Claude Huriez, Lille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Facon
authors.affiliation: Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Ludwig
authors.affiliation: Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Oriol
authors.affiliation: Heidelberg Medical University, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosiñol
authors.affiliation: Vseobecna fakultni nemocnice v Praze, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Straub
authors.affiliation: Hematological Department, First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Suvorov
authors.affiliation: Centre Hospitalier de la Cote Basque, Bayonne, France.
authors.forename: Carla
authors.initials: C
authors.lastname: Araujo
authors.affiliation: Semashko Central Clinical Hospital, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Rimashevskaya
authors.affiliation: Department of Hematooncology, University Hospital Olomouc, Olomouc, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Pika
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Universitatsklinikum Tubingen, Tubingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Weisel
authors.affiliation: University Multiprofile Hospital for Active Treatment Sveti Georgi and Hematology Clinic, Plovdiv, Bulgaria.
authors.forename: Vesselina
authors.initials: V
authors.lastname: Goranova-Marinova
authors.affiliation: Box Hill Hospital, Box Hill, Victoria, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Schwarer
authors.affiliation: London Health Sciences Centre, Western University, London, Ontario, Canada.
authors.forename: Leonard
authors.initials: L
authors.lastname: Minuk
authors.affiliation: Department of Haematology and Stem-cell Transplant, St Istvan and St Laszlo Hospital of Budapest, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Masszi
authors.affiliation: Kyiv Center for Bone Marrow Transplantation, Kyiv, Ukraine.
authors.forename: Ievgenii
authors.initials: I
authors.lastname: Karamanesht
authors.affiliation: Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I-G.M. Lancisi-G. Salesi di Ancona, Ancona, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Offidani
authors.affiliation: Irmandade da Santa Casa de Misericórdia de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Vania
authors.initials: V
authors.lastname: Hungria
authors.affiliation: Alfred Health-Monash University, Melbourne, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.affiliation: The University of Texas MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Gillenwater
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Nehal
authors.initials: N
authors.lastname: Mohamed
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
authors.forename: Shibao
authors.initials: S
authors.lastname: Feng
authors.affiliation: National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib / Q000008:administration & dosage / Q000009:adverse effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects; D011014:Pneumonia / Q000139:chemically induced; D019233:Retreatment; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D009842:Oligopeptides; D000069286:Bortezomib; C524865:carfilzomib; D003907:Dexamethasone