1 School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 2 University of Nantes, Nantes, France; 3 University of Torino, Torino, Italy; 4 Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; 5 University Hospital Brno, Brno, Czech Republic; 6 University Hospital Brno and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 7 CHRU Lille Hôpital Claude Huriez, Lille, France; 8 Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria; 9 Institut Català d’Oncologia, Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain; 10 Heidelberg Medical University, Heidelberg, Germany; 11 Hospital Clínic de Barcelona, Barcelona, Spain; 12 Vseobecna fakultni nemocnice v Praze, Prague, Czech Republic; 13 Hematological Department, First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia; 14 Centre Hospitalier de la Côte Basque, Bayonne, France; 15 Semashko Central Clinical Hospital, Moscow, Russia; 16 Department of Hematooncology, University Hospital Olomouc, Olomouc, Czech Republic; 17 Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 18 Universitatsklinikum Tubingen, Tubingen, Germany; 19 University Multiprofile Hospital for Active Treatment Sveti Georgi and Hematology Clinic, Plovdiv, Bulgaria; 20 Box Hill Hospital, Box Hill, Victoria, Australia; 21 London Health Sciences Centre, Western University, London, Ontario, Canada; 22 St. Istvan and St. Laszlo Hospital, Department of Haematology and Stem-Cell Transplantation, Budapest, Hungary; 23 Kyiv Center for Bone Marrow Transplantation, Kyiv, Ukraine; 24 Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I-G.M. Lancisi-G. Salesi di Ancona, Dipartimento Onco-ematologico, Ancona, Italy; 25 Irmandade da Santa Casa de Misericórdia de Sao Paulo, Sao Paulo, Brazil; 26 Alfred Health-Monash University, Melbourne, Victoria, Australia; 27 Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA; 28 National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute of Singapore, National University of Singapore, Singapore Carfilzomib and Dexamethasone Improves Progression-Free Survival and Response Rates vs Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma: the Phase 3 Study ENDEAVOR Meletios A. Dimopoulos, 1 Philippe Moreau, 2 Antonio Palumbo, 3 Douglas Joshua, 4 Ludek Pour, 5 Roman Hájek, 6 Thierry Facon, 7 Heinz Ludwig, 8 Albert Oriol, 9 Hartmut Goldschmidt, 10 Laura Rosiñol, 11 Jan Straub, 12 Aleksandr Suvorov, 13 Carla Araujo, 14 Elena Rimashevskaya, 15 Tomas Pika, 16 Gianluca Gaidano, 17 Katja Weisel, 18 Vesselina Goranova-Marinova, 19 Anthony Schwarer, 20 Leonard Minuk, 21 Tamás Masszi, 22 Ievgenii Karamanesht, 23 Massimo Offidani, 24 Vania Hungria, 25 Andrew Spencer, 26 Heidi H. Gillenwater, 27 Nehal Mohamed, 27 Shibao Feng, 27 Wee-Joo Chng, 28 on behalf of the ENDEAVOR investigators

Background Bortezomib with dexamethasone (Vd) is a standard-of-care regimen for patients with relapsed multiple myeloma (MM) 1 Carfilzomib is an irreversible epoxyketone proteasome inhibitor approved in the United States and several other countries as a single agent in relapsed and refractory MM at a dose of 20/27 mg/m 2 infused over 2–10 minutes 2 In a phase 1b/2 study, the maximum tolerated dose for carfilzomib was 20/56 mg/m 2 infused over 30 minutes in combination with dexamethasone (Kd), which showed higher response rates in relapsed and/or refractory MM compared with lower doses 3 Thus, we initiated the randomized, open-label, multicenter phase 3 ENDEAVOR study (NCT ), which compared Kd with Vd in patients with relapsed MM 2 1. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Multiple Myeloma (v4.2015); 2. Kyprolis [prescribing information]. Thousand Oaks: Onyx Pharmaceuticals, Inc., an Amgen subsidiary; 2015; 3. Papadopoulos KP, et al. J Clin Oncol. 2015;33:732–739.

Conclusions ENDEAVOR is the first head-to-head study comparing 2 proteasome inhibitors Kd resulted in a 2-fold decrease in the risk of progression or death compared with Vd ‒ Median PFS of 18.7 months (Kd) vs 9.4 months (Vd) ORR was significantly higher with Kd than Vd (77% vs 63%) ‒ Twice as many patients achieved a complete response (13% vs 6%) or a very good partial response or better (54% vs 29%) 3 Kd, carfilzomib and dexamethasone; ORR, overall response rate; Vd, bortezomib and dexamethasone.

Conclusions (continued) Rates of grade ≥3 hypertension (9% vs 3%), dyspnea (5% vs 2.2%), and cardiac failure (5% vs 1.8%) were higher in the Kd group compared with the Vd group Grade ≥2 PN rates were significantly lower in the Kd group than in the Vd group (6% vs 32%), despite 79% of Vd patients receiving subcutaneous bortezomib throughout their treatment Although Kd patients remained on study treatment longer (40 weeks vs 27 weeks), treatment discontinuation due to AEs and on-study deaths due to AEs were comparable between groups Kd was superior to Vd regardless of age or prior bortezomib exposure, and represents a new standard of care 4 AE, adverse event; Kd, carfilzomib and dexamethasone; PN, peripheral neuropathy; Vd, bortezomib and dexamethasone.

Acknowledgments (continued) We are grateful to the patients for their participation in the ENDEAVOR study We also thank the members of the data monitoring and independent review committees The ENDEAVOR study was supported by Onyx Pharmaceuticals, Inc., an Amgen subsidiary Editorial assistance was provided by BlueMomentum, an Ashfield Company, and supported by Onyx Pharmaceuticals, Inc., an Amgen subsidiary 5