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. FINDINGS: 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%]). INTERPRETATION: 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. FUNDING: Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Alfred Health Monash University Melbourne Victoria Australia

Box Hill Hospital Box Hill Victoria Australia

Centre Hospitalier de la Cote Basque Bayonne France

CHRU Lille Hôpital Claude Huriez Lille France

Clinica di Ematologia Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto 1 G M Lancisi G Salesi di Ancona Ancona Italy

Department of Haematology and Stem cell Transplant St Istvan and St Laszlo Hospital of Budapest Budapest Hungary

Department of Hematooncology University Hospital Olomouc Olomouc Czech Republic

Division of Hematology Department of Translational Medicine Amedeo Avogadro University of Eastern Piedmont Novara Italy

Heidelberg Medical University Heidelberg Germany

Hematological Department 1st Republican Clinical Hospital of Udmurtia Izhevsk Russia

Hospital Clínic de Barcelona IDIBAPS Barcelona Spain

Institut Català d'Oncologia Institut Josep Carreras Hospital Germans Trias i Pujol Barcelona Spain

Irmandade da Santa Casa de Misericórdia de Sao Paulo Sao Paulo Brazil

Kyiv Center for Bone Marrow Transplantation Kyiv Ukraine

London Health Sciences Centre Western University London Ontario Canada

National University Cancer Institute National University Health System Singapore and Cancer Science Institute of Singapore National University of Singapore Singapore

Onyx Pharmaceuticals Inc an Amgen subsidiary South San Francisco CA USA

Royal Prince Alfred Hospital Camperdown New South Wales Australia

School of Medicine National and Kapodistrian University of Athens Athens Greece

Semashko Central Clinical Hospital Moscow Russia

The University of Texas MD Anderson Cancer Center The University of Texas Houston TX USA

Universitatsklinikum Tubingen Tubingen Germany

University Hospital Brno Brno Czech Republic

University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

University Multiprofile Hospital for Active Treatment Sveti Georgi and Hematology Clinic Plovdiv Bulgaria

University of Nantes Nantes France

University of Turin Turin Italy

Vseobecna fakultni nemocnice Praha Prague Czech Republic

Wilhelminen Cancer Research Institute Wilhelminenspital Vienna Austria

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ClinicalTrials.gov
NCT01568866