Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial

• Published in: The lancet oncology 2017-10, Vol.18 (10), p.1327-1337
• Main Authors: Dimopoulos, Meletios A, Goldschmidt, Hartmut, Niesvizky, Ruben, Joshua, Douglas, Chng, Wee-Joo, Oriol, Albert, Orlowski, Robert Z, Ludwig, Heinz, Facon, Thierry, Hajek, Roman, Weisel, Katja, Hungria, Vania, Minuk, Leonard, Feng, Shibao, Zahlten-Kumeli, Anita, Kimball, Amy S, Moreau, Philippe
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bortezomib; Bortezomib - administration & dosage; Bortezomib - adverse effects; Cause of Death; Cell number; Dexamethasone; Dexamethasone - administration & dosage; Dexamethasone - adverse effects; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Drugs; Dyspnea; Fatigue; Female; Health risk assessment; Humans; Hypertension; Infusions, Intravenous; Inhibitor drugs; Internationality; Intravenous administration; Kaplan-Meier Estimate; Leukemia; Lung diseases; Male; Maximum Tolerated Dose; Middle Aged; Motivation; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - mortality; Multiple Myeloma - pathology; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - mortality; Neoplasm Recurrence, Local - pathology; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Patients; Peripheral neuropathy; Pneumonia; Prognosis; Proportional Hazards Models; Prospective Studies; Proteasome inhibitors; Quality of life; Respiration; Response rates; Septic shock; Studies; Survival Analysis; Targeted cancer therapy; Thrombocytopenia; Treatment Outcome
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(17)30578-8

The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups. ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m2) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients. Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff dat