Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study
Moreau, Mateos, Berenson, Weisel, Lazzaro, Song, Dimopoulos, Huang, Zahlten-Kumeli & Stewart. Lancet Oncol, June 2018.
Background Twice a week carfilzomib at 27 mg/m² is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly carfilzomib dosing, established the maximum tolerated dose at 70 mg/m² in combination with dexamethasone. We aimed to compare progressionfree survival in patients with relapsed and refractory multiple myeloma given once weekly carfilzomib or twice weekly carfilzomib.
Findings Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11·2 months [95% CI 8·6–13·0] vs 7·6 months [5·8–9·2]; hazard ratio [HR] 0·69, 95% CI 0·54–0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff.
Interpretation Once weekly carfilzomib at 70 mg/m² significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma.
COMMENT More convenient proteasome inhibition for improved outcomes
Holger W Auner & Kwee L Yong. Lancet Oncol, June 2018.
Further studies are therefore still needed to establish standard carfilzomib doses and administration schedules for combinations therapies for relapsed multiple myeloma. Meanwhile, physicians will need to rely on careful scrutiny of adverse event profiles in patient subgroups, as well as reports of real-world experience. Undoubtedly, though, the results of the A.R.R.O.W. study usher in a new era in carfilzomib treatment.
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