Moreau P, et al. - Researchers present the results of an interim analysis of a randomized, phase 3 study that was conducted to compare once weekly carfilzomib to twice weekly carfilzomib regimen with respect to progression-free survival in patients with relapsed and refractory multiple myeloma. Significantly prolonged progression-free survival was achieved with once weekly carfilzomib at 70 mg/m² vs the twice weekly schedule, with comparable overall safety between the groups. In this group of patients, once weekly carfilzomib vs the twice weekly schedule showed more efficacy with a convenient dosing regimen and appeared safe.

Methods

• This is a prespecified interim analysis of the randomized, open-label, phase 3 A.R.R.O.W. trial.
• Participants were patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, recruited from hospital, clinic, oncology or medical centers.
• Refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease and Eastern Cooperative Oncology Group Performance Status of 0 or 1 was the key eligibility criteria.
• Patients were randomized (1:1) to receive carfilzomib once a week (70 mg/m²) or twice a week (27 mg/m²).
• Using a validated randomization software, the randomization sequence was generated.
• For implementing the randomization sequence, researchers used an interactive response technology system that assigned patients to treatment sequentially based on the randomization sequence as patients were enrolled at participating clinical sites.
• Stratification of patients by International Staging System stage at study entry or baseline, irrespective of if they were refractory to bortezomib treatment, and age (block size of 4) was done.
• For the once weekly group, treatment regimen was carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m² day 1 [cycle 1] and 70 mg/m² thereafter).
• For twice weekly group, treatment regimen was carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m² days 1 and 2 during cycle 1 and 27 mg/m² thereafter).
• Dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1–9 only]) was administered to all patients.
• Until disease progression or unacceptable toxic effects, the treatment was continued.
• The comparison of progression-free survival between groups in the intention-to-treat population was the primary objective.
• Safety analysis including all randomly assigned patients who received at least one dose of study treatment was carried out.

Results

• Recruitment of 578 patients from 118 sites was done between September, 2015, and August, 2016.
• The efficacy analyses included 478 patients who were randomly assigned (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib).
• In the once weekly group vs the twice weekly group, higher median progression-free survival was noted (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).
• Researchers found that in the once weekly group vs the twice weekly group, there was a higher incidence of grade 3 or worse adverse events (68% [n=161] vs 62% [n=145]); the most common events were anemia, 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).
• Data revealed that in the once weekly group (7 [3%]) vs in the twice weekly group (10 [4%]), a lower percentage of patients had grade 3 or worse cardiac failure.
• Occurrence of treatment-related deaths was reported 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 tumor 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]).
• They found 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff.