Once-weekly carfilzomib (Kyprolis) therapy at a higher dose significantly improved progression-free survival (PFS) and reduced the risk of disease progression or death compared with twice-weekly carfilzomib in patients with relapsed or refractory multiple myeloma. The overall safety profile for both regimens in the randomized phase 3 ARROW clinical trial were similar, said co-lead investigator María-Victoria Mateos, MD, PhD, Director, Myeloma Unit, University Hospital Salamanca-IBSAL, Spain, at the 2018 European Hematology Association Congress.
As a single agent, carfilzomib, a selective proteasome inhibitor, is approved by the FDA for patients with relapsed or refractory multiple myeloma who have received ≥2 previous therapies. The approved dose is 27 mg/m2 administered intravenously on 2 consecutive days for 3 weeks followed by a 12-day rest in a 28-day cycle.
Compared with recent standard treatments, twice-weekly carfilzomib plus dexamethasone or with lenalidomide (Revlimid) and dexamethasone have demonstrated significant improvements in PFS and overall survival (OS), Dr Mateos said.
Promising results of the phase 1/2 CHAMPION-1 study, which was designed to test a more convenient regimen of carfilzomib, led investigators to explore once-weekly carfilzomib. In the CHAMPION-1 study, patients with relapsed or refractory multiple myeloma and 1 to 3 previous regimens who received once-weekly carfilzomib had a 77% overall response rate and a median PFS of 12.6 months. The maximum tolerated dose (MTD) was established at 70 mg/m2; 62% of patients receiving the MTD had grade ≥3 adverse events.
The ARROW Study
The ARROW study included 478 patients with relapsed or refractory disease (median age, 66 years) who were randomized in a 1:1 ratio to once-weekly or twice-weekly carfilzomib at 70 mg/m2 or at 27 mg/m2, respectively. All patients received dexamethasone 40 mg as well, and all had exposure to 2 to 3 previous lines of therapy. Nearly all (99%) patients had received bortezomib (Velcade), and 84% had received lenalidomide. Overall, 42% had disease refractory to bortezomib. The primary end point was PFS.
Patients in the once-weekly group received 20 mg/m2 for the first cycle of carfilzomib and 70 mg/m2 for the remaining cycles. Patients in the twice-weekly arm received 20 mg/m2 for the first cycle of carfilzomib and 27 mg/m2 for the remaining cycles.
The cumulative carfilzomib dose received in the once-weekly arm was 1799 mg/m2 and was 1148 mg/m2 in the twice-weekly arm. The median duration of treatment was 38.0 weeks in the once-weekly arm and 29.1 weeks in the twice-weekly arm.
After a median follow-up of 12.6 months in the once-weekly arm and 12.0 months in the twice-weekly arm, the median PFS was 11.2 months in the once-weekly arm and 7.6 months in the twice-weekly arm (hazard ratio [HR], 0.693; P = .0029). Subgroup analysis, Dr Mateos noted, showed consistent benefit with the once-weekly treatment across age, baseline Eastern Cooperative Oncology Group and ISS stage, and baseline creatinine clearance groups. The benefit was observed regardless of the number of previous lines of therapy, and disease refractory to bortezomib or lenalidomide.
The overall response rates were 62.9% and 40.8% for the once- and twice-weekly regimens (P <.0001) with 5% and 2% complete responses, respectively, and very good partial response rates were 34% in the once-weekly and 13% in the twice-weekly carfilzomib groups.
Stringent complete responses were observed only in the once-weekly arm.
Although the median OS was not reached in either group, the rate of death was 24.2% and 28.6% in the once- and twice-weekly carfilzomib groups, respectively (HR, 0.80; P = .214).
Serious adverse events were 43% and 41% in the once- and twice-weekly arms, respectively. Discontinuations attributed to treatment-related adverse events were at 13% and 12%, respectively. “Safety findings were consistent with the known safety profile of carfilzomib, and no new risks were identified,” Dr Mateos said.
“Thus, in comparison with twice-weekly carfilzomib at the 27 mg/m2 schedule, once-weekly carfilzomib at 70 mg/m2 showed a favorable benefit-risk profile for patients with relapsed or refractory multiple myeloma. It provides a more convenient schedule and can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” she concluded.