Once-Weekly Bests Twice-Weekly Carfilzomib in R/R Multiple Myeloma

A once-weekly regimen of carfilzomib plus dexamethasone significantly improved response and delayed progression compared with a twice-weekly regimen in patients with relapsed or refractory multiple myeloma, according to results of a pre-planned interim analysis of the ARROW study (abstract 8000) presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.

“Once-weekly carfilzomib/dexamethasone at 70 mg/m² showed a favorable benefit-risk profile for patients with relapsed/refractory multiple myeloma, and, most importantly, provides a more convenient schedule and can improve access to a more efficacious therapy for patients unable to make a twice-weekly visit to the clinic,” said Victoria Mateos, PhD, Hospital Clinico Universitario de Salamanca-IBSAL, Salamanca, Spain.

Carfilzomib is currently approved as a single agent given as a twice-weekly regimen in patients with relapsed or refractory multiple myeloma.

The phase I/II CHAMPION-1 study was conducted in patients with relapsed or refractory myeloma who had already received one to three prior lines of treatment, with the goal of developing a more convenient regimen of carfilzomib. Investigators evaluated a once-weekly carfilzomib regimen, and the maximum tolerated dose was established at 70 mg/m². The overall response rate was 77%, with a median progression-free survival (PFS) of 12.6 months.

Based on these results, the phase III ARROW study was designed to compare two schedules of carfilzomib plus dexamethasone. Included were 478 patients who had received two to three prior therapies and had prior exposure to a proteasome inhibitor and immunomodulatory agent. Patients were randomly assigned to one of two arms:

• Once-weekly carfilzomib as a 30-min IV infusion on days 1, 8, and 15 of all cycles (20 mg/m² on day 1, cycle 1; 70 mg/m² thereafter).
• Twice-weekly carfilzomib as a 10-minute infusion on days 1, 2, 8, 9, 15, and 16 (20 mg/m² on day 1, cycle 1, and 27 mg/m² thereafter).

In addition, all patients were treated with 40-mg dexamethasone on days 1, 8, 15, and 22.

The median duration of treatment was higher for patients assigned to the once-weekly vs twice-weekly arm (38.0 weeks vs 29.1 weeks). The average dose per administration was 66.4 mg/m² for the once-weekly arm vs 26.3 mg/m² for the twice-weekly arm. The median cumulative dose was higher in the once-weekly arm compared with the twice-weekly arm (1,799 mg/m² vs 1,148 mg/m²).

After a median follow-up of 12 months, once-weekly carfilzomib plus dexamethasone resulted in a significantly longer PFS compared with the twice-weekly regimen. Median PFS was 11.2 months with the once-weekly regimen and 7.6 months with the twice-weekly regimen (hazard ratio [HR], 0.693; P = .0029).

According to Mateos, superiority of once-weekly over twice-weekly carfilzomib was observed across different subgroups, including patients both younger and older 65 years of age, across ECOG (Eastern Cooperative Oncology Group) status, and regardless of baseline creatinine clearance.

The overall response rate (ORR) was 62.9% in the once-weekly arm, with 5% of patients achieving a complete response (CR). In the twice-weekly arm, the ORR was 40.8%, with 2% of patients achieving a CR.

The median duration of treatment was longer for patients assigned to once-weekly carfilzomib, but despite that the incidence of any-grade adverse events, grade 3 or worse events, or serious adverse events was only a slightly higher frequency compared with the twice-weekly arm.