FDA Approves Once-Weekly Kyprolis Regimen for Myeloma

The Food and Drug Admnistration (FDA) has approved a once-weekly dosing option of Kyprolis (carfilzomib) to use in combination with dexamethasone for patients with relapsed/refractory multiple myeloma, according to Amgen, the manufacturer of the proteasome inhibitor.

The approval is based on results from the phase 3 ARROW study, in which Kyprolis administered once weekly at 70 mg/m2 with dexamethasone resulted in a prolonged progression-free survival (PFS) compared with the standard twice-weekly schedule in patients with relapsed/refractory multiple myeloma.

The findings showed a median PFS of 11.2 months with once weekly Kyprolis and dexamethasone compared with 7.6 months for the standard twice-weekly schedule of Kyprolis at 27 mg/m2 with dexamethasone. These data met the primary endpoint of PFS.

Overall response rate (ORR) in patients in the once-weekly arm was 62.9 percent versus 40.8 percent in the twice-weekly arm. Additionally, 7 percent of patients in the once-weekly arm achieved a complete response (CR) or better. This is compared with 2 percent of patients who achieved a CR in the twice-weekly arm. ORR was a secondary endpoint, in addition to overall survival, and safety and tolerability.

"While great progress has been made in the last decade, multiple myeloma remains an incurable disease characterized by a recurring pattern of remission and relapse, and it is important that patients have treatment options that meet their individual needs," David S. Siegel, M.D., Ph.D., chief of the Division of Multiple Myeloma at John Theurer Cancer Center at Hackensack University Medical Center, said in a press release.

"The availability of a more convenient once-weekly dosing regimen, with superior efficacy, comparable safety, and longer duration of therapy versus the twice-weekly regimen studied in the trial could allow patients to spend more time outside of the infusion center," added Siegel.

Relapsed/refractory myeloma is a difficult-to-treat population, as progression often occurs. With ARROW, investigators aimed to prove PFS would not be compromised with an altered dosing schedule.

The phase 3 study enrolled 478 patients who had received two or three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. Patients were randomized to either the once-weekly (238 patients) or twice-weekly schedule (235 patients), and were stratified by the International Stage System.

The maximum tolerated dose of Kyprolis at 70 mg/m2 when given in combination with dexamethasone was established in the phase 1/2 CHAMPION-1 study, which was the first study to explore the once-weekly schedule.

Investigators reported that the once-weekly regimen, in addition to having a superior PFS, was more convenient for patients. Patients in the once-weekly group received Kyprolis intravenously for 30 minutes (20 mg/m2 on day 1 of cycle 1; 70 mg/m2 on days 8 and 15 of cycle 1; and 70 mg/m2 on days 1, 8, and 15 of subsequent cycles), while patients in the twice-weekly group received it intravenously for 10 minutes (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15, and 16 of cycle 1; and 27 mg/m2 on days 1, 2, 8, 9, 15, and 16 of subsequent cycles). Patients received 40 mg of dexamethasone on days 1, 8, and 15 of all days and also on day 22 during cycles 1-9 in both arms.

Safety was comparable in each arm, and there were no new standard safety risks in the once-weekly arm, noted investigators. Common side effects were anemia, pneumonia, diarrhea, and thrombocytopenia. Even though patients in the once-weekly group experienced a higher rate of grade 3 or higher side effetcs (68 percent) than the twice-weekly group (62 percent), they had less grade 3 or higher cardiac side effects (3 percent vs 4 percent, respectively).

There were five treatment-related deaths in the once-weekly group, and two in the twice-weekly group. Deaths in the once-weekly group were attributed to sepsis, acute lung injury, acute respiratory distress syndrome, and tumor lysis syndrome. In the twice-weekly group, deaths were attributed to plasma cell myeloma and congestive heart failure.

Kyprolis is approved for use in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. The proteasome inhibitor is also approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma who have received one or more lines of therapy.