Carfilzomib Possible Bortezomib Substitute in Multiple Myeloma

Chemical structure of carfilzomib

Results from a phase I/II trial indicate that the proteasome inhibitor carfilzomib may be a safe and effective substitute for bortezomib in patients with multiple myeloma whose disease progressed during or within 12 weeks of treatment with a bortezomib-containing regimen.

“Carfilzomib treatment for patients that failed bortezomib therapy in an otherwise novel treatment combination has shown clinical activity, yet the concept of substituting a proteasome inhibitor with another into an otherwise unchanged combination treatment in an attempt to overcome proteasome inhibitor resistance has not been investigated in the clinic,” wrote researchers led by James R. Berenson, MD, of the Institute of Myeloma and Bone Cancer Research, West Hollywood, Calif.

“Given that single-agent carfilzomib can produce responses in some bortezomib-refractory patients and shows high response rates when combined with other agents, we hypothesized that carfilzomib would be an effective and well-tolerated replacement for bortezomib among multiple myeloma patients who had failed bortezomib-containing combination regimens.”

To test this theory, Berenson and colleagues conducted an open-label, trial where bortezomib was replaced with carfilzomib in 37 patients who experienced disease progression. Otherwise, the regimen, dose and schedule remained the same. The results of the study were published in Leukemia.

Carfilzomib was given at a dose escalated from 20 mg/m² to 45 mg/m² on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All bortezomib-containing regimens were required to also have an alkylating agent, anthracycline, IMiD, and/or a glucocorticosteroid.

Overall, the researchers tested 14 different drug combinations. Only one regimen, which combined carfilzomib, ascorbic acid, and cyclophosphamide, reached a maximum tolerated dose.

The overall response rate was 43.2% and the clinical benefit rate was 62.2%. According to the researchers, similar clinical benefit rates were found among the four therapeutic classes combined with carfilzomib. Median progression-free survival was 8.3 months and overall survival was 15.8 months. The median time to progression was 9.9 months.

“The mechanisms by which carfilzomib produces responses for patients who have failed bortezomib-based combinations treatments is unclear, but it may partially depend on differences in the chemical properties and mode of action of these two proteasome inhibitors,” the researchers wrote. “For example, bortezomib is a reversible proteasome inhibitor, whereas carfilzomib binds selectively and irreversibly to the proteasome.”

The most commonly occurring grade 3 or higher adverse event was lymphopenia (35.1%). Other common events were thrombocytopenia (24.3%), anemia (10.8%), and neutropenia (10.8%).

Further phase I and phase II trials are needed to identify which specific carfilzomib-containing treatment regimens have the best safety and efficacy profiles.

Single-agent carfilzomib is currently FDA-approved for the treatment of relapsed and refractory multiple myeloma.