The FDA has issued an alert that melphalan flufenamide (Pepaxto®, Oncopeptides AB) in combination with dexamethasone has demonstrated an increased risk of death in the OCEAN trial (NCT03151811) of patients with multiple myeloma. Melphalan flufenamide plus dexamethasone was granted accelerated approval in February 2021 for patients with relapsed/refractory multiple myeloma who have been treated with at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.
"Despite considerable improvements in the clinical outcomes for patients with multiple myeloma in recent decades, multiple myeloma remains incurable with a high burden of disease," wrote Fredrik Schjesvold, MD, PhD, Head of the Oslo Myeloma Center in Norway, and colleagues, in the study protocol of OCEAN, the phase 3 confirmatory trial for the accelerated approval. "As the disease progresses, patients experience a repeating pattern of remission and relapse as they cycle through therapeutic options. Each period of remission is usually shorter than the last as the tumor becomes more aggressive."
The trial enrolled 495 patients with relapsed/refractory multiple myeloma following two to four lines of prior therapy and who were refractory to lenalidomide and their last line of therapy. Patients were randomized to receive 40 mg melphalan flufenamide on Day 1 or to receive 4 mg pomalidomide on Days 1 through 21, both in combination with 40 mg dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle. Patients who were 75 years or older received reduced doses of 20 mg dexamethasone. The study's primary end point was progression-free survival, with secondary end points of overall response rate, duration of response, overall survival, safety, and tolerability.
At a median follow-up of 19.1 months, median overall survival was 19.7 months for patients receiving melphalan flufenamide compared with 25.0 months for those receiving pomalidomide, with a hazard ratio of 1.104 in favor of pomalidomide. There were 117 deaths (48%) in the melphalan flufenamide arm and 108 deaths (43%) in the pomalidomide arm.
Due to this detrimental effect on overall survival, the FDA has suspended enrollment in OCEAN and other clinical trials evaluating melphalan flufenamide. Patients who are currently receiving clinical benefit in the OCEAN trial may continue treatment upon being informed of the risks and then signing a revised written consent. The FDA is continuing to assess the trial results and explore the future marketing of melphalan flufenamide.
For More Information
Schjesvold F, Robak P, Pour L, et al (2020). OCEAN: a randomized phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma. Future Oncol, 16(11):631-641. DOI:10.2217/fon-2020-0024
Pepaxto® (melflufen flufenamide) prescribing information (2021). Oncopeptides AB. Available at: https://pepaxto.com/docs/pepaxto_pi.pdf
US Food & Drug Administration (2021). FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melflufen flufenamide). Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-patients-and-health-care-professionals-about-clinical-trial-results-showing-increased
Image credit: KGH. Licensed under CC BY-SA 3.0