The US Food and Drug Administration (FDA) has issued a safety alert regarding an increased risk of death associated with Pepaxto (melphalan flufenamide) used in patients with multiple myeloma participating in the ongoing OCEAN clinical trial.
The drug was granted an accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adult patients with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.
As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.
Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.
The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone group, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.
Healthcare professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their healthcare professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”
The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
Accelerated Approval Data
Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial looking at adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody.
Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.
Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by the drug’s maker, Oncopeptides, received priority review and orphan drug status.
Confirmatory Trial Data
The confirmatory OCEAN trial is comparing melphalan flufenamide plus low-dose dexamethasone to pomalidomide with low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of prior therapy and in patients who were resistant to lenalidomide in the last line of therapy.
The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cut-off date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients in the melphalan flufenamide group (48%) had died, compared with 108 of 249 (43%) in the pomalidomide control group.
“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.
The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna on September 8-11, 2021.
Healthcare professionals and patients should report adverse events or quality problems experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.
Sharon Worcester is an award-winning medical journalist at MDedge News, part of the Medscape Professional Network.
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