The Food and Drug Administration (FDA) is alerting health care professionals that the use of Pepaxto® (melphalan flufenamide) in combination with dexamethasone to treat patients with multiple myeloma may increase the risk of death following results from a confirmatory phase 3 trial.

Pepaxto is a peptide conjugated alkylating drug that is highly lipophilic, which allows it to be passively distributed into cells. In February 2021, the FDA granted accelerated approval to Pepaxto in combination with dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. 

The ongoing randomized, controlled, open-label phase 3 OCEAN trial ( Identifier: NCT03151811) is evaluating the efficacy and safety of Pepaxto with low-dose dexamethasone in 495 patients with relapsed or refractory multiple myeloma following 2-4 lines of prior therapy and who are refractory to lenalidomide in the last line of therapy.

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Patients were randomly assigned 1:1 to receive either Pepaxto 40mg intravenously on day 1 and dexamethasone 40mg orally on days 1, 8, 15, and 22 of each 28-day cycle or pomalidomide 4mg orally on days 1 to 21 and dexamethasone 40mg orally on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.

Findings from the study showed an increased risk of death in the Pepaxto treatment arm compared with the pomalidomide arm, 48% (n=117/246) vs 43% (n=108/249), respectively (hazard ratio [HR] 1.104; 95% CI, 0.846-1.441). Median overall survival was 19.7 months (95% CI, 15.1-25.6) for the Pepaxto arm and 25 months (95% CI, 18.1-31.9) for the pomalidomide arm; median follow-up for survival was 19.1 months.

For patients currently receiving Pepaxto, the FDA is recommending that health care professionals review their patients’ progress and discuss the risks of continued administration. The Agency is also requiring the manufacturer, Oncopeptides AB, suspend enrollment in the OCEAN trial, along with other ongoing Pepaxto clinical trials. Patients who are receiving clinical benefit from Pepaxto in the OCEAN trial may continue treatment; however, patients must be informed of the risks and sign a revised written informed consent.

In a safety communication, the FDA stated that they will continue to “evaluate the OCEAN trial results and may hold a future public meeting to discuss these safety findings and explore the continued marketing of Pepaxto.”

Adverse events or quality problems associated with Pepaxto should be reported to the FDA’s MedWatch Adverse Event Reporting program.

According to the Company, full data from the OCEAN study is expected to be submitted to the International Myeloma Workshop meeting in September.


FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). News release. US Food and Drug Administration. Accessed July 28, 2021.

This article originally appeared on MPR

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