FDA Withdraws Approval of Melphalan Flufenamide for the Treatment of Multiple Myeloma


The withdrawal comes after clinical trial results failed to demonstrate the safety and efficacy of melphalan flufenamide when combined with dexamethasone.

The FDA announced a final decision to withdraw the approval of melphalan flufenamide (Pepaxto; Oncopeptides AB) combined with dexamethasone for the treatment of certain patients with multiple myeloma. According to the FDA, the decision was made because the confirmatory study that was conducted after melphalan flufenamide received an accelerated approval did not actually confirm the clinical benefits of the drug, and the evidence that is available does not confirm whether melphalan flufenamide is safe or effective under its conditions of use.

According to the FDA, Oncopeptides was provided with a notice of the proposed approval withdrawal, an explanation for the proposed withdrawal, and an opportunity to meet with as well as submit a written appeal to the Commissioner. Despite a submitted appeal and meeting with the Commissioner, the FDA continued to withdraw the approval.

In February 2021, melphalan flufenamide was approved under an accelerated approval in combination with dexamethasone to treat adult patients with relapsed or refractory multiple myeloma who had received at least 4 prior lines of therapy. These patients’ disease was refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. The OCEAN clinical trial was conducted as a requirement of the accelerated approval program.

A few months later, the FDA alerted both patients and health care professionals of a clinical trial in which melphalan flufenamide in combination with dexamethasone to treat patients with multiple myeloma resulted in an increased risk of death. The trial had compared melphalan flufenamide with low-dose dexamethasone with pomalidomide in combination with low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2 to 4 prior lines of therapy who were resistant to lenalidomide.1

About the Trial

Trial Name: A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide (OCEAN)

ClinicalTrials.gov ID: NCT03151811

Sponsor: Oncopeptides AB

Completion Date: February 3, 2023

In this trial, a total of 495 patients were randomly assigned to receive either melphalan flufenamide with dexamethasone (Arm A, n = 246) or pomalidomide with dexamethasone (Arm B, n = 249). Patients in Arm A intravenously received 40-mg infusions of melphalan flufenamide on day 1 and 40 mg of dexamethasone on days 1, 8, 15, and 22 during the 28-day cycle, whereas patients in Arm B orally received 4-mg capsules of pomalidomide daily from days 1 to 21 and 40 mg of dexamethasone on days 1, 8, 15, and 22. Regardless of the group, patients aged 75 years and older only received 20 mg of dexamethasone. For both groups, patients were treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided to discontinue treatment if not in the patient’s best interest.

According to the study results, approximately 73.17% of patients (n = 180) in Arm A were at an increased risk of death. Those in Arm B had slightly better outcomes, with approximately 67.87% of patients (n = 169) having an increased risk of death. In addition, 43.42% of patients (n = 99) in Arm A and 50.41% of patients (n = 124) in Arm B experienced serious adverse events, including, blood and lymphatic system disorders, cardiac disorders, infections, and nervous system disorders.

The final decision to withdraw approval was made by Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. According to the FDA, the decision is effective immediately and the agency plans to publish an official notice to detail the decision and remove melphalan flufenamide from the Orange Book. The FDA notes that this is the first time amended procedures for a withdrawal of an accelerated approval were used as part of the Food and Drug Omnibus Report Act of 2022.1


  1. Food & Drug Administration. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). News release. February 23, 2024. Accessed February 26, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide
  2. A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide (OCEAN).ClinicalTrials.gov identifier: NCT03151811. Last Updated: January 30, 2024. Accessed February 26. 2024. https://clinicaltrials.gov/study/NCT03151811
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