FDA’s ODAC Gives Negative Opinion on Continued Melphalan Flufenamide Approval for Relapsed/Refractory Myeloma


The FDA’s Oncologic Drugs Advisory Committee voted against continued use of melphalan flufenamide for the treatment of relapsed/refractory multiple myeloma.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 14 to 2 against upholding an accelerated approval of melphalan flufenamide (Pepaxto) as a treatment for patients with relapsed/refractory multiple myeloma after the drug’s unfavorable risk/benefit profile was revealed.1

“After listening closely to both the sponsor and the FDA presentations, I concluded that [melphalan flufenamide] has demonstrated a lack of confirmed benefit, inferior overall survival [OS], and a potential for actual harm,” David Mitchell, a multiple myeloma patient, consumer representative for ODAC, and founder of Patients for Affordable Drugs, said during the meeting.

The agent had previously received accelerated approval for the aforementioned indication in patients who have been treated with a minimum of 4 prior lines of therapy and were refractory to at least 1 proteosome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.2 The application was supported by findings from the phase 2 HORIZON study (NCT02963493) in which patients with relapsed/refractory disease were treated with a 40-mg intravenous dose of melphalan flufenamide on day 1 and 40 mg of dexamethasone on day 1, 8, 15, and 22 of every 28-day cycle until disease progression or unacceptable toxicity.

The overall response rate by International Myeloma Working Group Criteria was 23.7% (95% CI, 15.7%-33.4%) with a median response duration of 4.2 months.

“A critical aspect of accelerated approval is that follow-up trials actually confirm the initial benefit that’s seen. Unfortunately, in this case, the follow-up trial flopped, and not only did it not show the magnitude of benefit that we saw initially, but it potentially showed an increased risk of death in patients with significant toxicity. For that reason, I voted ‘no’,” Mikkael Sekeres, MD, MS, chief of the division of hematology at Sylvester Comprehensive Cancer Center, University of Miami Health System, said during the ODAC meeting.

The FDA issued a warning about a possible increased risk of death following treatment with melphalan flufenamide in July 2021.3 This was observed in the phase 3 OCEAN trial (NCT03151811), assessing the agent vs standard-of-care pomalidomide (Pomylast) plus low-dose dexamethasone in both cohorts in a relapsed/refractory population. Continued approval for the agent hinged on findings from a confirmatory trial. Frequent adverse effects were laboratory abnormalities, including decrease leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, as well as increased creatinine.

Melphalan flufenamide was withdrawn from the United States market on October 2021 following discourse with the FDA.4 Data from the OCEAN trial indicated that the OS among patients who were treated with the melphalan flufenamide/dexamethasone combination was not improved vs the pomalidomide/dexamethasone group. The FDA determined that the findings did not warrant a confirmatory trial, leading developer Oncopeptides AB to scale down and refocus on the development of a proprietary peptide drug conjugate platform.


  1. Oncologic Drugs Advisory Committee (ODAC) Meeting, September 22-23, 2022 (Day 1). Streamed live September 22, 2022. Accessed September 26, 2022. https://bit.ly/3LNcW9a
  2. FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. News release. February 26, 2021. Accessed September 26, 2022. https://bit.ly/3SeTdl1
  3. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). FDA. July 28, 2021. Accessed September 26, 2022. https://bit.ly/3f4jgKb
  4. Oncopeptides withdraws Pepaxto® in US, scale down organization and focus on R&D. News release. Oncopeptides AB. October 22, 2021. Accessed September 26, 2022. https://bit.ly/3B5OCIC
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