FDA Seeks to Withdraw Melphalan Flufenamide for Relapsed/Refractory Multiple Myeloma

Oncopeptides AB announced December 7, 2022, that the FDA has asked the company to withdraw melphalan flufenamide from the US market.

Oncopeptides AB announced December 7, 2022, that the FDA has asked the company to withdraw melphalan flufenamide (Pepaxto) from the US market. The company stopped marketing the peptide-drug conjugate in the United States as of October 22, 2021.1

“We respect FDA´s accelerated approval regulations,” Jakob Lindberg, chief executive officer of Oncopeptides, said in a news release. “Multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study [NCT03151811] demonstrated clinical benefit for multiple myeloma patients, in particular for non-transplanted elderly patients where the unmet medical need remains very high.”

The agency granted an accelerated approval to the targeted agent combination with dexamethasone for adults with relapsed/refractory multiple myeloma following at least 4 lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody in February 2021.

The approval was based in findings from the phase 2 HORIZON trial (NCT02963493) evaluating the melphalan flufenamide/dexamethasone combination in 157 patients. The overall response rate (ORR) was 29% (95% CI, 22%-37%) with a median response duration of response of 5.5 months (95% CI, 3.9-7.6). The median progression-free survival (PFS) was 4.2 months (95% CI, 3.4-4.9) and the median overall survival (OS) was 11.6 months (95% CI, 9.3-15.4).2

However, shortly after granting the accelerated approval, the FDA placed a partial clinical hold on all trials of melphalan flufenamide/dexamethasone. The partial clinical hold halted accrual of patients into any study using the agent and the FDA issued a warning about a death risk associated with the OCEAN study shortly thereafter.

On September 22, 2022, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted against final approval after reviewing data from the confirmatory phase 3 OCEAN trial comparing melphalan flufenamide/dexamethasone vs pomalidomide (Pomalyst)/dexamethasone.3 ODAC concluded that the results from OCEAN failed to verify clinical benefit for the exploratory combination.

OCEAN met its primary end point for PFS improvement (HR, 0.79; 95% CI, 0.64-0.98; P = .032). However, investigators observed weaker OS results in the relapsed or refractory myeloma subgroups (HR, 1.10; 95% CI, 0.85-1.44; P =.47).4

“The important point about the OCEAN trial is that it was a positive trial overall, for its primary end point of PFS and it attained statistical significance,” said ODAC member Paul Richardson, MD, said in an interview following the hearing. He is clinical program leader of the Jerome Lipper Multiple Myeloma Center, director of Clinical Research, at the Jerome Lipper Multiple Myeloma Center, and institute physician at Dana-Farber Cancer Center, as well as the RJ Corman Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

“The problem was survival,” he added. “When you see the hazard ratio 1.104, once it tips across that boundary, the FDA by law [has] to say, wait a second.”

The drug, also known as melflufen, remains available in Europe. Oncopeptides has not said whether it plans to seek FDA approval again.


  1. Oncopeptides provides update on Pepaxto US marketing authorization. News release. Oncopeptides AB. December 7, 2022. Accessed December 7, 2022. https://cisn.co/3iywZgL
  2. Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2021;39(7):757-767. doi:10.1200/JCO.20.02259
  3. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed December 7, 2022. https://www.youtube.com/watch?v=SON2biqVX_8.
  4. Schjesvold FH, Dimopoulos MA, Delimpasi S, et al. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol. 2022;9(2):e98-e110. doi:10.1016/S2352-3026(21)00381-1
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