FDA Approves Melphalan Flufenamide for Relapsed/Refractory Multiple Myeloma


The FDA has approved melphalan flufenamide for use in combination with dexamethasone in the treatment of select adult patients with relapsed/refractory multiple myeloma.

The FDA has approved melphalan flufenamide (Pepaxto; melflufen) for use in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma, who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.1

The regulatory decision was based on data from the phase 2 HORIZON study (NCT02963493), where the doublet was found to elicit an overall response rate (ORR) of 23.7% in heavily pretreated patients with relapsed/refractory multiple myeloma; the median duration of response (DOR) in these patients was 4.2 months. Notably, the combination also showed activity in a subset of patients who had extramedullary disease (EMD; 41%).

“The accelerated approval of [melphalan flufenamide] in the United States is an important milestone for Oncopeptides, and a major step ahead in fulfilling our mission, to bring hope to patients with difficult-to-treat hematological diseases, through innovative science," Marty J. Duvall, chief executive officer at Oncopeptides AB, stated in a press release.

The phase 2 trial, investigators enrolled a total of 157 patients with relapsed/refractory multiple myeloma who had received 2 or more prior lines of therapy, were exposed to an immunomodulatory drug and a proteasome inhibitor, and were refractory to pomalidomide (Pomalyst) and/or daratumumab (Darzalex). Participants had triple-class refractory disease and/or EMD and/or high-risk cytogenetic features. To be eligible for enrollment, patients had to have had an ECOG performance status of 0 to 2. Notably, Ninety-seven of the patients enrolled had triple-class refractory disease and had received at least 4 previous lines of treatment.

Study participants were given 40 mg of melphalan flufenamide on day 1 plus 40 mg of dexamethasone on days 1, 8, and 15. However, patients who were 75 years of age or older were given 20 mg of dexamethasone instead. Treatment was administered in 28-day cycles until either progressive disease or unacceptable toxicity.

The primary end point of the trial was ORR, while secondary end points included clinical benefit rate, progression-free survival (PFS), overall survival (OS), DOR, time to response, time to progression, time to next treatment, safety, and health-related quality of life.

Data from the trial presented during the 2020 European Hematology Association Annual Meeting showed that among participants who experienced responses with the combination, the median PFS was 8.5 months (95% CI, 5.4-13.4) in the intent-to-treat population, whereas it was 8.5 months (95% CI, 5.3-13.4) and 17.3 months (95% CI, 5.3–not evaluable) in those with triple-class refractory disease and those with EMD, respectively.2

Additionally, the median OS in the ITT population was 11.6 months (95% CI, 9.3-15.4) vs 11.2 months (95% CI, 7.7-13.2) and 6.5 months (95% CI, 5.1-9.7) in the triple-class refractory and EMD subgroups, respectively.

The most frequently reported grade 3 or 4 toxicities with the doublet included neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most commonly experienced non-hematologic toxicity that was grade 3 or 4 in severity was pneumonia (10%).

“Moving ahead, our focus is to further advance [melphalan flufenamide]. We look forward to receiving top-line data from the phase 3 OCEAN study in relapsed/refractory multiple myeloma, in the second quarter," added Duvall. "The comparative study with pomalidomide, is designed to support a future supplementary new drug application to expand the label”.


  1. FDA approves Oncopeptides' PEPAXTO (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides AB (publ). February 26, 2021. Accessed February 26, 2021. http://cisn.co/3q2bZgq
  2. Richardson PG, Oriol A, Larocca A, et al. HORIZON (OP-106): Melflufen plus dexamethasone in relapsed/refractory multiple myeloma refractory to pomalidomide and/or an anti-CD39 monoclonal antibody – primary and subgroup analysis. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. https://bit.ly/3dTqayA.
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