FDA Grants Accelerate Approval to Melphalan flufenamide for Heavily Pretreated Myeloma

Based on phase 2 data, the FDA granted accelerated approval to melphalan flufenamide in combination with dexamethasone for the treatment of multiple myeloma following 4 or more prior lines of therapy.

Melphalan flufenamide (Pepaxto) in combination with dexamethasone has been granted accelerated approved by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma following 4 or more prior lines of therapy, according to the agent’s developer Oncopeptides AB.1

Patients may be treated with this therapy if their prior lines of treatment have included at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. Melphalan flufenamide represents the first anticancer peptide-drug conjugate to receive approval from the FDA.

The accelerated approval was based on results from the phase 2 HORIZON trial (NCT02963493), which evaluated intravenous melphalan flufenamide plus dexamethasone in patients with heavily pretreated disease. Results of the trial were reported in December 2020 in the Journal of Clinical Oncology.2 Of the 157 patients evaluated, 119 (76%) were considered to be triple-class refractory and had experience with 4 or more prior lines of therapy; 55 (35%) had extramedullary disease, a rare and aggressive manifestation of myeloma; and 92 (59%) were refractory to prior alkylator therapy.2

The overall response rate (ORR), which was the study’s primary end point, was 29% (95% CI, 18%-35%) with a median response duration 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).

In the triple-class refractory group, the ORR was 26% (95% CI, 18%-35%), with a median duration of response (DOR) of 4.4 months (95% CI, 3.4-7.6). Median PFS and OS were 3.9 months (95% CI, 3.0-4.6) and 11.2 months (95% CI, 7.7-13.2), respectively.

Grade 3 or grade adverse events happened in most patients (96%), with neutropenia (79%), thrombocytopenia (76%), and anemia (43%) occurring the most. Grade 3 or greater pneumonia was the most nonhematologic high-grade event, occurring in 10% of patients.

“The accelerated approval of Pepaxto 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, said in a press release. “Moving ahead, our focus is to further advance Pepaxto. We look forward to receiving top-line data from the phase 3 OCEAN study [NCT03151811] in relapsed/refractory multiple myeloma, in the second quarter. The comparative study with pomalidomide [Pomalyst], is designed to support a future supplementary New Drug Application to expand the label.”

The confirmatory OCEAN trial has a target enrollment of 495 patients who will be randomized to receive either dexamethasone plus either melphalan flufenamide or pomalidomide. The primary end point is PFS with secondary end points of ORR, DOR, OS, and safety. Patients who have received 2 to 4 prior lines of therapy and have an ECOG performance status of 2 or below are included in the trial population.

“Melphalan flufenamide is a novel and innovative therapeutic option which is active in patients with multiple myeloma who have a refractory disease, and the product has a manageable toxicity,” says Ola Landgren, MD, PhD, chief of the Myeloma Program and leader of the Experimental Therapeutics Program, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Health System in Miami, Florida, said in a press release. “Melphalan flufenamide will complement existing treatment regimens and contribute to address the growing unmet medical need among patients with relapsed or refractory multiple myeloma.”

First-in-class Melphalan flufenamide targets aminopeptidases and selectively releases alkylating agents into tumor cells. As a result, the agent is rapidly and passively taken up by cells by way of its high lipophilicity, which enables transporter-associated resistance evasion.


1. FDA approves Oncopeptides’ Pepaxto (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides AB. February 26, 2021. February 27, 2021. https://bit.ly/2ZUmvMn

2. Richardson PG, Oriol A, Larocca A, et al; HORIZON (OP-106) Investigators. 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