Melphalan Flufenamide Approved for Triple-Class Refractory Multiple Myeloma

Multiple myeloma model.

The FDA has approved melphalan flufenamide (Pepaxto®, Oncopeptides AB) in combination with dexamethasone for the treatment of patients with relapsed and refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy and whose disease is refractory to at least one CD38–directed monoclonal antibody, one proteasome inhibitor, and one immunomodulatory agent.

“Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells,” report Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research at Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, and colleagues in their recent publication of results of the HORIZON trial (NCT02963493), on which the approval was based, in the Journal of Clinical Oncology. “The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in RRMM, a population with an important unmet medical need.”

HORIZON enrolled 157 patients with RRMM who had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and who were refractory to pomalidomide and/or an anti–CD38 monoclonal antibody. Of these, 119 patients had triple-class refractory MM, 92 patients were refractory to previous alkylator therapy, and 55 had extramedullary disease. Patients received melflufen 40 mg once monthly on Day 1 of each 28-day cycle in combination with dexamethasone 40 mg (or 20 mg for patients 75 or older) once weekly on Days 1, 8, 15, and 22 of each 28-day cycle. The study’s primary end point was overall response rate, with secondary end points including progression-free survival, overall survival, and safety.

The overall response rate was 30% in the all-treated population and 26% in the triple-class refractory population as assessed by an independent review committee and 29% in the all-treated population and 26% in the triple-class refractory population as assessed by the investigators. At a median follow-up of 14 months, the median progression-free survival was 4.2 months in the all-treated population and 3.9 months in the triple-class refractory populations. The median overall survival was 11.6 months in the all-treated and 11.2 months in the triple-class refractory populations.

Grade ≥3 treatment-emergent adverse events occurred in 96% of patients, with the most common grade 3/4 events including neutropenia (79%), thrombocytopenia (76%), anemia (43%), pneumonia (10%), and hypophosphatemia (5%).

“The results from HORIZON suggest that melflufen has the potential to be an important therapeutic option in RRMM by providing a novel mechanism of action, clinically meaningful efficacy, and manageable safety when combined with dexamethasone in heavily pretreated patients,” conclude Dr. Richardson and colleagues.

The recommended dose of melflufen for patients with RRMM is 40 mg once monthly on Day 1 of each 28-day cycle, administered intravenously over 30 minutes, in combination with dexamethasone.

For More Information

Richardson PG, Oriol A, Larocca A, et al (2021). Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol, 39(7):757-767. DOI:10.1200/JCO.20.02259 (2021). A study of melphalan flufenamide (melflufen) in combination with dexamethasone in relapsed refractory multiple myeloma patients (HORIZON). NLM identifier: NCT02963493.

Oncopeptides AB (2021). FDA approves Oncopeptides’ PEPAXTO® (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma [news release]. Available at:

Pepaxto® (melphalan flufenamide) prescribing information (2021). Oncopeptides AB. Available at:

US Food & Drug Administration (2021). FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. Available at:

Image credit: Michaela Reagan. Courtesy of the National Cancer Institute  

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