On February 26, 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to melphalan flufenamide (Pepaxto®) in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38–directed monoclonal antibody.
The approval was based on the results from a multicenter, single-arm trial (HORIZON; NCT02963493). Eligible patients received melphalan flufenamide 40 mg via IV infusion on day 1 and dexamethasone 40 mg orally (20 mg for patients ≥ 75 years of age) on days 1, 8, 15, and 22 of each 28-day cycle until they experienced disease progression or unacceptable toxicity.
Efficacy was evaluated in a subpopulation of 97 patients who received four or more prior lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and a CD38-directed antibody. The main efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) assessed by investigators according to the international myeloma working group criteria. ORR was 23.7% (95% CI = 15.7, 33.4) and median DOR was 4.2 months (95% CI = 3.2, 7.6).
Safety was evaluated in 157 patients. The most common adverse reactions (> 20%) were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities (≥ 50%) were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin and increased creatinine.
The safety and efficacy have not been established for melphalan flufenamide’s use as a conditioning regimen in patients receiving transplantations. The United Surgical Partners International includes a limitations of use statement that melphalan flufenamide is not indicated and is not recommended for use as a conditioning regimen for transplantations outside of controlled clinical trials.
The recommended dose of melphalan flufenamide is 40 mg via IV over 30 minutes on day 1 of each 28-day treatment cycle, in combination with dexamethasone.
FDA approved the indication under accelerated approval based on ORR. Continued approval for the indication is contingent on verification and description of clinical benefit in confirmatory trials.
FDA granted the application priority review and orphan drug designations. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.