FDA Warns of Increased Death Risk With Melphalan Flufenamide in R/R Myeloma

Based on detrimental effects on overall survival, the FDA has issued a safety warning for melphalan flufenamide in relapsed multiple myeloma.

The FDA has issued a safety warning regarding melphalan flufenamide (melflufen; Pepaxto) that was recently approved to treat multiple myeloma based on evidence that the agent is associated with an increased risk of death in a confirmatory clinical trial, according to the agency.1

The trial in question, the phase 3 OCEAN study (NCT03151811), compared melflufen to standard-of-care pomalidomide (Pomylast), both in combination with low-dose dexamethasone, as systemic therapy for patients with relapsed or refractory disease after 2 to 4 prior lines of treatment and in those who were resistant to lenalidomide (Revlimid) in their last line of therapy.

The agent was granted accelerated approval in February 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma following 4 or more prior lines of therapy based on results of the phase 2 HORIZON trial (NCT02963493), which evaluated intravenous melflufen plus dexamethasone in patients with heavily pretreated disease.

Results of the HORIZON study were reported in December 2020 in the Journal of Clinical Oncology,2 and showed an overall response rate (ORR) of 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). Of the 157 patients evaluated, 119 (76%) were considered to have triple-class refractory disease 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.

Continued approval is contingent upon results of a confirmatory trial, for which OCEAN was ongoing. The primary end point is PFS as assessed by independent review committee with secondary end points of ORR, duration of response, OS, and safety.

However, a detrimental effect of melflufen on OS has been documented and the FDA has required the manufacturer to suspend all enrollment to OCEAN and other ongoing studies examining the agent. Patients who are already enrolled to trials of melflufen may continue to receive therapy if they are experiencing benefit and are informed of the risks of treatment. Continued evaluation of OCEAN is ongoing and future public meetings may be held to discuss how these results impact the use of melflufen in practice.

Previous reports from OCEAN indicate that melflufen was noninferior to pomalidomide when treating patients with relapsed or refractory multiple myeloma. Pomalidomide is currently the most common medicine used to treat patients with relapsed or refractory multiple myeloma, with results suggesting that melfufen may be a significant therapeutic option for patients who may need alternative treatment options moving forward.

The study enrolled 495 patients from over 100 hospitals across 21 countries to evaluate the safety and efficacy of melfufen versus pomalidomide. The PFS assessed by independent review committee showed noninferiority of melflufen compared with pomalidomide (HR, 0.817, 95% CI, 0.659-1.012; P = .064). For investigator assessed PFS, the hazard ratio in favor of melflufen was 0.790 (95% CI, 0.639-0.976).

The median PFS when assessed by both independent review committee and investigators was 42% higher in the melflufen arm compared with the pomalidomide arm. The ORRs observed were 32.1% and 26.5% for the melflufen and pomalidomide arms, respectively.

At the time of reporting, the OCEAN investigators reported that the safety profile for melflufen was consistent with previously reported safety data across age subgroups. For both the melflufen and pomalidomide arms, discontinuation rates due to adverse effects were similar.


1. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). FDA. July 28, 2021. Accessed July 29, 2021. https://bit.ly/3f4jgKb

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

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