FDA Withdraws Melphalan Flufenamide Approval Status in Multiple Myeloma

The FDA has issued a final decision to withdraw approval status for melphalan flufenamide (Pepaxto) when administered in combination with dexamethasone for select patients with multiple myeloma, according to a press release from the FDA.¹

The final decision was issued by Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, and indicated that findings from a confirmatory study intended to convert accelerated approval status for melphalan flufenamide to full approval status did not validate the clinical benefit of the agent. Additionally, the decision to withdraw the agent was based on available data demonstrating that melphalan flufenamide was not effective or safe as part of its current indication.

The regulatory agency will publish a Federal Register notice confirming its decision and retract melphalan flufenamide from the Orange Book. Developers will not have the right to market melphalan flufenamide in the United States.

The FDA originally granted accelerated approval to melphalan flufenamide for patients with relapsed/refractory multiple myeloma following at least 4 prior lines of therapy in February 2021.² Supporting data for the accelerated approval came from the phase 2 HORIZON trial (NCT02963493), in which patients received melphalan flufenamide at 40 mg intravenously and dexamethasone at 40 mg orally. Regarding the trial’s primary end points, the combination produced an overall response rate (ORR) of 23.7% (95% CI, 15.7%-33.4%) and a median duration of response (DOR) of 4.2 months (95% CI, 3.2-7.6) among a subgroup of 97 evaluable patients.

The regulatory agency required developers to assess melphalan flufenamide as part of the confirmatory phase 3 OCEAN trial (NCT03151811) to fulfill post-approval requirements based on the agent’s accelerated approval status.¹ In July 2021, the agency announced an update to patients and healthcare providers that treatment with melphalan flufenamide correlated with an increased risk of death in the OCEAN trial.

Developers decided to withdraw melphalan flufenamide from the market in October 2021.³ Withdrawal of the agent was based on findings from the OCEAN trial, which highlighted a hazard ratio of 1.104 with melphalan flufenamide plus dexamethasone vs control treatment with pomalidomide (Pomalyst) plus dexamethasone for overall survival (OS) in the intent-to-treat (ITT) population.

The FDA’s Oncologic Drugs Advisory Committee voted against melphalan flufenamide in September 2022.⁴ In a 14-to-2 vote, the ODAC decided that the benefit/risk profile of the agent in patients with multiple myeloma was not favorable based on findings from the OCEAN trial.

The FDA requested withdrawal of marketing authorization for melphalan flufenamide in December 2022.⁵

“We respect the FDA’s accelerated approval regulations,” Jakob Lindberg, chief scientific officer at Oncopeptides, developers of melphalan flufenamide, said in a press release at the time the FDA requested withdrawal of marketing authorization.⁵ “Multiple myeloma remains an incurable disease, and the treatment options for patients with triple class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for [patients with] multiple myeloma, in particular for non-transplanted elderly patients where the unmet medical need remains very high.”

Investigators of the open-label OCEAN trial compared melphalan flufenamide plus dexamethasone with pomalidomide plus dexamethasone for those with relapsed/refractory multiple myeloma. The primary end point of the trial was progression-free survival. Secondary end points included ORR, DOR, OS, and safety and tolerability.

Patients 18 years and older with a prior diagnosis of multiple myeloma and documented disease progression, a life expectancy of at least 6 months, and an ECOG performance status of 0 to 2 were eligible for enrollment on the OCEAN trial.

References

1. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). News release. FDA. February 23, 2024. Accessed February 28, 2024. http://tinyurl.com/588y2kdt
2. WITHDRAWN: FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. News release. February 23, 2024. Accessed February 28, 2024. http://tinyurl.com/5n6fjrxh
3. Oncopeptides withdraws Pepaxto® in US, scale down organization and focus on R&D. News release. Oncopeptides AB. October 22, 2021. Accessed February 28, 2024. https://bit.ly/3B5OCIC
4. Oncologic Drugs Advisory Committee (ODAC) Meeting, September 22-23, 2022 (Day 1). Streamed live September 22, 2022. Accessed February 28, 2024. https://bit.ly/3LNcW9a
5. Oncopeptides provides update on Pepaxto US marketing authorization. News release. Oncopeptides AB. December 7, 2022. Accessed February 28, 2024. https://bit.ly/3YcSMuG