European Commission Approves Melphalan Flufenamide for Relapsed/Refractory Multiple Myeloma

The European Commission (EU) has approved melphalan flufenamide (melflufen; Pepaxti) for use in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 3 prior therapies, whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory drug (IMiD), and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy. For patients with prior autologous stem cell transplantation (ASCT), the time to progression should be at least 3 years from transplantation.¹

The marketing authorization, which is valid in all EU member states, as well as in the European Economic Area countries Iceland, Lichtenstein, and Norway, is based on data from the phase 2 HORIZON study (NCT02963493) and the confirmatory phase 3 OCEAN study (NCT03151811).

“The approval of [melphalan flufenamide] in Europe is foundational for Oncopeptides, and brings excellent news for patients and shareholders,” Jakob Lindberg, chief executive officer of Oncopeptides AB, stated in a press release. “Despite the introduction of novel therapies, patients with triple-class refractory disease have a high unmet medical need, since their treatment options ultimately become exhausted.”

The company is planning on submitting a type II variation in the fourth quarter of 2022 to allow access to earlier lines of treatment for patients with relapsed/refractory multiple myeloma.

In February 2021, the FDA approved melphalan flufenamide for use in combination with dexamethasone in adult patients with relapsed/refractory multiple myeloma, who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 PI, 1 IMiD, and 1 CD38-directed monoclonal antibody.²

The multi-center, single-arm phase 2 HORIZON study evaluated melphalan flufenamide in combination with dexamethasone in 157 patients with relapsed/refractory multiple myeloma who had previously received 2 or more lines of therapy, were exposed to an IMiD and a PI, and were refractory to pomalidomide and/or daratumumab (Darzalex). Notably, 97 patients were triple-class refractory and had received at least 4 prior lines of treatment.

Patients received melphalan flufenamide at a dose of 40 mg on day 1 plus dexamethasone at a dose of 40 mg on days 1, 8, and 15. Patients aged 75 years or older received dexamethasone at a reduced dose of 20 mg. Treatment was given in 28-day cycles until patients experienced disease progression or intolerable toxicity.

The primary end point of the trial was overall response rate (ORR), and secondary end points comprised clinical benefit rate, progression-free survival (PFS), overall survival, duration of response (DOR), time to response (TTR), time to next treatment, safety, and health-related quality of life.

The efficacy results for triple-class refractory patients who had received at least 3 prior lines of therapies and who had no ASCT or progressed more than 36 months after ASCT (n = 52) demonstrated an investigator-assessed ORR of 28.8% (95% CI, 17.1%-43.1%).

The DOR was 7.6 months (95% CI, 3.0-12.3), and the TTR was 2.3 months (range, 1.0-10.5).

Regarding safety, the most common grade 3 or 4 toxicities with the combination included neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most common grade 3 or 4 non-hematologic toxicity was pneumonia (10%).³

In the multicenter, open-label phase 3 OCEAN trial, investigators evaluated melphalan flufenamide plus dexamethasone vs pomalidomide (Pomalyst) plus dexamethasone in patients with relapsed/refractory multiple myeloma who had received 2 to 4 prior lines of therapy and were resistant to lenalidomide (Revlimid) in the last line of therapy.⁴

The results showed that melphalan flufenamide met the primary end point of superior PFS assessed by independent review committee compared with pomalidomide (HR, 0.792; 95% CI, 0.640-0.979; P = .0311).⁵

On July 29, 2021, the FDA released a statement that data from the OCEAN study demonstrated that the combination led to an increased risk of death in this population.⁶

In the statement, the regulatory agency encouraged that the progress of patients who are receiving melphalan flufenamide be assessed and that the risks of continued administration be discussed with each recipient in the context of other options.

On July 20, 2022, the FDA announced they will be holding a public advisory meeting of the Oncologic Drugs Advisory Committee on September 22, 2022, to discuss the benefit/risk of melphalan flufenamide.⁷

References

1. European Commission approves Oncopeptides' Pepaxti for the treatment of patients with relapsed refractory multiple myeloma. News release. Oncopeptides AB. August 18, 2022. Accessed August 18, 2022. https://prn.to/3wdLjzt
2. FDA approves Oncopeptides' PEPAXTO (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides AB. February 26, 2021. Accessed August 18, 2022. http://cisn.co/3q2bZgq
3. Richardson PG, Oriol A, Larocca A, et al. HORIZON (OP-106): Melflufen plus dexamethasone in relapsed/refractory multiple myeloma refractory to pomalidomide and/or an anti-CD39 monoclonal antibody – primary and subgroup analysis. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. https://bit.ly/3dTqayA
4. A study of melphalan flufenamide (melflufen)-dex or pomalidomide-dex for RRMM patients refractory to lenalidomide (OCEAN). ClinicalTrials.gov. Updated August 17, 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03151811
5. Updated results from phase 3 OCEAN study shows melflufen met primary endpoint of superior PFS - overall survival data lead to partial clinical hold. News release. Oncopeptides AB. July 8, 2021. Accessed August 18, 2022. https://prn.to/3A87h83
6. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). News release. FDA. July 28, 2021. Accessed August 18, 2022. https://bit.ly/3f81zJu
7. FDA announces an Oncologic Drugs Advisory Committee meeting to discuss benefit/risk profile of Oncopeptides’ Pepaxto. News release. Oncopeptides AB. July 20, 2022. Accessed August 18, 2022. https://prn.to/3QQ2Q8H