Updated EHA-EMN Guidelines Include Melphalan Flufenamide for R/R Myeloma

Updated guidelines from the European Hematology Association (EHA) and the European Myeloma Network (EMN) now include melphalan flufenamide (Pepaxti) for the treatment of patients with relapsed/refractory multiple myeloma.¹

Specifically, the guidelines recommend melphalan flufenamide for patients who have received multiple prior lines of therapy and whose disease is triple-class refractory. This addition to the guidelines is supported by level 1 evidence, and melphalan flufenamide carries a Grade B recommendation, according to an announcement from Oncopeptides. The guidelines also include melphalan flufenamide as an option for patients with even more advanced disease, such as those who have also been treated with CAR T-cell therapy or an antibody-drug conjugate.

“The fact that [melphalan flufenamide] has received a recommendation by this expert group once again confirms the drug’s value in later lines of treatment and will support awareness of [melphalan flufenamide] as a treatment option,” Sofia Heigis, chief executive officer of Oncopeptides, stated in a news release. “We are happy to see [melphalan flufenamide] having the highest combination of recommendation and clinical evidence of all non–CAR T[-cell] therapies, supporting the use of [melphalan flufenamide] as the first choice in subsequent treatment of multiple myeloma.”

In February 2021, the FDA granted accelerated approval to melphalan flufenamide in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.² In August 2022, the European Commission approved melphalan flufenamide in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 3 prior lines of therapies, whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 anti-CD38 monoclonal antibody, and who have disease progression on or after the last therapy.³

However, in February 2024, the FDA withdrew the indication for the combination, citing that a confirmatory study to further support the accelerated approval did not confirm the clinical benefit of the agent, and available evidence had not demonstrated that melphalan flufenamide is safe or effective under its conditions of use.⁴

The initial accelerated approval was supported by findings from the multicenter, single-arm phase 2 HORIZON trial (NCT02963493), which showed that patients previously treated with 4 or more prior lines of therapy who had triple-class refractory disease (n = 97) achieved an overall response rate of 23.7% (95% CI, 15.7%-33.4%) and a median duration of response of 4.2 months (95% CI, 3.2-7.6).²

Regarding safety (n = 157), the most common adverse effects reported in more than 20% of patients included fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. Common laboratory abnormalities that occurred in more than 50% of patients comprised decreased leukocyte counts, decreased platelet counts, reduced lymphocyte counts, decreased neutrophil counts, lowered hemoglobin levels, and increased creatinine levels.

The confirmatory phase 3 OCEAN trial (NCT03151811) included patients with relapsed or refractory multiple myeloma who were refractory to lenalidomide (Revlimid) and their last line of therapy.⁵ Patients needed to have received 2 to 4 prior lines of therapy.

Findings showed that at a median follow-up of 15.5 months (interquartile range [IQR], 9.4-22.8) for the experimental arm and 16.3 months (IQR, 10.1-23.2) in the control arm, melphalan flufenamide plus dexamethasone (n = 246) yielded a median progression-free survival of 6.8 months (95% CI, 5.0-8.5) compared with 4.9 months (95% CI, 4.2-5.7) for pomalidomide (Pomalyst) plus dexamethasone (n = 249; HR, 0.79; 95% CI, 0.64-0.98; P = .032).⁵

The median overall survival was 19.8 months (95% CI, 15.1-25.6) for the melphalan flufenamide group vs 25.0 months (95% CI, 18.1-31.9) for the pomalidomide group (HR 1.10; 95% CI, 0.85-1.44; P = .47).

References

1. Oncopeptides’ drug Pepaxti included in European Guidelines for the treatment of multiple myeloma. News release. Oncopeptides. July 8, 2025. Accessed July 8, https://oncopeptides.com/en/media/press-releases/oncopeptides-drug-pepaxti-included-in-european-guidelines-for-the-treatment-of-multiple-myeloma/
2. FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. FDA. February 26, 2021. Accessed July 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple
3. European Commission approves Oncopeptides’ Pepaxti for the treatment of patients with relapsed refractory multiple myeloma. News release. Oncopeptides AB. August 18, 2022. Accessed July 8, 2025. https://www.prnewswire.com/news-releases/european-commission-approves-oncopeptides-pepaxti-for-the-treatment-of-patients-with-relapsed-refractory-multiple-myeloma-301608459.html
4. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). FDA. February 23, 2024. Accessed July 8, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide
5. Schjesvold FH, Dimopoulos MA, Delimpasi S, et al. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol. 2022;9(2):e98-e110. doi:10.1016/S2352-3026(21)00381-1