European Commission Expands Melflufen Label to Third-Line Multiple Myeloma

The European Commission (EC) has approved a label expansion for melflufen (melphalan flufenamide; Pepaxti) in combination with dexamethasone, broadening its marketing authorization to adult patients with multiple myeloma who have received at least 2 prior lines of therapy and whose disease is refractory to lenalidomide (Revlimid) and the last line of therapy, according to Oncopeptides announced.¹

The approval formally confirms the earlier positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). By broadening the indication from the prior fourth-line setting, the decision eliminates the requirement for triple-class refractoriness.

What did the European Commission approve?

The EC formally approved the Type II variation application for melflufen, expanding the marketing authorization to the third-line-and-later setting for adults with multiple myeloma who are refractory to lenalidomide and the last line of therapy. The expansion removes the prior triple-class refractory requirement that had limited use to the fourth-line setting. For patients with a prior autologous stem cell transplantation (ASCT), the approved label specifies that the time to progression should be at least 3 years from transplantation. Melflufen is approved in the European Union; the European Economic Area countries Iceland, Liechtenstein, and Norway; and the UK.

What supported the approval?

The expanded indication is supported by data from the phase 3 OCEAN trial (NCT03151811), along with safety data from several clinical trials and real-world use of melflufen plus dexamethasone in relapsed/refractory multiple myeloma. In OCEAN, which randomly assigned 495 patients with lenalidomide-refractory disease and 2 to 4 prior lines of therapy to melflufen plus dexamethasone or pomalidomide (Pomalyst) plus dexamethasone, melflufen met the primary end point of progression-free survival (PFS) by independent review.² The median PFS was 6.8 months (95% CI, 5.0-8.5) with melflufen vs 4.9 months (95% CI, 4.2-5.7) with pomalidomide (HR, 0.79; 95% CI, 0.64-0.98; P = .032).

Overall survival (OS), a key secondary end point, was not significantly different and numerically favored pomalidomide (median, 19.8 vs 25.0 months; HR, 1.10; 95% CI, 0.85-1.44; P = .47). Exploratory and post hoc analyses indicated that the OS difference was driven primarily by patients who had received a prior ASCT—among whom OS favored pomalidomide (HR, 1.61; 95% CI, 1.09-2.40; P = .017)—while patients without a prior transplant derived greater benefit from melflufen (PFS HR, 0.59; 95% CI, 0.44-0.79; P = .0004), findings that underpin the prior-transplant caveat in the approved label.

The most common grade 3/4 treatment-emergent adverse events with melflufen were hematologic, including thrombocytopenia (63%), neutropenia (54%), and anemia (43%).

“The formal approval by the EC is a key milestone and allows physicians to prescribe [melflufen] in earlier lines of therapy, providing its benefit for more patients,” said Sofia Heigis, chief executive officer of Oncopeptides, in a news release.¹ “The broadened indication has the potential to double the addressable patient base...removing the [triple-class refractory] requirement.”

What is melflufen, and what comes next?

Melflufen is a first-in-class, aminopeptidase-targeted peptide-drug conjugate that rapidly releases alkylating agents inside tumor cells. As demonstrated in OCEAN, earlier-line treatment allowed patients to remain on therapy longer, which the company stated effectively doubles the average number of treatment cycles per patient in the third-line setting compared with the fourth-line setting. Developers indicated that they plan to submit their access dossier in Germany within approximately 1 month, which permits immediate commercial sales in the third-line setting while benefit assessment and pricing negotiations proceed, with formal pricing and reimbursement procedures to follow in other key markets, including Spain and Italy.

References

1. European Commission approves label expansion of Pepaxti to third-line treatment. News release. Oncopeptides AB. November 9, 2026. Accessed November 10, 2026. https://tinyurl.com/24evhau3
2. 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