Melflufen Gains EU Expansion in Third-Line Lenalidomide-Refractory Multiple Myeloma

The European Commission (EC) has approved a label expansion for melphalan melflufen (Pepaxti) plus dexamethasone in adults with multiple myeloma that is refractory to both lenalidomide (Revlimid) and the most recent therapy after at least 2 prior lines of treatment.¹ The decision follows a positive opinion issued on September 17, 2026, by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), and it shifts melflufen from fourth-line use to third-line use and later while dropping the need for triple-class–refractory disease.^1,2

Efficacy findings from the phase 3 OCEAN trial (NCT03151811), along with safety findings from other clinical studies and real-world practice, formed the basis for the expansion.¹

In OCEAN, the median progression-free survival (PFS) reached 6.8 months (95% CI, 5.0-8.5) with melflufen plus dexamethasone (n = 246) vs 4.9 months (95% CI, 4.2-5.7) with pomalidomide (Pomalyst) plus dexamethasone (n = 249; HR, 0.79; 95% CI, 0.64-0.98; log-rank P = .032).³ Median overall survival (OS) was 19.8 months (95% CI, 15.1-25.6) in the melflufen arm vs 25.0 months (95% CI, 18.1-31.9) in the pomalidomide arm (HR, 1.10; 95% CI, 0.85-1.44; P = .47).

“The formal approval by the EC is a key milestone and allows physicians to prescribe melflufen in earlier lines of therapy,” Sofia Heigis, chief executive officer of Oncopeptides, said in a news release. “While this formal decision was anticipated following CHMP’s recommendation, its strategic importance cannot be overstated. The broadened indication has the potential to double the addressable patient base, and enable longer as well as removing the triple-class–refractory requirement.”

How was the OCEAN trial designed?

The open-label, head-to-head, randomized phase 3 study evaluated patients who were at least 18 years of age with with relapsed/refractory multiple myeloma and 2 to 4 prior lines of treatment, which had to include lenalidomide and a proteasome inhibitor.⁴ Patients also had to be refractory to their most recent line and to lenalidomide, have an ECOG performance status of 2 or lower and could not have received pomalidomide (Pomalyst) previously.

If patients had primary refractory disease, evidence of mucosal or internal bleeding, immunomodulatory drug intolerance, or active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization, they were not included in the trial.

Patients were randomly assigned following stratification by age, prior lines of therapy, and International Staging System score.³ Treatment consisted of melflufen 40 mg intravenously on day 1 or pomalidomide 4 mg orally on days 1 to 21 of 28-day cycles.⁴ Both arms also received dexamethasone 40 mg on days 1, 8, 15, and 22, or 20 mg for patients 75 years of age or older. Therapy continued until disease progression or unacceptable adverse effects (AEs).

The primary end point was PFS, with overall response rate, duration of response, OS, and safety serving as secondary end points.

What is the safety data and next steps for melflufen?

Safety analyses included 474 treated patients (melflufen, n = 228; pomalidomide, n = 246).³ Thrombocytopenia (melflufen, 63%; pomalidomide, 11%), neutropenia (54%; 41%), and anemia (43%; 18%) were the leading grade 3 or 4 treatment-emergent AEs (TEAEs) in the melflufen and pomalidomide arms, respectively. Serious TEAEs affected 42% of patients given melflufen and 46% of those given pomalidomide.

A German access dossier is planned within approximately 1 month, and its submission will allow third-line sales to begin during benefit assessment and pricing negotiations. Spain, Italy, and other key markets will proceed with pricing and reimbursement according to their local timelines.

References

1. European Commission approves label expansion of Pepaxti to third-line treatment. News release. Oncopeptides AB. November 9, 2026. Accessed November 9, 2026. https://oncopeptides.com/press-releases/european-commission-approves-label-expansion-of-pepaxti-to-third-line-treatment/
2. CHMP issues positive opinion of label expansion of Pepaxti to third-line treatment. News release. Oncopeptides AB. September 17, 2026. Accessed November 9, 2026. https://oncopeptides.com/press-releases/chmp-issues-positive-opinion-of-label-expansion-of-pepaxti-to-third-line-treatment/
3. Schjesvold FH, Dimopoulos MA, Delimpasi S, et al; OCEAN (OP-103) Investigators. 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
4. A study of melphalan flufenamide (melflufen)-dex or pomalidomide-dex for RRMM patients refractory to lenalidomide (OCEAN). ClinicalTrials.gov. Updated January 30, 2024. Accessed November 9, 2026. https://clinicaltrials.gov/study/NCT03151811