CHMP Recommends Label Expansion of Melflufen to Third-Line Lenalidomide-Refractory Multiple Myeloma

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending an expanded indication for melflufen (Pepaxti) in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 2 prior lines of therapy and whose disease is refractory to lenalidomide (Revlimid) and to the last line of therapy.¹

Melflufen is currently approved in the European Union for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 3 prior lines of therapy and have disease that is triple-class refractory.

The positive opinion is supported by data from the phase 3 OCEAN trial (NCT03151811), in which melflufen plus dexamethasone improved progression-free survival (PFS) vs pomalidomide (Pomalyst) plus dexamethasone in patients with lenalidomide-refractory disease.² At a data cutoff of February 3, 2021, the median PFS by independent review committee assessment was 6.8 months (95% CI, 5.0-8.5) in the melflufen group (n = 246) compared with 4.9 months (95% CI, 4.2-5.7) in the pomalidomide group (n = 249; HR, 0.79; 95% CI, 0.64-0.98; P = .032).

Overall survival (OS) numerically favored the pomalidomide group. The median OS was 19.8 months (95% CI, 15.1-25.6) with melflufen vs 25.0 months (95% CI, 18.1-31.9) with pomalidomide (HR, 1.10; 95% CI, 0.85-1.44; P = .47).

“Expanding into the third line removes the triple-class refractory barrier [and] effectively doubles our addressable patient population,” Sofia Heigis, chief executive officer of Oncopeptides, stated in the news release.¹

Following the CHMP’s positive opinion, a final decision on potential approval is expected from the European Commission in the next 30 to 60 days.

What is the mechanism of action of melflufen?

Melflufen is a first-in-class alkylating peptide-drug conjugate. The lipophilic agent is rapidly taken up by myeloma cells and cleaved by aminopeptidases, which are overexpressed in multiple myeloma cells, releasing hydrophilic alkylator molecules that become entrapped intracellularly. This mechanism is intended to concentrate the cytotoxic payload within tumor cells, producing DNA damage and apoptosis. Melflufen is administered as a 40-mg intravenous infusion over 30 minutes on day 1 of each 28-day cycle, in combination with weekly dexamethasone.

How was the OCEAN trial designed?

OCEAN was a randomized, open-label, head-to-head, phase 3 study that enrolled adult patients with relapsed/refractory multiple myeloma who received 2 to 4 prior lines of therapy, including lenalidomide and a proteasome inhibitor; patients were required to be refractory to lenalidomide administered within 18 months of randomization and to their last line of therapy.² Eligible patients needed to have an ECOG performance status of 0 to 2.

Patients were randomly assigned 1:1 and stratified by age, number of prior lines of therapy, and International Staging System score. In the experimental arm, patients received melflufen at 40 mg intravenously on day 1 of each 28-day cycle, and in the control arm, patients were administered pomalidomide at 4 mg on days 1 through 21 of each cycle. All patients received dexamethasone at 40 mg on days 1, 8, 15, and 22 of each 28-day cycle, with a reduced dose of 20 mg for patients 75 years of age or older.

The primary end point was PFS by independent review committee in the intention-to-treat population, and secondary end points included overall response rate, duration of response, OS, and safety.

What was the safety profile of melflufen in OCEAN?

Among the 474 patients in the safety population (melflufen, n = 228; pomalidomide, n = 246), the most common grade 3 or 4 treatment-emergent adverse effects (TEAEs) in the melflufen and pomalidomide groups, respectively, were thrombocytopenia (63% vs 11%), neutropenia (54% vs 41%), and anemia (43% vs 18%).

Serious TEAEs occurred in 42% of patients in the melflufen group and 46% of those in the pomalidomide group; the most common were pneumonia (6% vs 9%), COVID-19 pneumonia (5% vs 4%), and thrombocytopenia (4% vs 1%). Fatal TEAEs were reported in 12% of patients in the melflufen group and 13% in the pomalidomide group, and were considered possibly treatment-related in 2 patients who received melflufen and 4 who received pomalidomide.

References

1. CHMP issues positive opinion of label expansion of Pepaxti to third-line treatment. News release. Oncopeptides AB. September 17, 2026. Accessed September 17, 2026. https://oncopeptides.com/press-releases/chmp-issues-positive-opinion-of-label-expansion-of-pepaxti-to-third-line-treatment/
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