Extended Melphalan Flufenamide Indication Approaches EU Approval for R/R Multiple Myeloma


The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion regarding a Type II variation application to extend the therapeutic indication of melphalan flufenamide for use in adult patients with multiple myeloma who have received at least 2 prior lines of treatment and whose disease is refractory to lenalidomide and the last line of therapy.

multiple myeloma

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion regarding a Type II variation application to extend the therapeutic indication of melphalan flufenamide (Pepaxti) for use in adult patients with multiple myeloma who have received at least 2 prior lines of treatment and whose disease is refractory to lenalidomide (Revlimid) and the last line of therapy.1

The application is supported by findings from the phase 3 OCEAN trial (NCT03151811), in which melphalan flufenamide plus dexamethasone (n = 246) improved median progression-free survival (PFS) vs pomalidomide and dexamethasone (n = 249), at 6.8 months (95% CI, 5.0-8.5) and 4.9 months (95% CI, 4.2-5.7), respectively (HR, 0.79; 95% CI, 0.64-0.98; log-rank P = .032).2 The median follow-up in the melphalan and pomalidomide arms was 15.5 months (interquartile range [IQR], 9.4-22.8) and 16.3 months (IQR, 10.1-23.2), respectively.

The addition of melphalan flufenamide to dexamethasone resulted in an overall response rate (ORR) of 33% (95% CI, 27%-39%) compared with 27% (95% CI, 22%-33%) with pomalidomide plus dexamethasone (P = .16); complete response rates were 3% vs 1%, very good partial response rates were 9% vs 7%, and partial response rates were 20% vs 18%, respectively. Time to first response with melphalan flufenamide was 2.1 months (IQR, 1.1-3.7) vs 2.0 months (IQR, 1.1-2.9) with pomalidomide; the time to best confirmed response was 3.2 months (IQR, 1.9-5.9) and 2.8 months (IQR, 1.2-5.6), respectively.

Moreover, at a median follow-up of 19.8 months (IQR, 12.0-25) in the investigative arm and 18.6 months (IQR, 11.8-23.7) in the control arm, the median overall survival (OS) was 19.8 months (95% CI, 15.1-25.6) vs 25.0 months (95% CI, 18.1-31.9), respectively (HR, 1.10; 95% CI, 0.85-1.44; log-rank P = .47).

“The positive opinion from the CHMP further validates the scientific data on the efficacy, safety and increased quality of life that Pepaxti is able to bring to patients,” Sofia Heigis, chief executive officer of Oncopeptides, stated in a press release.1 “While we are convinced that our drug best serves patients in later lines of treatment where the unmet need and our chances to receive a price that reflects our innovation are high, we will closely evaluate the CHMP opinion and our potential next steps, always keeping value for patients and our shareholders as paramount priorities.”

The controlled, open-label, head-to-head, phase 3 OCEAN study enrolled patients with a diagnosis of multiple myeloma and disease progression who were aged 18 years or older and who had previously received 2 to 4 lines of therapy, including lenalidomide and a proteasome inhibitor sequentially or in the same line.2 Patients had disease that was refractory to both the last line of therapy and to lenalidomide given within 18 months before randomization. They also need to have an ECOG performance status of 0 to 2 and measurable disease.

If patients previously received pomalidomide, were intolerant to immunomodulatory drugs or steroid therapy, had primary refractory disease, or previously underwent allogeneic hematopoietic stem cell transplant (HSCT) with active graft-vs-host disease, they were excluded.

Study participants were randomly assigned 1:1 to receive melphalan flufenamide at 40 mg on day 1 of each cycle plus dexamethasone or pomalidomide at 4 mg on days 1 to 21 of each cycle plus dexamethasone. Dexamethasone was administered at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle.

Stratification factors included age (≥75 years vs <75 years), prior lines of therapy (2 vs 3 to 4), and International Staging System score (I vs II vs III). Treatment continued until disease progression, intolerable toxicity, or patient or physician determination to discontinue.

PFS by independent review committee assessment served as the trial’s primary end point and this was evaluated according to International Myeloma Working Group Uniform Response criteria. Key secondary end points included ORR, OS, and safety. Other end points of interest included duration of response, clinical benefit rate, time to first confirmed response, and duration of clinical benefit, among others. Pharmacokinetic data were also evaluated.

The median age was 68 years (IQR, 60-72) in the investigative arm and 68 years (IQR, 61-72) in the control arm. The majority (>99%) of patients had disease that was lenalidomide refractory and half had prior autologous HSCT. Seventy-one percent of patients were enrolled in Europe, 23% in the rest of the world, and 5% in the United States.

At the data cutoff date of February 3, 2021, 76% of those on the melphalan flufenamide arm and 80% of those on the pomalidomide arm had discontinued treatment; 17% vs 18% of patients, respectively, continued therapy.

The most common hematologic grade 3 or 4 adverse effects (AEs) in the investigative and control arms were neutropenia (54% vs 41%), thrombocytopenia (63% vs 11%), and anemia (43% vs 18%). The most common grade 3 or 4 non-hematologic event was pneumonia (4% vs 8%).

Moreover, the most common grade 3 or 4 treatment-related toxicities in the melphalan flufenamide and pomalidomide arms included thrombocytopenia (61% vs 22 9%), neutropenia (54% vs 39%), and anemia (38% vs 10%. Serious treatment-emergent AEs were reported in 42% of patients in the melphalan flufenamide arm vs 46% of those in the pomalidomide arm, with the most common being pneumonia (6% vs 9%), COVID-19 pneumonia (5% vs 4%), and thrombocytopenia (4% vs 1%). These effects were considered to be related to treatment related for 18% of those in the melphalan flufenamide arm and 21% of those in the pomalidomide arm.

In September 2022, the FDA’s Oncologic Drugs Advisory Committee voted 14 to 2 that the benefit-risk profile of melphalan flufenamide is not favorable for the approved indicated population of patients with relapsed/refractory multiple myeloma.3 Although agent received accelerated approval for use in combination with dexamethasone in 2021,4 findings from the confirmatory OCEAN trial did not meet the primary or secondary end points of improved PFS and OS vs pomalidomide and dexamethasone according to FDA standards.

In December 2022, Oncopeptides AB announced that the FDA asked the company to withdraw melphalan flufenamide from the US market.5 The company stopped marketing the peptide-drug conjugate in the United States as of October 22, 2021.


  1. CHMP issues positive opinion on Type II variation to extend the therapeutic indication of Pepaxti based on OCEAN trial results. News release. Oncopeptides. September 14, 2023. Accessed September 14, 2023. https://www.oncopeptides.com/en/media/press-releases/chmp-issues-positive-opinion-on-type-ii-variation-to-extend-the-therapeutic-indication-of-pepaxti-based-on-ocean-trial-results
  2. Schjesvold FH, Dimopoulos M-A, 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
  3. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed September 22, 2022. https://www.youtube.com/watch?v=SON2biqVX_8.
  4. FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. FDA. Updated March 1, 2022. Accessed September 14, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple-myeloma
  5. Oncopeptides provides update on Pepaxto US marketing authorization. News release. Oncopeptides AB. December 7, 2022. Accessed September 14, 2023. https://cisn.co/3iywZgL
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