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Melflufen Update: A Modern Myeloma Saga
Posted: Mar 16, 2022
Melflufen Update: A Modern Myeloma Saga image


The word ‘saga’ typically means something like ‘a dramatic and often complicated story or series of events.’ The events over the past year relative to melflufen are both (somewhat) dramatic but (definitely) complicated, earning the story of melflufen the moniker of ‘saga’.

Myeloma Crowd by HealthTree posted several articles last year about Melflufen, a novel drug conjugate to treat relapsed/refractory myeloma. Melflufen received  accelerated approval  by FDA on February 6th, 2021 for triple class refractory MM (including Revlimid and a proteasome inhibitor) following at least four prior lines of therapy. This approval, however, was contingent on the future results of a confirmatory study [the OCEAN study].

OCEAN was a large study (nearly 500 patients, evenly divided over two treatment arms) that was a head-to-head comparison between two treatment regimens: melflufen + dexamethasone versus pomalidomide-dexamethasone. The outcomes of this study are summarized below:

  Progression Free Survival (PFS) Overall Survival Serious treatment related adverse events
Melfufen + dex (median) 6.8 months 19.8 months 42%

Pomalidomide + dex (media)

4.9 months 25.0 months 46%

At the end of July, 2021 and based on the early read of the outcomes of this trial, showing that melflufen had a negative impact on Overall Survival, the FDA sent out a safety alert stating:

“Due to the detrimental effect on overall survival in the OCEAN trial, FDA is requiring the manufacturer suspend enrollment in the trial. FDA has also suspended enrollment in other ongoing Pepaxto clinical trials. Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”


But at the same time also commenting :

“FDA continues to evaluate the OCEAN trial results and may hold a future public meeting to discuss these safety findings and explore the continued marketing of Pepaxto.”


Out of an abundance of caution, Oncopeptides announced at the end of October, 2021:

“… that the company has decided to withdraw Pepaxto® (INN melphalan flufenamide) from the market in the US, following the phase 3 OCEAN study, which showed an overall survival in the ITT population with a HR of 1.104. The decision has been made after interactions and dialogue with the US Food and Drug Administration, FDA. Pepaxto was granted accelerated approval on February 26th, 2021. During our dialogue with FDA, it has become evident that the FDA does not consider that the Phase 3 OCEAN study meets the criteria of a confirmatory study. Oncopeptides believes that the OCEAN data are scientifically meaningful and that the findings warrant further evaluation.”


In other words, Oncopeptides, voluntarily withdrew Pepaxto (melflufen) from the US market as opposed to being forced by FDA to do so.

This “further evaluation” was published in the journal Lancet Haematology on January 12, 2022, together with a lengthy addendum (but still very worthwhile reading) presenting a variety of relevant analyses.

The striking conclusion presented is that the outcomes of both study arms differ substantially when analyzing the sub-groups of patients who either did or did not have an autologous stem cell transplant (aSCT) prior to relapse of their myeloma and treatment with Melflufen. These different outcomes are presented in the table below:

Patients with Previous SCT Melflufen + dex Pom + dex
Progression Free Survival 4.4 months 5.2 months
Overall Survival 16.7 months 31.0 months
Patients Without Previous SCT    
Progression Free Survival 9.3 months 4.6 months
Overall Survival 12.6 months 16.5 months

In their conclusions, the authors of the Lancet article state a very interesting result for patients who did NOT have a prior stem cell transplant as part of their treatment regimen: the combination of Melflufen +dex results in better outcomes than the combination Pomalyst (pomalidomide) + dex.

“A post-hoc analysis suggested that having received an autologous HSCT—and by extension, previous high-dose melphalan conditioning therapy—was a significant negative prognostic factor for survival. Because patients who had not received a previous autologous HSCT had similar outcomes regardless of whether their disease was refractory to alkylators (cyclophosphamide or melphalan [excluding high-dose melphalan]) or not, it is reasonable to hypothesise that the negative prognostic effect of previous autologous HSCT in the melflufen group might be driven by exposure to high-dose melphalan in this context. Previous studies suggest that a patient's haematopoietic reserve might be negatively affected by alkylators used for stem-cell harvest and myeloablation before an autologous HSCT. In this scenario, patients might have difficulties tolerating subsequent treatments that induce cytopenias and could be more prone to developing haematological toxicities as a result. Furthermore, patients who relapse soon after receiving an autologous HSCT might be less likely to respond to any treatment, particularly one in which alkylation is the primary mechanism of action.” [Emphasis added]



“In summary, we found that melflufen plus dexamethasone improves progression-free survival for patients with lenalidomide-refractory relapsed or refractory multiple myeloma. Whether the treatment combination is beneficial for those who have or have not received a previous autologous HSCT needs to be investigated further.” [Emphasis added]


In practical terms, this means that Oncopeptides now needs to convince FDA to lift the earlier safety alert and possibly proceed with an indication that the use of Pepaxto be limited to those patients who have not had a prior stem cell transplant (with exposure to high dose melphalan) prior to relapse.

Following the publication of the Lancet article, Oncopeptides has released the following statement:

            “… the Company has contacted the US Food and Drug Administration and rescinded the October 22, 2021, letter requesting voluntary withdrawal of the NDA of Pepaxto® (INN melphalan flufenamide, also called melflufen) in the US. Further review and analyses of the heterogenous Overall Survival data from the phase 3 OCEAN study and other relevant trials have led the Company to reconsider its previous voluntary withdrawal request. Oncopeptides has discontinued the marketing of Pepaxto in the US and does not intend to market Pepaxto in the US at this time. The company has initiated a dialogue with the FDA to review the new data.” [emphasis added]


It has been stated on numerous occasions in previous posts by Myeloma Crowd and the HealthTree Foundation that multiple myeloma is a heterogeneous disease.

In other words, there is NO “size that fits all” and that our treatment programs are ideally tailored to our very specific patient characteristics. The path of Melflufen is a case in point. As patients, we rarely see head-to-head studies between different treatment regimens, or we see outcomes of studies of a new triplet or quadruplet against a comparator that is no longer even considered ‘standard of care’, with the predictable result that the novel triplet or quadruplet is ‘better’.

The Melflufen OCEAN trial has taught us now that some patients may be well served with Melfufen, but that it not be used for other patients. That is progress that may be of value to some of us in the future.



The author Paul Kleutghen

about the author
Paul Kleutghen

I am a patient diagnosed in 2014 with primary plasma cell leukemia (pPCL), a rare and aggressive variant of multiple myeloma and have been very fortunate to find successful treatment at the division of Cellular Therapy at the Duke University Cancer Institute. My wife, Vicki, and I have two adult children and two grandsons who are the ‘lights of our lives’. Successful treatment has allowed Vicki and I to do what we love best : traveling the world, albeit it with some extra precautions to keep infections away. My career in the pharmaceutical industry has given me insights that I am currently putting to use as an advocate to lower drug pricing, especially prices for anti-cancer drugs. I am a firm believer that staying mentally active, physically fit, compliant to our treatment regimen and taking an active interest in our disease are keys to successful treatment outcomes.

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