|Other names||Melflufen, 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-phenylalanine ethyl ester, J1|
|Drug class||Alkylating agent|
|Main uses||Multiple myeloma|
|Side effects||Low platelets, low neutrophils, low red blood cells, nausea, diarrhea, fever|
|Typical dose||40 mg|
|Metabolism||Aminopeptidase hydrolysis, Spontaneous hydrolyisis on N-mustard|
|Elimination half-life||10 min in vitro|
|Chemical and physical data|
|Molar mass||498.42 g·mol−1|
|3D model (JSmol)|
Melphalan flufenamide, sold under the brand name Pepaxto, is an medication used to treat multiple myeloma. It is used when other treatments have failed, together with dexamethasone. It is given by gradual injection into a vein.
Common side effects include low platelets, low neutrophils, low red blood cells, nausea, diarrhea, and fever. Severe side effects include pneumonia. Use in pregnancy may harm the baby. It is an alkylating agent that interferes with the normal repair of DNA.
Melphalan flufenamide was approved for medical use in the United States in February of 2021 and Europe in 2022. The manufacturer withdrew the medication in October of 2021 due to concerns of worsened outcomes; however, it is thinking of reversing this decision. It is not approved in the United Kingdom as of 2022.
Melphalan flufenamide is indicated in combination with dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma, with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody.
In a human Phase 1 trial, no dose-limiting toxicities (DLTs) were observed at lower doses. At doses above 50 mg, reversible neutropenias and thrombocytopenias were observed, and particularly evident in heavily pretreated patients. These side-effects are shared by most chemotherapies, including alkylating agents in general.
Compared to melphalan, melphalan flufenamide exhibits significantly higher in vitro and in vivo activity in several models of human cancer. A preclinical study, performed at Dana–Farber Cancer Institute, demonstrated that melphalan flufenamide induced apoptosis in multiple myeloma cell lines, even those resistant to conventional treatment (including melphalan). In vivo effects in xenografted animals were also observed, and the results confirmed by M Chesi and co-workers – in a unique genetically engineered mouse model of multiple myeloma – are believed to be predictive of clinical efficacy.
Melphalan flufenamide is metabolized by aminopeptidase hydrolysis and by spontaneous hydrolysis on N-mustard. Its biological half-life is 10 minutes in vitro.
Chemically, the drug is best described as the ethyl ester of a dipeptide consisting of melphalan and the amino acid derivative para-fluoro-L-phenylalanine.
Pharmacokinetic analysis of plasma samples showed a rapid formation of melphalan; concentrations generally exceeded those of melphalan flufenamide during ongoing infusion. Melphalan flufenamide rapidly disappeared from plasma after infusion, while melphalan typically peaked a few minutes after the end of infusion. This suggests that melphalan flufenamide is rapidly and widely distributed to extravasal tissues, in which melphalan is formed and thereafter redistributed to plasma.
This rapid disappearance from plasma is likely due to hydrolytic enzymes. The Zn(2+) dependent ectopeptidase (also known as alanine aminopeptidase), degrades proteins and peptides with a N-terminal neutral amino acid. Aminopeptidase N is frequently overexpressed in tumors and has been associated with the growth of different human cancers suggesting it as a suitable target for anti-cancerous therapy.
Melphalan flufenamide is a peptidase enhanced cytotoxic (PEnC) with a targeted delivery within tumor cells of melphalan, a widely used classical chemotherapeutic belonging to a group of alkylating agents developed more than 50 years ago. Substantial experience has been accumulated about melphalan since then. Numerous derivatives of melphalan, designed to increase the activity or selectivity, have been developed and investigated in vitro or in animal models. Melphalan flufenamide was synthesized, partly due to previous experience of an alkylating peptide cocktail named Peptichemio and its anti-tumor activity is being investigated.
Efficacy was evaluated in horizon, a multicenter, single-arm trial. Eligible patients were required to have relapsed refractory multiple myeloma. Patients received melphalan flufenamide 40 mg intravenously on day 1 and dexamethasone 40 mg orally (20 mg for patients ≥75 years of age) on day 1, 8, 15 and 22 of each 28-day cycle until disease progression or unacceptable toxicity. Efficacy was evaluated in a subpopulation of 97 patients who received four or more prior lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and a CD38-directed antibody.
The application for melphalan flufenamide was granted priority review and orphan drug designations.
Society and culture
On 23 June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation, intended for the treatment of multiple myeloma. The applicant for this medicinal product is Oncopeptides AB.
Melphalan flufenamide is the international nonproprietary name (INN).
In a Phase 1/2 trial, in solid tumors refractory to standard therapy, response evaluation showed disease stabilization in a majority of patients. In relapsed and refractory multiple-myeloma (RRMM) patients, promising activity was seen in heavily pre-treated RRMM patients where conventional therapies had failed; the median Progression-Free Survival was 9.4 months and the Duration of Response was 9.6 months. An overall response rate of 41% and a clinical benefit rate of 56% were also shown, with similar results seen across populations regardless of their refractory status.
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