Melphalan flufenamide
Melphalan flufenamide, sold under the brand name Pepaxto, is an anticancer medication used to treat multiple myeloma.The most common adverse reactions include fatigue, nausea, diarrhea, pyrexia and respiratory tract infection.Melphalan flufenamide is a peptidase enhanced cytotoxic (PEnC) that exerts a targeted delivery of melphalan in cells with high expression of aminopeptidases, such as aminopeptidase N, which has been described as over-expressed in human malignancies. Aminopeptidase N plays a functional role in malignant angiogenesis.Melphalan flufenamide was approved for medical use in the United States in February 2021.

Medical uses
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.

Metabolism
Melphalan flufenamide is metabolized by aminopeptidase hydrolysis and by spontaneous hydrolysis on N-mustard.  Its biological half-life is 10 minutes in vitro.

Origin and development
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 clinical 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.

Pharmacology
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.

Structure
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.

Pharmacokinetics
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.

Adverse effects
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.

Drug interactions
No drug interaction studies have been reported. Several in vitro studies indicate that melphalan flufenamide may be successfully combined with standard chemotherapy or targeted agents.

Therapeutic efficacy
In a Phase 1/2 trial, in solid tumor patients 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 patient populations regardless of their refractory status.
Hematologic toxicity was common, but manageable with cycle prolongations, dose modifications and supportive therapy, and non-hematologic treatment-related adverse events were infrequent.

History
Efficacy was evaluated in HORIZON (NCT02963493), 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
Legal status
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 for the medicinal product Pepaxti, intended for the treatment of multiple myeloma. The applicant for this medicinal product is Oncopeptides AB.

Names
Melphalan flufenamide is the international nonproprietary name (INN).

References
External links
"Melphalan flufenamide". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02963493 for "A Study of Melphalan Flufenamide (Melflufen) in Combination With Dexamethasone in Relapsed Refractory Multiple Myeloma Patients (HORIZON)" at ClinicalTrials.gov
"FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide)". U.S. Food and Drug Administration (FDA). 23 August 2021.