INTRODUCTION:

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.

Melphalan Flufenamide is a peptide-drug conjugate composed of a peptide conjugated, via an aminopeptidase-targeting linkage, to the alkylating agent melphalan, with potential antineoplastic and anti-angiogenic activities. Upon administration, the highly lipophilic melphalan flufenamide penetrates cell membranes and enters cells. In amino peptidase-positive tumor cells, melphalan flufenamide is hydrolyzed by peptidases to release the hydrophilic alkylating agent melphalan. This results in the specific release and accumulation of melphalan in amino peptidase-positive tumor cells. Melphalan alkylates DNA at the N7 position of guanine residues and induces DNA intra- and inter-strand cross-linkages. This results in the inhibition of DNA and RNA synthesis and the induction of apoptosis, thereby inhibiting tumor cell proliferation. Peptidases are over expressed by certain cancer cells. The administration of melphalan flufenamide allows for enhanced efficacy and reduced toxicity compared to melphalan.

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 Peptichemioand its anti-tumor activity is being investigated.^2,3

STRUCTURE

IUPAC Name:

ethyl (2S)-2-[[(2S)-2-amino-3-[4-[bis(2-chloroethyl) amino] phenyl] propanoyl] amino]-3-(4-fluorophenyl) propanoate

Pharmacokinetic:

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.^3,4

Mechanism of action:

Melphalan flufenamide attaches alkyl groups to the N-7 position of guanine and N-3 position of adenine, leading to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the error.It can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription. Finally, melphalan can induce a number of different mutations gnostic imaging. The pattern and intensity of emission during imaging is used in the diagnosis of Alzheimer's disease.

Protein binding:

Moderate to high (60 to 90%), primarily to albumin and, to a lesser extent, alpha 1-acid glycoprotein. 30% is irreversibly bound.

Toxicity:

Vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the gastrointestinal tract; The principal toxic effect is bone marrow suppression. LD₅₀=11.2 mg/kg (orally in rat).

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.^5,6

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 Peptichemio⁸ and its anti-tumor activity is being investigated.

Adverse effects:

In a human Phase 1 trial, no dose-limiting toxicities (DLTs) were observed at lower doses. At doses above 50mg, 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.

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.²⁷ 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.

Contraindications:

Contraindicated in patients with a history of serious hypersensitivity reaction to melphalan flufenamide

Dosage Forms and Strengths:

For Injection: 20mg melphalan flufenamide as a sterile lyophilized white to off-white powder in a single-dose vial for reconstitution and further dilution.

Multiple Myeloma:

Indicated in combination with dexamethasone for relapsed or refractory multiple myeloma (RRMM) in adults who have received ≥4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody^5,6

Each cycle is 28 days

Melphalan flufenamide 40mg IV on Day 1, PLUS

Dexamethasone 40mg PO/IV on Days 1, 8, 15, and 22 (reduce dose to 20mg in patients aged ≥75 yr)

Continue until disease progression or until unacceptable toxicity

FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma

On February 26, 2021, the Food and Drug Administration granted accelerated approval to melphalan flufenamide (Pepaxto, Oncopeptides AB) in combination with dexamethasone for adult patients 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.

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 40mg intravenously on day 1 and dexamethasone 40mg orally (20mg 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 main efficacy outcome measure was overall response rate (ORR) and duration of response (DOR) assessed by investigators according to the International Myeloma Working Group (IMWG) Criteria. The ORR was 23.7% (95% CI: 15.7, 33.4) and median DOR 4.2 months (95% CI: 3.2, 7.6).

Safety was evaluated in the 157 patients enrolled in HORIZON. Most common adverse reactions (> 20%) are fatigue, nausea, diarrhea, pyrexia and respiratory tract infection. Most common laboratory abnormalities (≥50%) are decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.

The safety and efficacy of melphalan flufenamide has not been established for use as a conditioning regimen in patients receiving transplant. The USPI includes Limitations of Use statement that melphalan flufenamide is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials.

The recommended dose of melphalan flufenamide is 40 mg intravenously over 30 minutes on day 1 of each 28-day treatment cycle, in combination with dexamethasone.^7,8

Synthesis:

Computed Properties

Property Name	Property Value
Molecular Weight	498.4g/mol
XLogP3	3.2
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	14
Exact Mass	497.164825g/mol
Monoisotopic Mass	497.164825g/mol

Multiple myeloma (MM):

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies.^6] Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur.¹⁰ Complications may include amyloidosis.

The cause of multiple myeloma is unknown. Risk factors include obesity, radiation exposure, family history, and certain chemicals. Multiple myeloma may develop from monoclonal gammopathy of undetermined significance that progresses to smoldering myeloma. The abnormal plasma cells produce abnormal antibodies, which can cause kidney problems and overly thick blood. The plasma cells can also form a mass in the bone marrow or soft tissue. When one tumor is present, it is called a plasmacytoma; more than one is called multiple myeloma. Multiple myeloma is diagnosed based on blood or urine tests finding abnormal antibodies, bone marrow biopsy finding cancerous plasma cells, and medical imaging finding bone lesions.⁶ Another common finding is high blood calcium levels.

Multiple myeloma is considered treatable, but generally incurable.³ Remissions may be brought about with steroids, chemotherapy, targeted therapy, and stem cell transplant.³ Bisphosphonates and radiation therapy are sometimes used to reduce pain from bone lesions.

Globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. In the United States, it develops in 6.5 per 100,000 people per year and 0.7% of people are affected at some point in their lives. It usually occurs around the age of 60 and is more common in men than women. It is uncommon before the age of 40. Without treatment, typical survival is seven months. With current treatments, survival is usually 4–5 years. The five-year survival rate is about 54%. The word myeloma is from the Greek myelo- meaning "marrow" and -oma meaning "tumor".

CONCLUSION:

Melphalan Flufenamide is a peptide-drug conjugate composed of a peptide conjugated, via an aminopeptidase-targeting linkage, to the alkylating agent melphalan, with potential antineoplastic and anti-angiogenic activities. Upon administration, the highly lipophilic melphalan flufenamide penetrates cell membranes and enters cells. In aminopeptidase-positive tumor cells, melphalan flufenamide is hydrolyzed by peptidases to release the hydrophilic alkylating agent melphalan. This results in the specific release and accumulation of melphalan in aminopeptidase-positive tumor cells. Melphalan alkylates DNA at the N7 position of guanine residues and induces DNA intra- and inter-strand cross-linkages. This results in the inhibition of DNA and RNA synthesis and the induction of apoptosis, thereby inhibiting tumor cell proliferation. Peptidases are overexpressed by certain cancer cells. The administration of melphalan flufenamide allows for enhanced efficacy and reduced toxicity compared to melphalan.. ^[8,9,]

ACKNOWLEDGEMENT:

We are very thankful to Secretary Shri. Manoj Kumar Kawadiya for providing us facility and support completion of this work.

REFERENCES:

1. www,drug bank.com

2. "FDA grants accelerated approval to melphalan flufenamide for relapsed". U.S. Food and Drug Administration (FDA). 26 February 2021. Retrieved 1 March 2021.

3. Strese, Sara; Wickström, Malin; Fuchs, Peder Fredlund; Fryknäs, Mårten; Gerwins, Pär; Dale, Tim; Larsson, Rolf; Gullbo, Joachim (2013). "The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo". Biochemical Pharmacology. 86 (7): 888–95

4. "FDA Approves Oncopeptides' Pepaxto (melphalan flufenamide) for Patients with Triple-Class Refractory Multiple Myeloma" (Press release). Oncopeptides AB. 1 March 2021.

5. "Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Health Professional Version". NCI. July 29, 2016. Archived from the original on 4 July 2016. Retrieved 8 August 2016.

6. Gullbo, J; Tullberg, M; Våbenø, J; Ehrsson, H; Lewensohn, R; Nygren, P; Larsson, R; Luthman, K (2003). "Structure-activity relationship for alkylating dipeptide nitrogen mustard derivatives". Oncology Research. 14 (3): 113–32.

7. World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 2.3 and 2.6.

8. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

9. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct; 5(10): 821-34.

10. Monahan SD, Subbotin VM, Budker VG, Slattum PM, Neal ZC, Herweijer H, Wolff JA: Rapidly reversible hydrophobization: an approach to high first-pass drug extraction. Chem Biol. 2007 Sep; 14(9):1065-77

Received on 16.03.2021 Modified on 28.05.2021

Asian J. Res. Pharm. Sci. 2021; 11(4):291-294.

DOI: 10.52711/2231-5659.2021.00045