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Drugs Jun 2021Melphalan flufenamide (melflufen, Pepaxto) is a peptide conjugated alkylating drug developed by Oncopeptides for the treatment of multiple myeloma (MM) and amyloid... (Review)
Review
Melphalan flufenamide (melflufen, Pepaxto) is a peptide conjugated alkylating drug developed by Oncopeptides for the treatment of multiple myeloma (MM) and amyloid light-chain amyloidosis. It is an ethyl ester of a lipophilic dipeptide consisting of melphalan and para-fluoro-L-phenylalanine. Due to its lipophilicity, melphalan flufenamide is rapidly transported across the cell membrane and almost immediately hydrolyzed by aminopeptidases in the cytoplasm to yield more hydrophilic alkylating molecules, such as melphalan and desethyl-melflufen. Like other nitrogen mustard drugs, melphalan flufenamide exerts antitumor activity through DNA crosslinking. In February 2021, melphalan flufenamide, in combination with dexamethasone, received its first approval in the USA for the treatment of adults with relapsed or refractory (r/r) MM who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent, and one CD38-directed monoclonal antibody. A multinational clinical study of melphalan flufenamide in amyloid light-chain amyloidosis is underway across several countries, and preclinical studies for various haematological and solid cancers are underway. This article summarizes the milestones in the development of melphalan flufenamide leading to this first approval.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multicenter Studies as Topic; Multiple Myeloma; Randomized Controlled Trials as Topic
PubMed: 33961277
DOI: 10.1007/s40265-021-01522-0 -
Drugs of Today (Barcelona, Spain : 1998) Aug 2022Despite therapeutic advances and improved patient outcomes in recent years, multiple myeloma (MM) remains a mostly incurable hematologic malignancy. Patients with... (Review)
Review
Despite therapeutic advances and improved patient outcomes in recent years, multiple myeloma (MM) remains a mostly incurable hematologic malignancy. Patients with relapsed/refractory MM (RRMM), especially those with triple-class-refractory disease or poor-prognostic features, have substantially unmet needs for new therapies with novel mechanisms of action. Melphalan flufenamide (melflufen) is the first alkylating peptide-drug conjugate that targets aminopeptidases to show efficacy and manageable safety, in combination with dexamethasone, in patients with RRMM who had received at least 4 prior lines of therapy, including at least 1 immunomodulatory drug, at least 1 proteasome inhibitor and at least 1 anti-CD38 monoclonal antibody, and received accelerated approval by the U.S. Food and Drug Administration (FDA) in early 2021 for use in this patient population. Initial analyses of the phase III OCEAN study data led to melflufen being voluntarily withdrawn from the U.S. market in late 2021, but subsequent analyses have prompted the manufacturer to rescind its voluntary withdrawal to allow further discussions with the U.S. FDA and the regulatory review with the European Medicines Agency (EMA) is also ongoing. Here, we provide a review of the novel mechanism of action and pharmacokinetics of melflufen, as well as key efficacy and safety from clinical studies that supported its initial approval, and discuss the nuances of the OCEAN study data. Melflufen demonstrates the potential of novel peptide-drug conjugates to positively impact the treatment landscape in RRMM.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Phenylalanine
PubMed: 35983927
DOI: 10.1358/dot.2022.58.8.3367680 -
Drug Design, Development and Therapy 2021Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment.... (Review)
Review
Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptide-conjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased off-target cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third- or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Melphalan; Multiple Myeloma; Phenylalanine
PubMed: 34262262
DOI: 10.2147/DDDT.S295215 -
IARC Monographs on the Evaluation of... 1975
Review
Topics: Acute Disease; Adenofibroma; Animals; Carcinogens; Drug Evaluation, Preclinical; Female; Humans; Lethal Dose 50; Leukemia; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasms; Rats; Stereoisomerism
PubMed: 791831
DOI: No ID Found -
Bone Marrow Transplantation Apr 2019The application of high-dose melphalan and autologous stem cell transplant (SCT) to systemic AL amyloidosis (AL) has evolved over the past two decades and remains an... (Review)
Review
The application of high-dose melphalan and autologous stem cell transplant (SCT) to systemic AL amyloidosis (AL) has evolved over the past two decades and remains an important component of therapy for patients with AL. The era of novel agents created the opportunity to provide well -tolerated induction and post-SCT consolidation to AL patients eligible for SCT and the current availability of new monoclonal antibody therapies will likely provide additional opportunities to enhance the outcomes with SCT. In this review, we touch on the history of SCT for AL and examine the data on eligibility, mobilization, induction, risk-adapted melphalan dosing, engraftment, consolidation and maintenance, and long-term outcomes with SCT. We note that induction therapy may deprive some patients of the opportunity to proceed to SCT but is likely needed if the marrow plasmacytosis is > 10%, that risk-adapted melphalan dosing continues to be relevant, and that post-SCT consolidation improves the complete response rate as well as long-term overall survival. The importance of baseline cytogenetics is also highlighted, particularly for patients whose clonal plasma cells are ≤ 10% but harbor the t(11;14), because they may have improved survival with SCT.
Topics: Female; Humans; Male; Antineoplastic Agents, Alkylating; Immunoglobulin Light-chain Amyloidosis; Melphalan; Stem Cell Transplantation
PubMed: 30089901
DOI: 10.1038/s41409-018-0284-4 -
Report on Carcinogens : Carcinogen... 2004
Topics: Animals; Antineoplastic Agents, Alkylating; Carcinogenicity Tests; Carcinogens; Female; Government Regulation; Guidelines as Topic; Humans; Male; Melphalan; Mice; Models, Biological; Occupational Exposure; Rats; United States
PubMed: 21089900
DOI: No ID Found -
Journal of Pediatric Oncology Nursing :... Jan 1990
Topics: Humans; Melphalan; Neoplasms
PubMed: 2363868
DOI: 10.1177/104345429000700110 -
Nucleic Acids Research Aug 2023Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA...
Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA interstrand crosslinks (ICLs). In this study, we have developed and characterized a new tool to investigate ICL repair: a clickable version of the crosslinking agent melphalan which we name click-melphalan. Our results demonstrate that click-melphalan is as effective as its unmodified counterpart in generating ICLs and associated toxicity. The lesions induced by click-melphalan can be detected in cells by post-labelling with a fluorescent reporter and quantified using flow cytometry. Since click-melphalan induces both ICLs and monoadducts, we generated click-mono-melphalan, which only induces monoadducts, in order to distinguish between the two types of DNA repair. By using both molecules, we show that FANCD2 knock-out cells are deficient in removing click-melphalan-induced lesions. We also found that these cells display a delay in repairing click-mono-melphalan-induced monoadducts. Our data further revealed that the presence of unrepaired ICLs inhibits monoadduct repair. Finally, our study demonstrates that these clickable molecules can differentiate intrinsic DNA repair deficiencies in primary FA patient cells from those in primary xeroderma pigmentosum patient cells. As such, these molecules may have potential for developing diagnostic tests.
Topics: Humans; Melphalan; Fanconi Anemia; DNA Repair; DNA Damage; DNA
PubMed: 37395445
DOI: 10.1093/nar/gkad559 -
Clinical Pharmacology and Therapeutics Dec 1979The systemic availability of melphalan after oral administration is not well known. Most patients are put on a fixed oral dosage regimen. We have studied the disposition...
The systemic availability of melphalan after oral administration is not well known. Most patients are put on a fixed oral dosage regimen. We have studied the disposition of melphalan in 14 patients after single oral doses. Five were also studied after receiving the same dose intravenously. Oral melphalan had a mean plasma terminal phase half-life (t1/2) of 90 +/- 17 min. The mean area under the plasma concentration:time curve (CXT) was 53 +/- 33 micrograms . min/ml. Urinary excretion of oral melphalan averaged 10.9 +/- 4.9% during the first 24 hr. The CXT ratio (oral:intravenous) for the 5 patients studied after both oral and intravenous melphalal (0.6 mg/kg) ranged between 0.25 and 0.89 and averaged 0.56. After oral dosing in 14 fasting patients, the time at which melphalan first appeared in the plasma varied between 15 min and 6 hr. In a myeloma patient who took oral melphalan, no melphalan was found in plasma or urine up to 24 hr. Some instances of failure of tumor response to oral melphalan may be due to inadequate bioavailability rather than inherent tumor resistance.
Topics: Administration, Oral; Adult; Aged; Biological Availability; Female; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Melphalan; Middle Aged; Neoplasms
PubMed: 498715
DOI: 10.1002/cpt1979266737 -
Journal of Clinical Oncology : Official... Nov 1988Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of... (Clinical Trial)
Clinical Trial Review
Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.
Topics: Administration, Oral; Body Water; Bone Marrow; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Humans; Infusions, Intravenous; Melphalan; Neoplasms
PubMed: 3054005
DOI: 10.1200/JCO.1988.6.11.1768