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Spotlight on Melphalan Flufenamide: An Up-and-Coming Therapy for the Treatment of Myeloma.
- Source :
-
Drug design, development and therapy [Drug Des Devel Ther] 2021 Jul 08; Vol. 15, pp. 2969-2978. Date of Electronic Publication: 2021 Jul 08 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- 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.<br />Competing Interests: The authors report no conflicts of interest in this work.<br /> (© 2021 Morabito et al.)
- Subjects :
- Antineoplastic Agents, Alkylating adverse effects
Antineoplastic Agents, Alkylating pharmacology
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Drug Resistance, Neoplasm
Humans
Melphalan administration & dosage
Melphalan adverse effects
Melphalan pharmacology
Multiple Myeloma pathology
Phenylalanine administration & dosage
Phenylalanine adverse effects
Phenylalanine pharmacology
Antineoplastic Agents, Alkylating administration & dosage
Melphalan analogs & derivatives
Multiple Myeloma drug therapy
Phenylalanine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1177-8881
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- Drug design, development and therapy
- Publication Type :
- Academic Journal
- Accession number :
- 34262262
- Full Text :
- https://doi.org/10.2147/DDDT.S295215