Spotlight on Melphalan Flufenamide: An Up-and-Coming Therapy for the Treatment of Myeloma

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 peptideconjugated 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 offtarget 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.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021

“…Umbralisib is well tolerated (Dhillon and Keam 2021 ). Melphalan flufenamide (melflufen) is a derivative of melphalan, which was developed nearly 60 years ago and is still used for palliation in the therapy of multiple myeloma (Morabito et al 2021 ). Melphalan flufenamide is an ester conjugate of melphalan with para-fluoro- l -phenylalanine, and it was approved for multiple myeloma based on a priority review but shortly afterwards withdrawn from the US market because of inferior patient survival in a phase 3 trial (Olivier and Prasad 2022 ).…”

Liposome-Encapsulated Melphalan Exhibits Potent Antimyeloma Activity and Reduced Toxicity

“…Peptide conjugation conferred a hydrophilic nature to melflufen, which entered cells more efficiently than the parental melphalan compound. Within cells, melflufen can be processed by aminopeptidase to release free melphalan for function . By 2021, melflufen had been temporally approved by the FDA for relapsed or refractory MM (RRMM) treatment .…”

“…Within cells, melflufen can be processed by aminopeptidase to release free melphalan for function. 14 By 2021, melflufen had been temporally approved by the FDA for relapsed or refractory MM (RRMM) treatment. 15 The other melphalan modifications were mainly in preclinical stages.…”

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

“…85). [291][292][293][294] While the parent drug exhibited poor membrane permeability associated with its charged and hydrophilic character, thereby limiting its full potential as an anti-neoplastic agent, the prodrug was shown to enter neoplastic cells more efficiently due to the increased lipophilicity. After entering the cell, 7r was hydrolyzed to 7q by aminopeptidases, which are heavily overexpressed in multiple myeloma cells, thus allowing for the selective release of the melphalan payload.…”