Melflufen – first PDC with an alkylating payload

Melflufen is the first PDC with an alkylating payload. The drug utilizes peptidases and esterases that are overexpressed in multiple myeloma cells, to release a toxic payload inside cells, and damage DNA and kill cancer cells.

Mechanism of action

Melflufen is rapidly taken up by myeloma cells due to its lipophilicity. The drug is hydrolyzed by peptidases and esterases and releases a hydrophilic cytotoxic payload that becomes entrapped in the cells. The enzymes are upregulated in cancer cells and play a key role in protein homeostasis, cell-cycle progression and programmed cell death. Increased aminopeptidase expression is associated with advanced disease and a poorer outcome in multiple myeloma.

The melflufen molecule

Image of the Melflufen molecule

In vitro, melflufen is 50-fold more potent in myeloma cells than the toxic payload, due to increased concentration of alkylators in the cells. Melflufen has cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, it inhibits angiogenesis and metastatic processes in preclinical studies and overcomes p53-deficiency-mediated resistance, a common mechanism of resistance to antimyeloma therapies. Melflufen rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells.