General Information

Pepaxto (melphalan flufenamide) is a peptide conjugated alkylating drug. Pepaxto uses innovative technology that links a peptide carrier to a cytotoxic agent, resulting in a lipophilic compound. This lipophilicity distributes Pepaxto into cells. Pepaxto is designed to leverage aminopeptidases, which are overexpressed in multiple myeloma cells and cause the release of cytotoxic agents.

Pepaxto is specifically indicated for use in combination with dexamethasone for the treatment of 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 CD38-directed monoclonal antibody.

Pepaxto is supplied as a solution for intravenous administration. The recommended dosage of Pepaxto is 40 mg administered intravenously over 30 minutes on Day 1 of each 28-day cycle until disease progression or until unacceptable toxicity. Administer dexamethasone 40 mg orally or intravenously on Days 1, 8, 15 and 22 of each cycle. For patients 75 years of age or older, reduce the dose of dexamethasone to 20 mg. Refer to the prescribing information for dexamethasone for additional dosing information.

Recommended Premedication and Concomitant Medications: Consider providing a serotonin-3 (5-HT3) receptor antagonist or other antiemetics prior to and during the treatment with Pepaxto.

Mechanism of Action

Pepaxto (Melphalan flufenamide) is a peptide conjugated alkylating drug. Due to its lipophilicity, melphalan flufenamide is passively distributed into cells and thereafter enzymatically hydrolyzed to melphalan. Similar to other nitrogen mustard drugs, crosslinking of DNA is involved in the antitumor activity of melphalan flufenamide. In cellular assays, melphalan flufenamide inhibited proliferation and induced apoptosis of hematopoietic and solid tumor cells. Additionally, melphalan flufenamide showed synergistic cytotoxicity with dexamethasone in melphalan resistant and non-resistant multiple myeloma cell lines.

Side Effects

Adverse effects associated with the use of Pepaxto may include, but are not limited to, the following:

• fatigue
• nausea
• diarrhea
• pyrexia
• respiratory tract infection
• laboratory abnormalities (≥50%): leukocytes decrease, platelets decrease, lymphocytes decrease, neutrophils decrease, hemoglobin decrease and creatinine increase

Clinical Trial Results

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 

The approval of Pepaxto was based on a subgroup of HORIZON patients (n=97) that were refractory to at least one treatment in each of the three standard-of-care classes: proteasome inhibitor, immunomodulatory agent, and CD38-directed monoclonal antibody and had received at least four prior lines of treatment. In this subset of patients, the Overall Response Rate (ORR) was 23.7% and Median Duration of Response (DOR) was 4.2 months.