1. Shultes, Kendall C. PharmD, BCOP

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What is melphalan flufenamide?

Melphalan flufenamide (melflufen) is a first-in-class anticancer peptide-drug conjugate for adults with refractory or relapsed multiple myeloma (RRMM). The unique peptide carrier increases the lipophilicity of the drug allowing for passive distribution into cells.


Melflufen, as a peptide-drug conjugate, is a peptide carrier combined with the alkylating payload, melphalan. The peptide-drug conjugate is passively distributed into the cells where the peptide carrier is released through enzymatic hydrolysis allowing for melphalan to exert its irreversible crosslinking of DNA.


What is this approved for?

Melflufen was granted accelerated approval for adults with RRMM who have received at least four lines of therapy, including at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.


Melflufen was approved based on the results the HORIZON study, a Phase II, single-arm, multicenter study in patients with RRMM. Patients had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody, had an ECOG performance status of 0-2, and measurable disease. Patients received melphalan flufenamide 40 mg intravenously on Day 1 in combination with dexamethasone 40 mg orally (20 mg for age greater than or equal to 75 years) once weekly on Day 1, 8, 15, and 22 of a 28-day cycle. Overall response rate (ORR) was the primary endpoint assessed by International Myeloma Work Group response criteria. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.


Median lines of prior therapy was five. ORR was 29 percent (95% CI: 22,37) with one stringent complete response, 17 very good partial response (VGPR), and 28 partial responses (PR). In patients who were triple-class refractory (TCR), ORR was 26 percent (95% CI: 18,35) with 13 VGPR and 18 PR. In all patients, PFS was 4.2 months (95% CI: 3.4,4.9) compared to 3.9 months (95% CI: 3.0,4.6) for TCR patients. Among responders, PR or greater, median PFS was 8.5 months for both all patients and TCR groups, median OS was 17.6 months (95% CI: 13.2,28.9) and 16.5 months (95% CI: 11.5,18.5), and DOR was 5.5 months (95% CI: 3.9,7.6) and 4.4 months (95% CI: 3.4, 7.6) for all patients and triple-class refractory, respectively.


All patients experienced at least one treatment-emergent adverse event, including neutropenia (79%), thrombocytopenia (76%), and anemia (43%) being most common. Common nonhematologic adverse events were nausea (32%), diarrhea (27%), and constipation (15%). Grade 3 neutropenia with concurrent infection occurred in 11 percent of patients (J Clin Oncol 2020;39:757-767).


How do you administer this drug?

Melflufen is given as a 40 mg intravenously infusion over 30 minutes on Day 1 of a 28-day cycle in combination with either oral/intravenous dexamethasone. No required premedications but an anti-emetic may be considered as needed.


What are common side effects (> or =10%)?


* Hematologic: anemia, thrombocytopenia, neutropenia


* Cardiovascular: edema


* Central nervous system: headache, dizziness


* GI: diarrhea, nausea, constipation, vomiting


* General: fatigue, decreased appetite


* Endocrine & Metabolic: hypokalemia, hypocalcemia


* Neuromuscular & Skeletal: myalgia, arthralgia, pain


* Respiratory: dyspnea, cough


* Infectious: respiratory tract, pneumonia


What are the uncommon side effects?

Additional side effects included hypersensitivity reaction (7%), febrile neutropenia (6), sepsis (3.8%), Grade 3 or 4 hemorrhage (3.8%).


Are there any important drug interactions?

There are no metabolism or transport effects associated with melflufen, but other drugs causing immunosuppression should be avoided.


How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no known renal or hepatic dose adjustments. It hasn't been studied in patients with creatinine clearance less than 45mL/min or moderate-severe hepatic dysfunction.


Practical tips


* Ensure platelets are greater than 50,000 and absolute neutrophil count is greater than 1,000 prior to each dose of melflufen. Hold and monitor counts weekly until resolution then resume at same or reduced dose based on duration of interruption.


* Melflufen degrades rapidly at room temperature. The infusion of diluted solution must start within 60 minutes of reconstitution.


* Patients should contact their health care provider if they experience any of the following:


- Any signs or symptoms of bleeding or infection


- This drug may cause embryo-fetal harm. Effective birth control should be utilized during and after treatment.


What else should I know?


* Secondary cancers such as myelodysplastic syndrome or acute leukemia have occurred. Patients should be aware and monitored for development of secondary malignancies.


* Any grade infections were reported in 58 percent of patients-consider use of antimicrobials as clinically appropriate.


What useful links are available regarding melphalan flufenamide?


* Prescribing Information:


* Drug Information:


Any ongoing clinical trials?

Clinical trials with melflufen are investigating its role in the treatment of patients with amyloidosis, and in combination with other agents such as daratumumab, bortezomib, or pomalidomide for RRMM. More information is available at


KENDALL C. SHULTES, PHARMD, BCOP, is Clinical Pharmacist Specialist at the VA Tennessee Valley Healthcare System, Nashville, Tenn. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

Kendall C. Shultes, ... - Click to enlarge in new windowKendall C. Shultes, PharmD, BCOP. Kendall C. Shultes, PharmD, BCOP
Janelle E. Mann, Pha... - Click to enlarge in new windowJanelle E. Mann, PharmD, BCOP. Janelle E. Mann, PharmD, BCOP
Ramaswamy Govindan, ... - Click to enlarge in new windowRamaswamy Govindan, MD. Ramaswamy Govindan, MD