1. Melaragno, Adam PHARMD, BCOP

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What is propylene glycol-free melphalan?

A new formulation of melphalan that uses a modified cyclodextrin, Captisol(R), instead of propylene glycol, to improve stability and potentially avoid toxicities associated with propylene glycol.


How does propylene glycol-free melphalan work?

Melphalan is an alkylating agent, inhibiting DNA synthesis by cross-linking DNA strands. It acts on resting and dividing tumor cells.


What is this approved for?

This formulation of melphalan is approved for conditioning chemotherapy for multiple myeloma patients undergoing autologous stem cell transplant, as well as palliative chemotherapy for multiple myeloma when oral therapy is not feasible.


What is the basis for this approval?

Propylene glycol-free melphalan was FDA-approved based on a phase IIa bioequivalence crossover study, as well as a phase IIb, open-label, multi-center study. This single-arm study administered propylene glycol-free melphalan 100 mg/m2 on 2 consecutive days, followed by autologous stem cell transplantation. All 61 patients achieved myeloablation, as well as neutrophil and platelet engraftment at a median of 12 and 13 days post-transplant, respectively. Blinded, independent response evaluation revealed a 100 percent overall response. No patients experienced treatment-related mortality at 100 days. Grade 3 mucositis occurred in 10 percent of patients, and no patients experienced grade 4 mucositis. Overall, the efficacy and safety outcomes appear similar to those using conventional melphalan (Biol Blood Marrow Transplant 2015;21:2100-2105).


How do you administer this drug?

As part of conditioning chemotherapy, this formulation should be administered at a dose of 100 mg/m2 for 2 consecutive days as a 30-minute infusion. For palliative chemotherapy, the dose is 16 mg/m2 every 2 weeks for four doses, followed by every 4 weeks thereafter, given as a 15-20 minute infusion.


Are there any premedications needed?

Melphalan is considered moderately emetogenic and, therefore, patients should receive appropriate prophylaxis with combination antiemetics.


What are the common side effects associated with propylene glycol-free melphalan (> or =10%)?

The most common toxicities reported with melphalan are GI related including nausea, vomiting, mucositis, diarrhea, and decreased appetite. Hematologic toxicities including neutropenia, thrombocytopenia, and anemia are expected. Incidence appears to be similar between traditional melphalan and propylene glycol-free melphalan; however, they have never been directly compared.


What are the uncommon side effects associated with propylene glycol-free melphalan (less than 10%)?

Less frequent toxicities include hypersensitivity reactions, transaminitis, secondary malignancies, cardiac arrhythmias, and hyper- or hypotension.


Are there any important drug interactions I should be aware of?

No drug interactions have been identified due to metabolism or transport effects. However, melphalan is expected to decrease the efficacy of any therapies requiring an immune response, such as vaccines.


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

Dose reductions are not necessary for renal dysfunction. However, many transplant centers dose reduce to 140 mg/m2 (70 mg/m2/dose) in patients with severe renal impairment due to increased toxicity.


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

No adjustments are required for hepatic insufficiency.


Practical tips

The major proposed advantage compared to conventional melphalan is the 4-hour stability once diluted in NS to a concentration of 0.45 mg/mL. The powder is also reconstituted with NS instead of a propylene glycol/alcohol solution, which may avoid associated toxicities including nephrotoxicity, metabolic acidosis, and arrhythmias.


A proposed disadvantage of the new product is the need to dilute to a final concentration of 0.45 mg/mL. Many transplant centers administer melphalan as a single dose of 200 mg/m2, which would not be feasible at this final concentration due to large volumes. However, extended stability has been reported, but not endorsed by the package insert (Pharm Dev Technol 2016;1-6).


What should my patients know about propylene glycol-free melphalan?

Patients may be instructed to suck on ice chips during and after the melphalan infusion to decrease the incidence and severity of mucositis.


What else should I know about propylene glycol-free melphalan?

Although not FDA-approved, propylene glycol-free melphalan also has been used in lymphoma patients undergoing autologous transplant using the preparative regimen BEAM (carmustine, etoposide, cytarabine, melphalan). The single-arm, phase II study found an expected toxicity and efficacy profile similar to that of conventional melphalan (Biol Blood Marrow Transplant 2016;22:2155-2158).


What useful links are available regarding propylene glycol-free melphalan?






Any ongoing clinical trials related to propylene glycol-free melphalan?

A study is planned using propylene glycol-free melphalan for conditioning chemotherapy for amyloidosis patients undergoing stem cell transplantation.


ADAM MELARAGNO, PHARMD, BCOP, is Clinical Pharmacy Specialist, Blood and Marrow Transplant, University of Rochester Medical Center, Rochester, N.Y. Oncology Times Clinical Advisory Editor RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor.

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