Melphalan

Approved Indications:

• Multiple Myeloma: Used alone or in combination with other agents for the treatment of multiple myeloma, including as part of conditioning regimens prior to autologous hematopoietic stem cell transplantation (HSCT).
• Ovarian Carcinoma: Indicated for the palliative treatment of advanced ovarian carcinoma.
• Malignant Melanoma (regional perfusion): Used in isolated limb perfusion for local control of melanoma metastases.
• Hematopoietic Stem Cell Transplant Conditioning: High-dose melphalan is used as a myeloablative agent before autologous stem cell transplantation, particularly in multiple myeloma.

Clinically Accepted Off-Label Uses:

• AL Amyloidosis
• Chronic Lymphocytic Leukemia (CLL)
• Waldenström’s Macroglobulinemia
• Low-Grade Non-Hodgkin Lymphoma
• Preparative regimens for autoimmune diseases prior to HSCT

Route of Administration: Oral and Intravenous (IV)

Adults:

• Multiple Myeloma (Oral): 0.15 mg/kg/day PO for 4 days every 6 weeks.
• Multiple Myeloma (IV): 100–200 mg/m² IV as a single dose prior to stem cell transplantation.
• Ovarian Carcinoma: 0.2 mg/kg/day IV or PO for 5 days every 4 to 6 weeks.
• HSCT Conditioning (IV): 200 mg/m² IV as a single dose or divided over 2 days.

Elderly:

• Dose reduction may be necessary due to reduced bone marrow reserve.

Renal Impairment:

• Dose adjustment recommended. Start with reduced doses and monitor hematologic toxicity closely.

Hepatic Impairment:

• No specific guidelines, but caution advised due to hepatic metabolism.

Pediatrics:

• Not routinely used outside transplant settings. Dose individualized based on body surface area and conditioning protocol.

Melphalan is a bifunctional alkylating agent of the nitrogen mustard type. It cross-links DNA strands by forming covalent bonds with nucleophilic centers, primarily at the N7 position of guanine. This results in DNA strand breakage, inhibition of DNA replication and transcription, and ultimately apoptosis. Its cytotoxic activity is cell cycle–nonspecific, though rapidly dividing cells are more susceptible to damage.

• Absorption (Oral): Rapid, but variable with 25–89% bioavailability.
• Peak Plasma Time: ~1–2 hours (oral)
• Distribution: Moderate protein binding (~60–90%); widely distributed into tissues.
• Metabolism: Hepatic and spontaneous hydrolysis; conjugation with glutathione.
• Half-life: ~1.5 to 2 hours
• Excretion: Primarily renal (unchanged and metabolites); some biliary/fecal elimination.

• Pregnancy Category: Category D (positive evidence of human fetal risk). Contraindicated during pregnancy due to risk of teratogenicity and fetal toxicity.
• Lactation: Excreted in breast milk. Breastfeeding is contraindicated during treatment and for at least one week after the last dose.

• Primary Class: Antineoplastic Agent
• Subclass: Alkylating Agent – Nitrogen Mustard Derivative

• Known hypersensitivity to melphalan or any component of the formulation
• Severe bone marrow suppression
• Active systemic infections
• Pregnancy and lactation
• Recent or ongoing vaccination with live vaccines

• Myelosuppression: Severe bone marrow suppression is dose-limiting. Regular monitoring of complete blood counts is essential.
• Infection Risk: Increased susceptibility to infections due to immunosuppression.
• Secondary Malignancies: Risk of therapy-related leukemia or myelodysplasia with long-term use.
• Pulmonary Toxicity: Rare reports of interstitial pneumonitis and pulmonary fibrosis.
• Hypersensitivity Reactions: Rare but possible; include anaphylaxis and skin reactions.
• Infertility: May cause permanent infertility in men and women.

Hematologic:

• Common: Neutropenia, thrombocytopenia, anemia
• Serious: Bone marrow aplasia, pancytopenia

Gastrointestinal:

• Nausea, vomiting, diarrhea, oral mucositis

General:

• Fatigue, malaise, anorexia

Dermatologic:

• Rash, alopecia, skin ulceration (regional perfusion use)

Respiratory (rare):

• Interstitial lung disease, pulmonary fibrosis

Others:

• Hepatotoxicity
• Secondary leukemia or myelodysplasia with prolonged use

• Other Myelosuppressive Agents: Additive hematologic toxicity.
• Live Vaccines: Avoid due to immunosuppression.
• Cyclosporine, Tacrolimus: Increased risk of nephrotoxicity and neurotoxicity.
• Nalidixic Acid (with high-dose Melphalan): May increase risk of fatal hemorrhagic colitis.
• Cimetidine: May alter melphalan bioavailability.

• Transplant Conditioning: Remains a core agent in myeloma transplant protocols. Recent studies favor split-dosing (e.g., 100 mg/m² over 2 days) to reduce mucositis without compromising efficacy.
• Combination Protocols: Emerging regimens combine melphalan with monoclonal antibodies or proteasome inhibitors.
• Guidelines: Updated NCCN and EBMT guidelines recommend individualized dosing based on renal function, performance status, and transplant eligibility.

Oral Tablets:

• Store at 2°C to 8°C (Refrigerated)
• Protect from light and moisture
• Do not freeze

IV Formulations (Lyophilized Powder):

• Store unopened vials at 20°C to 25°C
• Reconstituted solution should be used within 60 minutes
• Do not refrigerate or freeze reconstituted solution