Melphalan

Usage

• Melphalan is prescribed for the palliative treatment of multiple myeloma and nonresectable epithelial ovarian carcinoma. It is also used in high doses as a conditioning treatment prior to hematopoietic stem cell transplantation for multiple myeloma and other malignancies. It has been used in hyperthermic isolated limb perfusion for melanoma and soft tissue sarcoma. It is also used to treat AL amyloidosis.
• Pharmacological classification: Alkylating antineoplastic agent.
• Mechanism of Action: Melphalan acts as a bifunctional alkylating agent, crosslinking DNA strands, thereby inhibiting DNA replication and RNA synthesis, which ultimately leads to cell death. Its action primarily targets rapidly dividing cells, including cancer cells.

Alternate Names

• Alkeran (brand name), L-PAM, L-phenylalanine mustard, phenylalanine mustard, L-sarcolysin.

How It Works

• Pharmacodynamics: Melphalan exerts its cytotoxic effect by alkylating DNA, which disrupts cell division and leads to apoptosis (programmed cell death) of malignant cells.
• Pharmacokinetics:
  • Absorption: Oral absorption is variable and incomplete. IV administration bypasses absorption issues.
  • Metabolism: Primarily metabolized in the liver to less active metabolites.
  • Elimination: Excreted primarily through the kidneys.
• Mode of Action: Melphalan forms covalent bonds with DNA, primarily at the N7 position of guanine. This crosslinking prevents DNA replication and transcription, leading to cell cycle arrest and apoptosis.
• Receptor Binding/Enzyme Inhibition: No specific receptor binding; acts directly on DNA.
• Elimination Pathways: Primarily renal excretion with some hepatic metabolism.

Dosage

Standard Dosage

Adults:

• Multiple Myeloma (Oral):
  • 6 mg orally once daily for 2-3 weeks, followed by a rest period of up to 4 weeks, or 0.15 mg/kg/day for 7 days followed by maintenance dosing of 2 mg daily or 0.05 mg/kg/day. May also be given in combination with other medications.
• Multiple Myeloma (IV): 16 mg/m² IV over 15-20 minutes every 2 weeks for 4 doses, then every 4 weeks. High-dose regimens (100-200 mg/m²) are used prior to stem cell transplantation.
• Ovarian Cancer (Oral): 0.2 mg/kg/day for 5 days, repeated every 4-5 weeks.

Children:

• Dosing is based on body surface area (BSA) and specific protocols, usually in conjunction with stem cell transplantation. Generally not indicated for standard treatment in children.

Special Cases:

• Elderly Patients: Start at the lower end of the dosing range and monitor closely for myelosuppression and other toxicities.
• Patients with Renal Impairment: Reduce dosage based on the degree of impairment.
• Patients with Hepatic Dysfunction: No specific dose adjustments are typically recommended, but close monitoring is advised.
• Patients with Comorbid Conditions: Adjust dosage based on individual patient factors.

Clinical Use Cases

Melphalan is primarily used for systemic chemotherapy and not typically for the specific medical settings listed below (Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit [ICU] Use, Emergency Situations). For regional perfusion of the limbs in melanoma and sarcoma, please refer to the literature.

Dosage Adjustments

Adjustments are based on hematologic toxicity, renal function, and other patient-specific factors.

Side Effects

Common Side Effects

• Myelosuppression (leukopenia, thrombocytopenia, anemia)
• Nausea, vomiting, diarrhea
• Mucositis (oral sores)
• Alopecia (hair loss)
• Fatigue

Rare but Serious Side Effects

• Hypersensitivity reactions (including anaphylaxis)
• Secondary malignancies (leukemia, MDS)
• Pulmonary toxicity
• Cardiac toxicity
• Hepatotoxicity

Long-Term Effects

• Infertility
• Increased risk of secondary cancers

Adverse Drug Reactions (ADR)

• Severe myelosuppression
• Anaphylaxis
• Pulmonary fibrosis

Contraindications

• Prior resistance to melphalan
• Hypersensitivity to melphalan or any component of the formulation
• Severe bone marrow suppression

Drug Interactions

• Immunosuppressants (e.g., cyclosporin): Increased risk of toxicity.
• Live vaccines: Avoid concomitant use.
• Nalidixic acid: Increased risk of gastrointestinal toxicity.
• CYP450 interactions: Potential for interaction with drugs metabolized by CYP450 enzymes.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (FDA Classification)
• Fetal risks: Teratogenic; can cause fetal harm.
• Breastfeeding: Contraindicated.

Drug Profile Summary

See above sections for details.

Popular Combinations

• Melphalan is commonly used in combination with prednisone and thalidomide (MPT) for multiple myeloma.

Precautions

See above sections for details regarding precautions during pregnancy and breastfeeding. Monitor blood counts regularly. Avoid live vaccines. Counsel patients on reproductive risks. Patients should use reliable barrier contraception. Counsel patients regarding potential for long-term side effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Melphalan?

A: The dosage varies depending on the indication, route of administration, and patient factors. Refer to the detailed dosage section above.

Q2: What are the most common side effects of Melphalan?

A: Myelosuppression (decreased blood cell counts), nausea, vomiting, mucositis (oral sores), and alopecia (hair loss) are the most common side effects.

Q3: How does Melphalan work against cancer?

A: It crosslinks DNA, preventing cancer cells from replicating and leading to cell death.

Q4: Can Melphalan be used during pregnancy?

A: No, Melphalan is contraindicated during pregnancy due to the risk of fetal harm.

Q5: What precautions should be taken in patients with renal impairment?

A: Dosage adjustments are necessary based on creatinine clearance. Consider a dose reduction in moderate to severe renal impairment.

Q6: Are there any specific monitoring parameters for Melphalan?

A: Regularly monitor complete blood counts (CBC) including white blood cells, red blood cells, and platelets due to myelosuppressive effects. Liver and kidney function tests should also be monitored.

Q7: How is Melphalan administered?

A: It can be given orally as a tablet, intravenously, or via regional perfusion. Intravenous administration is through a central venous catheter for high dose therapy or peripheral vein for conventional doses.

Q8: Is there a risk of secondary cancers with Melphalan?

A: Yes, there is an increased risk of secondary malignancies, especially acute leukemia and myelodysplastic syndrome (MDS).

Q9: What should patients be advised regarding fertility?

A: Melphalan can cause infertility in both men and women. Sperm banking and oocyte or embryo cryopreservation should be discussed prior to starting therapy.

Q10: Are there any drug interactions I should be particularly aware of?

A: Concomitant use of cyclosporin and nalidixic acid can lead to increased toxicity. Concomitant administration of live vaccines should be avoided.