What is the role of Melphalan in cancer treatment?

Role of Melphalan in Cancer Treatment

High-dose melphalan is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma, with strong evidence supporting its use over other conditioning regimens. 1

Primary Uses of Melphalan

• Melphalan is a bifunctional alkylating agent that causes cytotoxicity through interstrand cross-linking with DNA, primarily by binding at the N7 position of guanine, making it active against both resting and rapidly dividing tumor cells 2
• Melphalan is primarily used in the treatment of multiple myeloma, both as:
  • High-dose therapy (200 mg/m²) for conditioning before ASCT in transplant-eligible patients 1
  • Part of conventional oral combination therapy (with prednisone) for elderly or transplant-ineligible patients 1
• It has also shown activity in other malignancies including ovarian cancer, breast cancer, melanoma, and certain pediatric tumors like rhabdomyosarcoma and neuroblastoma 3, 4

Melphalan in Multiple Myeloma Treatment

For Transplant-Eligible Patients:

• High-dose melphalan (200 mg/m²) is the recommended conditioning regimen for ASCT with strong evidence supporting its efficacy 1
• Melphalan doses may be attenuated at the physician's discretion for age, frailty, obesity, or renal function 1
• Comparative studies have shown high-dose melphalan to be superior to melphalan plus total body irradiation or melphalan with other chemotherapy (e.g., busulfan, cyclophosphamide, bortezomib) 1
• Important caveat: Patients who are potential candidates for stem cell transplantation should avoid melphalan during induction therapy as it can compromise stem cell collection 1
• Alternative induction regimens using high-dose glucocorticoid-based therapies (such as VAD - vincristine, adriamycin, and dexamethasone) are preferable before stem cell collection 1

For Transplant-Ineligible Patients:

• Oral melphalan combined with prednisone has been a standard treatment since the 1960s 1, 4
• The typical regimen is melphalan 9 mg/m²/day for 4 days with prednisone 30 mg/m²/day for 4 days, repeated every 4-6 weeks until stable response 1
• More recent approaches include combining melphalan-prednisone with novel agents:
  • Bortezomib-melphalan-prednisone (MPB) has shown superior outcomes compared to melphalan-prednisone alone 1
  • Thalidomide or lenalidomide combinations with melphalan have also shown improved efficacy 4

Toxicity and Safety Considerations

• Bone marrow suppression is the most significant toxicity associated with melphalan 2
• Regular monitoring is essential:
  • Platelet count, hemoglobin, white blood cell count, and differential should be performed before each dose 2
  • Thrombocytopenia and/or leukopenia are indications to withhold therapy until blood counts recover 2
• Secondary malignancies, particularly acute nonlymphocytic leukemia and myeloproliferative syndromes, have been reported with long-term use 2
  • Risk increases with cumulative dose and treatment duration
  • 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome was 19.5% for cumulative doses ranging from 730 to 9,652 mg 2
• Hypersensitivity reactions including anaphylaxis occur in approximately 2% of patients receiving IV formulation 2
• Melphalan is teratogenic and should not be used during pregnancy (Category D) 2

Evolving Trends in Melphalan Use

• There is a trend toward reduced use of melphalan as frontline therapy in multiple myeloma due to:
  • Risk of leukemogenicity and myelosuppression 1
  • Availability of novel agents with improved efficacy and reduced toxicity 1
• Development of targeted delivery systems:
  • Melphalan conjugated to monoclonal antibodies has shown promise in reducing systemic toxicity while maintaining efficacy against target cells 5
• High-dose melphalan with ASCT remains a standard approach for eligible patients, but the treatment landscape continues to evolve with the incorporation of novel agents 4

Clinical Pearls

• Ample stem cell collection (sufficient for more than one SCT) should be considered upfront due to concern for limited ability for future collection after prolonged treatment exposure 1
• Peripheral blood is the preferred source of autologous stem cells for transplant over bone marrow 1
• The minimum number of CD34+ cells needed for successful transplantation is 2×10⁶/kg per planned transplantation 1
• For patients with renal dysfunction, melphalan doses may need to be adjusted, as impaired renal function can increase toxicity 1, 2