Melphalan: Alkylating Cytostatic Agent in Multiple Myeloma
Melphalan is an alkylating cytostatic agent from the group of nitrogen mustard derivatives. Known trade names are Alkeran (oral and intravenous) and Evomela (lyophilized for infusion). Since its first use in the 1960s, melphalan has been a cornerstone of multiple myeloma therapy and is indispensable in hematologic oncology. In the high-dose setting, it is primarily used as conditioning therapy before autologous stem cell transplantation (HD MEL ASCT).
Melphalan was the first cytostatic agent proven to prolong survival in multiple myeloma. Even in the era of new active substances such as lenalidomide, bortezomib, daratumumab, and carfilzomib, melphalan remains a standard component of modern combination therapies (VMP, MPT) and is practically irreplaceable in high-dose conditioning.
Mechanism of Action
Melphalan is a bifunctional alkylating agent that forms active aziridinium intermediates in the cell. These react with nucleophilic sites on DNA, especially at the N7 position of guanine. Monofunctional adducts form, but more importantly, DNA interstrand crosslinks form between DNA strands, which block replication and transcription.
In the activated tumor cell clone of multiple myeloma (terminal plasma cells with high protein synthesis), this DNA damage leads to cell death via apoptosis. Since melphalan penetrates all proliferating cells, bone marrow, mucous membranes, and germ cells are also affected, which explains the toxicity.
Oral absorption of melphalan shows great interindividual variation (25 to 90 percent bioavailability), which is why intravenous administration is standard in high-dose conditioning. Half-life approximately 90 minutes, elimination both renal and through spontaneous hydrolysis in plasma.
Indications
- Multiple myeloma: combined with prednisone (MP), thalidomide (MPT), bortezomib (VMP) in patients not eligible for transplantation
- High-dose therapy as conditioning before autologous stem cell transplantation (HD MEL): standard for transplant-eligible patients with multiple myeloma and plasmacytoma
- AL amyloidosis: high-dose before autologous SCT, low-dose combined with dexamethasone
- Ovarian carcinoma: historical, replaced by platinum-based therapies
- Breast carcinoma and testicular carcinoma: rare, off-label in relapse setting
- Isolated limb perfusion (ILP) in sarcomas or melanoma: in specialized centers
Dosage and Administration
MP regimen in multiple myeloma: melphalan 0.15 to 0.25 mg/kg/day orally on days 1 to 4, cycles every 4 to 6 weeks. VMP regimen: melphalan 9 mg/m² orally plus bortezomib subcutaneously and prednisone.
High-dose therapy HD MEL: 200 mg/m² intravenously as single infusion on day minus 2 before autologous stem cell reinfusion. In renal insufficiency or elderly patients, the dose is reduced to 140 mg/m².
Renal insufficiency: reduce dose by 30 to 50 percent if eGFR below 30 ml/min. Hypothermia of oral mucosa (ice chips): during infusion in high-dose therapy demonstrably reduces mucositis severity through local vasoconstriction.
Side Effects
Very frequent: bone marrow suppression with neutropenia (nadir after 10 to 21 days), thrombocytopenia and anemia; gastrointestinal mucositis (mouth, esophagus, stomach, intestine), nausea, vomiting, diarrhea; alopecia reversible.
Frequent: susceptibility to infection, especially during neutropenic phase; skin reactions, hyperpigmentation; taste changes.
Serious, long-term: secondary malignancies, especially acute myeloid leukemia and myelodysplastic syndrome (risk approximately 2 to 8 percent after high-dose therapy); infertility in men and women; pulmonary fibrosis; veno-occlusive disease of the liver (VOD/SOS) after high-dose therapy.
Important: in high-dose therapy, close inpatient care with antibiotics, blood transfusion, and parenteral nutrition is required. Mucositis can make swallowing and speaking impossible for days.
Drug Interactions
- Cyclosporine: increased nephrotoxicity, caution with concomitant medication
- Other myelotoxic agents: additive bone marrow suppression
- Live vaccines: contraindicated during and for several months after therapy
- Nalidixic acid and carmustine: increased risk of hemorrhagic necrotic enterocolitis
- Radiotherapy: additive bone marrow suppression and mucositis
Special Notes
Pregnancy and lactation: contraindicated. Melphalan is teratogenic, mutagenic, and carcinogenic. Safe contraception during and for at least six months after therapy is required for both men and women. Before starting therapy, family planning discussion and possibly cryopreservation of sperm or oocytes should be performed.
High-dose therapy and stem cell transplantation: conditioning with HD MEL takes place exclusively in specialized transplant centers. Patients require comprehensive information about the course, complications, approximately 1 to 3 percent therapy-related mortality in younger patients and higher in older patients.
Before each cycle: complete blood count with differential, creatinine, liver transaminases. Therapy interruption or dose reduction if neutrophils below 1,500/microliter or platelets below 100,000/microliter.
Secondary malignancies: patients after melphalan high-dose therapy require long-term hematologic follow-up, as secondary AML/MDS can occur up to ten years after therapy.
You might also be interested in
- Bortezomib, proteasome inhibitor in combination therapy
- Lenalidomide, immunomodulator in multiple myeloma
- Daratumumab, Anti-CD38 antibody
- Cyclophosphamide, another alkylating agent
- Dexamethasone, glucocorticoid in myeloma therapy
Frequently Asked Questions
How long does it take after melphalan for the blood count to recover?
At standard dose, the blood count usually recovers within 4 to 6 weeks. After high-dose therapy with subsequent stem cell reinfusion, neutrophil engraftment usually occurs after 10 to 14 days, platelets after 14 to 21 days. During this phase, close inpatient care with protective isolation and supportive therapy is necessary.
What can I do about oral mucous membrane inflammation?
Hypothermia with ice chips during high-dose infusion demonstrably reduces mucositis severity. During therapy, gentle oral hygiene with a soft toothbrush, sage or saline rinses, locally anesthetic gels as needed, and parenteral analgesics for severe mucositis help. Avoid hot, spicy, and acidic foods.
What is my risk of secondary cancer?
After melphalan high-dose therapy, the risk for secondary AML or MDS is 2 to 8 percent over ten years. The risk depends on total dose, age, and concomitant therapies. Long-term hematologic follow-up with annual blood counts is required.
Does melphalan affect my fertility?
Yes. Melphalan is gonadotoxic and can lead to temporary or permanent infertility. Before starting therapy, cryopreservation of sperm or oocytes should be considered in patients desiring children. Even with initially preserved cycles or sperm production, reproductive function is often impaired.
Sources
- EMA, Alkeran (Melphalan) EPAR
- DGHO Onkopedia, Multiple Myeloma
- Gelbe Liste, Melphalan Active Substance Profile
- BfArM, Federal Institute for Drugs and Medical Devices
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