Melphalan

Melphalan is a bifunctional alkylating agent of the nitrogen mustard (bischloroethylamine) type. It is cytotoxic, immunosuppressive and myeloablative, and dose-limiting bone marrow suppression is its main toxicity.

Mechanism of Action

• DNA alkylation: each of the two bis-2-chloroethyl groups forms a carbonium intermediate that binds covalently to the 7-nitrogen of guanine. This cross-links the two DNA strands and prevents the separation and replication of DNA.
• Wider damage: it can also cross-link DNA to protein and damage RNA, proteins and lipids. It is cytotoxic to both resting and rapidly dividing tumour cells.
• Cell uptake: it is believed to enter tumour cells through a neutral amino acid transport pathway shared with leucine.
• Genotoxicity: it produces chromosome aberrations, is mutagenic and is potentially leukaemogenic.

Pharmacokinetics

• Absorption: oral absorption is highly variable, both in the time to first appearance in plasma and in peak concentration; mean absolute bioavailability ranged from 56% to 85%. Intravenous administration avoids this variability. A high-fat meal may lower oral exposure (by about 36–54% in one report).
• Distribution: distributed in most tissues. Plasma protein binding is moderate (69–78%), mainly to albumin (about 55–60% of the binding) and α1-acid glycoprotein (about 20%), with an irreversible component from alkylation of plasma proteins. Binding is linear at standard doses but may become concentration-dependent at high-dose levels. The volume of distribution at steady state was 40.2 L in patients given 70–200 mg/m². Penetration of the blood–brain barrier is limited: cerebrospinal fluid levels were about 10% of plasma levels in one high-dose study in children.
• Metabolism: mainly by spontaneous chemical hydrolysis to the inactive monohydroxymelphalan and dihydroxymelphalan. Spontaneous degradation, rather than enzymes, is the main determinant of its half-life.
• Elimination: very rapid. After 70–200 mg/m² as a 2–20-minute infusion the mean initial and terminal half-lives were 8.8 and 73.1 minutes; after 140 mg/m² with forced diuresis they were 6.5 and 41.4 minutes.
• Special populations: clearance may be reduced in renal impairment. In the data cited in the Melfalán Aspen SmPC, age did not correlate with clearance or terminal half-life.

Melphalan is authorised in the EU as several products with different indications.

• Phelinun (centrally authorised)
  • High-dose treatment, alone or in combination with other cytotoxic medicinal products and/or total body irradiation: multiple myeloma, malignant lymphoma (Hodgkin and non-Hodgkin), acute lymphoblastic and myeloblastic leukaemia, childhood neuroblastoma, ovarian cancer and mammary adenocarcinoma.
  • In adults, in combination with other cytotoxic medicinal products, as reduced-intensity conditioning (RIC) before allogeneic haematopoietic stem cell transplantation (allo-HSCT) in malignant haematological diseases.
  • In children, in combination with other cytotoxic medicinal products, as conditioning before allo-HSCT in haematological diseases: myeloablative conditioning (MAC) in malignant diseases, and RIC in non-malignant diseases.
• Melfalán Aspen 50 mg injection (Spain)
  • By regional arterial perfusion: localised malignant melanoma of the limbs and localised soft-tissue sarcoma of the limbs.
  • At conventional intravenous dose: multiple myeloma, alone or with other cytotoxic medicinal products (as effective as the oral formulation), and advanced ovarian cancer, alone or with other cytotoxic medicinal products.
  • At high intravenous dose: multiple myeloma, with or without haematopoietic stem cell transplantation, as first-choice treatment or to consolidate the response to conventional cytoreductive chemotherapy; and advanced childhood neuroblastoma, with stem cell transplantation, alone or with radiotherapy and/or other cytotoxic medicinal products, to consolidate the response to conventional treatment.
• Alkeran 2 mg tablets (Spain)
  • Multiple myeloma and advanced ovarian adenocarcinoma.
  • Advanced breast carcinoma, alone or in combination with other drugs, where a significant therapeutic effect is seen in a proportion of patients.
  • Polycythaemia rubra vera (it may be used in its management).

• Hypersensitivity to melphalan or to any of the excipients (all products).
• Breastfeeding (all products).
• Pregnancy, for Phelinun used before haematopoietic stem cell transplantation, because transplantation is contraindicated in pregnant women.

Bone marrow depression is the dominant effect, with gastrointestinal toxicity close behind. The Melfalán Aspen and Alkeran SmPCs note that current clinical documentation is not available to determine frequencies, and that incidence varies with dose and with the medicines combined. The groups below follow their tables.

Very common (≥1/10): bone marrow depression leading to leukopenia, thrombocytopenia, neutropenia (tablets) and anaemia; nausea, vomiting and diarrhoea (with the injection at high doses); stomatitis at high doses; alopecia at high doses; pyrexia; with the injection also muscle atrophy, muscle fibrosis, myalgia, raised creatine phosphokinase, and transient sensations of warmth and/or paraesthesia at the application site.

Common (≥1/100 to <1/10): alopecia at conventional doses; raised blood urea; compartment syndrome (injection).

Rare (≥1/10,000 to <1/1,000): haemolytic anaemia; hypersensitivity (urticaria, oedema, skin rashes, anaphylactic shock); interstitial lung disease and pulmonary fibrosis, including fatal cases; stomatitis at conventional doses; liver disorders from abnormal liver tests to hepatitis and jaundice, and hepatic veno-occlusive disease after high-dose treatment (injection); maculopapular rash and pruritus.

Not known: secondary acute myeloid leukaemia and myelodysplastic syndrome; acute kidney injury; azoospermia and amenorrhoea; deep vein thrombosis and pulmonary embolism; muscle necrosis and rhabdomyolysis (injection).

In the transplant conditioning setting (Phelinun), the most frequently reported reactions were haematological and gastrointestinal toxicities and immune system disorders, expected consequences of myelosuppression. Infections and acute and chronic graft-versus-host disease were the main causes of illness and death after allogeneic transplantation. Bone marrow failure, stomatitis, mucosal inflammation, gastrointestinal haemorrhage, diarrhoea, nausea, vomiting, amenorrhoea, ovarian disorders and premature menopause were also commonly reported. The Phelinun table lists further reactions, among them hepatic veno-occlusive disease, thrombotic microangiopathy, haemorrhagic cystitis, interstitial lung disease, idiopathic pneumonia syndrome, cardiac failure, cardiomyopathy and intracranial haemorrhage; see the SmPC for their frequencies.

• Nalidixic acid: high-dose intravenous melphalan given with nalidixic acid caused haemorrhagic enterocolitis with fatal outcome in children. Avoid the combination.
• Busulfan: in children on a busulfan–melphalan regimen, giving melphalan less than 24 hours after the last oral busulfan dose may influence toxicity.
• Ciclosporin: impaired renal function has been described in bone marrow transplant patients conditioned with high-dose intravenous melphalan who then received ciclosporin to prevent graft-versus-host disease.
• Live attenuated vaccines: a risk of generalised illness, which may be fatal, particularly in patients already immunosuppressed. Use an inactivated vaccine where one exists (for example against poliomyelitis).
• Lenalidomide, thalidomide, prednisone, dexamethasone: these combinations raise the risk of venous thromboembolism, and with lenalidomide or thalidomide plus prednisone the leukaemogenic risk (see Special Instructions).
• Combined oral contraceptives: not recommended during these combinations because of the higher thromboembolic risk. The Melfalán Aspen SmPC advises switching to another effective method, for example desogestrel-type progestogen-only pills or a barrier method.

Melphalan is a cytotoxic medicine that should be prescribed and supervised only by physicians experienced in treating malignant disease with such agents; Phelinun also calls for experience in conditioning before stem cell transplantation. High-dose treatment is restricted to specialised centres. Blood counts must be checked frequently, and treatment is interrupted temporarily if the white cell or platelet count falls abnormally.

Phelinun (Centrally Authorised Injection)

• Adults, high-dose treatment (multiple myeloma, lymphoma, acute leukaemia, ovarian cancer, mammary adenocarcinoma): one dose of 100–200 mg/m² body surface area (about 2.5–5.0 mg/kg), which may be divided equally over 2 or 3 consecutive days. Autologous haematopoietic stem cell transplantation is required after doses above 140 mg/m².
• Adults, before allogeneic transplantation (malignant haematological diseases): 140 mg/m² as a single daily infusion, or 70 mg/m² once daily for two consecutive days.
• Children, high-dose treatment of acute lymphoblastic and myeloblastic leukaemia: the same 100–200 mg/m² schedule, with autologous transplantation required above 140 mg/m².
• Children, neuroblastoma: one dose of 100–240 mg/m² (sometimes divided equally over 3 consecutive days) with autologous transplantation, to consolidate a response to conventional treatment, alone or with radiotherapy and/or other cytotoxic medicinal products.
• Children, before allogeneic transplantation: 140 mg/m² as a single daily infusion in malignant haematological diseases; 140 mg/m² as a single daily infusion or 70 mg/m² once daily for two consecutive days in non-malignant haematological diseases.

Melfalán Aspen 50 mg (Injection, Spain)

• Multiple myeloma: used intermittently, alone or with other cytotoxic medicinal products. In combination, 8–30 mg/m² every 2–6 weeks; several regimens add prednisone. Alone, typically 0.4 mg/kg (16 mg/m²) intravenously, repeated at suitable intervals (for example every four weeks) once blood counts have recovered. High-dose regimens usually use 100–200 mg/m² (about 2.5–5.0 mg/kg), with stem cell rescue essential above 140 mg/m².
• Advanced ovarian adenocarcinoma: alone, often 1 mg/kg (about 40 mg/m²) every 4 weeks; with other cytotoxic medicinal products, 0.3–0.4 mg/kg (12–16 mg/m²) every 4–6 weeks.
• Malignant melanoma and soft-tissue sarcoma of the limbs: hyperthermic regional perfusion, as an adjunct to surgery (and palliatively in advanced but localised melanoma); sarcoma regimens may add actinomycin D. Typical doses are 0.6–1.0 mg/kg for the upper limb, and 0.8–1.5 mg/kg (melanoma) or 1–1.4 mg/kg (sarcoma) for the lower limb. The SmPC refers to the literature for the perfusion technique.
• Advanced childhood neuroblastoma: doses including 100 and 240 mg/m² (sometimes divided equally over 3 consecutive days) with stem cell rescue, alone or with radiotherapy and/or other cytotoxic medicinal products. Conventional-dose melphalan is rarely indicated in children and no dosing guidance can be given.

Alkeran 2 mg Tablets (Spain)

• Multiple myeloma: a typical oral regimen is 0.15 mg/kg per day in divided doses for 4 days, repeated every six weeks; many other schedules are used. Oral Alkeran with prednisone may be more effective than Alkeran alone and is usually given intermittently. Continuing beyond one year in responders does not seem to improve the result.
• Advanced ovarian adenocarcinoma: 0.2 mg/kg per day orally in divided doses for 5 days, repeated every 4–8 weeks or as soon as the bone marrow has recovered.
• Breast carcinoma: 0.15 mg/kg or 6 mg/m² per day for 5 days, repeated every 6 weeks; the dose is reduced if bone marrow toxicity appears.
• Polycythaemia rubra vera: 6–10 mg daily for 5–7 days to induce remission, then 2–4 mg daily until the disease is satisfactorily controlled; maintenance is 2–6 mg once a week. Continuous dosing can cause severe myelosuppression, so frequent blood counts and dose adjustment or interruption are essential.
• Oral absorption varies, and the dose may need to be raised with care until myelosuppression shows that potentially therapeutic levels are reached. The tablets are rarely indicated in children and no absolute dosing guidance can be given.

Thromboprophylaxis with Combination Regimens

When melphalan is combined with lenalidomide and prednisone, with thalidomide and prednisone, or with dexamethasone, the risk of venous thromboembolism rises. Thromboprophylaxis should be given for at least the first 5 months, especially to patients with extra risk factors, after careful assessment of each patient. If a thromboembolic event occurs, treatment is stopped and standard anticoagulation started; once the patient is stable and complications are controlled, the combination can be restarted at the initial dose after a benefit–risk assessment, with anticoagulation continued throughout.

Special Populations

• Elderly: no specific dose recommendation; conventional doses are often used. Experience with high-dose melphalan is limited, so check performance status and organ function first.
• Renal impairment: clearance may fall. For the Melfalán Aspen injection, reduce the initial dose by 50% in moderate to severe impairment and set later doses by haematological response. For high-dose treatment without stem cell rescue in moderate impairment (creatinine clearance 30–50 mL/min) a 50% reduction is usual, and doses above 140 mg/m² without stem cell rescue should not be used in more severe impairment. High-dose treatment with stem cell rescue has been used successfully even in dialysis-dependent patients with end-stage renal failure. For the Alkeran tablets, the data do not justify a firm dose reduction, but a lower starting dose may be appropriate until tolerance is established.
• Hepatic impairment: for Phelinun, no adjustment in mild impairment; data in moderate or severe impairment are insufficient.

Method of Administration and Handling

• Injectable melphalan is given intravenously (by regional arterial perfusion for limb melanoma and sarcoma with Melfalán Aspen). It must not be injected directly into a peripheral vein.
• The 5 mg/mL solution is injected slowly into the port of a fast-running infusion or through a central venous catheter; if that is unsuitable, it is diluted further in 0.9% sodium chloride in an infusion bag. Dextrose solutions are incompatible. A central line is recommended for high doses, with or without transplantation, and when venous access is poor.
• Diluted melphalan is unstable. At about 25 °C the total time from preparation to the end of the infusion must not exceed 1 hour 30 minutes, and cloudy or crystallised solutions must be discarded.
• Ensure good hydration and forced diuresis, with anti-infective prophylaxis (bacterial, fungal, viral) and blood products as needed after high doses. Cyclophosphamide pre-treatment appears to reduce the gastrointestinal damage from high-dose melphalan, and immunosuppressive therapy after transplantation can prevent graft-versus-host disease.
• Cytotoxic solutions must be prepared by qualified healthcare professionals trained in alkylating agents, under conditions that protect staff and environment. Handle excreta and vomit with care; pregnant staff should avoid handling the product. After skin contact wash thoroughly with soap and water; after eye or mucous membrane contact rinse with plenty of water. Avoid inhalation, and dispose of remnants and materials as cytotoxic waste.

Bone Marrow Suppression

Melphalan is a potent myelosuppressive agent, so blood counts must be monitored carefully to avoid excessive myelosuppression and the risk of irreversible bone marrow aplasia or failure. Counts can keep falling after treatment stops, so interrupt treatment at the first sign of an abnormally large fall in white cells or severe thrombocytopenia. Use with caution after recent radiotherapy or chemotherapy, which increases bone marrow toxicity. After high doses, precautions against tumour lysis syndrome are advised.

Extravasation and Tissue Damage

Melphalan can cause local tissue damage if it leaks out of the vein, so it must not be given by direct injection into a peripheral vein. Take care to avoid extravasation where venous access is poor, and consider a central line.

Hepatic Veno-Occlusive Disease and Gastrointestinal Toxicity

Hepatic veno-occlusive disease is a major complication of melphalan treatment. With high intravenous doses and autologous marrow transplantation, diarrhoea, vomiting and stomatitis become dose-limiting.

Mutagenicity and Secondary Malignancy

Melphalan is mutagenic in animals and chromosome aberrations have been seen in treated patients. It is leukaemogenic: acute leukaemia and myelodysplastic syndromes have been reported after treatment of diseases such as amyloidosis, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer. The risk must be weighed against the benefit, especially in combination with thalidomide or lenalidomide and prednisone, which increase it. Alkylating agents have also been linked to second primary solid tumours, mainly in elderly patients with newly diagnosed myeloma given lenalidomide and prednisone, and less so with thalidomide and prednisone. Patients should have the usual checks to detect cancer early before, during and after treatment.

Live Vaccines

Vaccination with live attenuated vaccines can cause serious infection in immunosuppressed patients and is not recommended.

Pregnancy, Breastfeeding and Fertility

• Contraception: male and female patients should use effective, reliable contraception until six months after treatment ends.
• Pregnancy: there are few or no data. Animal studies showed reproductive toxicity, and because of its mutagenic properties and structural similarity to known teratogens, melphalan may cause congenital malformations. Anticancer use should be avoided in pregnancy whenever possible, particularly in the first trimester, and the benefit must outweigh the risk to the foetus.
• Breastfeeding: contraindicated.
• Fertility: melphalan suppresses ovarian function in premenopausal women, causing amenorrhoea in many. Animal studies show an adverse effect on spermatogenesis, so temporary or permanent sterility is possible in men; storing semen before treatment is advised.

Excipients

Reconstituted Phelinun contains sodium (15.63 mg in the 50 mg vial, 62.52 mg in the 200 mg vial), ethanol (400 mg and 1.6 g) and propylene glycol (6.2 g and 24.9 g). The alcohol is likely to affect children and adolescents. After reconstitution a Melfalán Aspen vial contains 46 mg (2 mmol) of sodium, ethanol and 6.0 mL of propylene glycol. The excipients of the Alkeran tablets are listed in its SmPC.

Effect on Driving

Phelinun has a moderate influence: nausea and vomiting may affect the ability to drive and use machines.

• Phelinun: do not refrigerate. Keep the vials in the outer carton to protect them from light. The reconstituted solution must not be refrigerated, because this causes precipitation.
• Melfalán Aspen 50 mg: store below 30 °C, in the outer carton to protect from light.
• Alkeran tablets: store in a refrigerator (2–8 °C), and keep the cold chain during transport and storage.

• Phelinun 50 mg and 200 mg: 3 years for the unopened vial. After reconstitution and dilution, stability has been shown for 1 hour 30 minutes at 25 °C, so the total time from reconstitution and dilution to the end of the infusion must not exceed 1 hour 30 minutes; the product should be used immediately.
• Melfalán Aspen 50 mg: 3 years for the closed vial. Once reconstituted it must be used immediately and any unused portion discarded.
• Alkeran tablets: 3 years.

Prescription only (Rx), on the prescription of specialists experienced in treating malignant disease; Phelinun is subject to restricted medical prescription. The injectable products (Phelinun and Melfalán Aspen) are given in hospital, with high-dose and conditioning treatment in specialised centres, so they are supplied to the hospital that administers them. Alkeran tablets are taken at home and are supplied to the patient or the treating clinic on prescription, with cold-chain delivery (2–8 °C).