Introduction

Antineoplastic agent; nitrogen mustard derivative alkylating agent.

Uses for Melphalan (Systemic)

Multiple Myeloma

Used alone and as a component of various chemotherapeutic regimens in the treatment of multiple myeloma. Designated an orphan drug by FDA for use in multiple myeloma.

Various preparations and formulations are commercially available; indications and dosage recommendations differ between the different preparations.

Melphalan tablets and melphalan hydrochloride for injection are indicated for the palliative treatment of multiple myeloma.

Melphalan hydrochloride for injection (Evomela) is a propylene glycol-free parenteral formulation used as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation (HSCT) in patients with multiple myeloma and also as palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

High-dose chemotherapy plus autologlous stem cell transplant (ASCT) is currently the preferred treatment of multiple myeloma in patients <65 years of age. For older patients and patients with clinically significant coexisting illnesses who are ineligible for transplant, combination treatment with newer drugs that have shown increased rates of survival are used.

A joint guideline published by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario recommends high-dose melphalan as a conditioning regimen for ASCT in transplant-eligible patients. For those who are transplant-ineligible, melphalan may be included as part of an initial combination regimen with daratumumab, bortezomib, and prednisone.

Ovarian Cancer

Palliative treatment of nonresectable epithelial ovarian cancer.

Has been administered intraperitoneally^{† [off-label]} for treatment of advanced ovarian cancer confined to the peritoneal cavity and/or associated with malignant ascites.

Platinum-based chemotherapy is currently considered the standard of care chemotherapy for the treatment of ovarian cancer.

Melanoma

Has been used alone and in combination regimens for isolated limb perfusion^{† [off-label]} or isolated limb infusion ^{† [off-label]} in patients with regionally recurrent melanoma not suitable for local or topical therapy.

Amyloidosis

Has been used with prednisone in the treatment of systemic light chain amyloidosis^{† [off-label]}.

Melphalan (Systemic) Dosage and Administration

General

Pretreatment Screening

• Perform a CBC with differential.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor platelet, neutrophil, and RBC counts at baseline, during treatment, and as clinically indicated.

• Monitor for signs and symptoms of infection.

• Monitor liver function tests.

• Perform long-term monitoring for development of secondary malignancies.

Premedication and Prophylaxis

• Consider administering an antiemetic prior to and during treatment with melphalan (Evomela) as a high-dose conditioning treatment.

Dispensing and Administration Precautions

• Employ safe handling and disposal precautions with melphalan since it is a hazardous medication.

• Avoid use of the abbreviation “MP” for melphalan and prednisone.

Other General Considerations

• Consult published protocols for information on dosage, method of administration, and administration of other antineoplastic agents used in combination regimens with melphalan.

Administration

Administer orally or by IV infusion. Has been administered by regional isolatedinfusion or perfusion^{† [off-label]} (e.g., for melanoma^†) and intraperitoneally^† (e.g., for advanced ovarian cancer).

Oral Administration

Administer continuously (as single daily doses) or intermittently (via various dosage regimens).

IV Administration

Administer IV only by individuals experienced in administration of the drug.

Parenteral preparations are commercially available as lyophilized powders that must be reconstituted and diluted prior to IV administration.

Consult published protocols for specific information on parenteral dosage regimens using IV melphalan for specific diseases.

Reconstitution and Dilution

Melphalan hydrochloride for injection: Reconstitute by adding 10 mL of the diluent provided by the manufacturer to a vial labeled as containing 50 mg of melphalan using a 20-gauge or larger needle to provide a solution containing 5 mg/mL. Dilute reconstituted dose further with 0.9% sodium chloride injection to a final concentration not exceeding 0.45 mg/mL.

Melphalan hydrochloride for injection (Evomela): Reconstitute by adding 8.6 mL of 0.9% sodium chloride injection to provide a solution containing 50 mg/10 mL (5 mg/mL). Dilute the required dose with an appropriate volume of 0.9% sodium chloride injection to a final concentration of 0.45 mg/mL.

Rate of Administration

Administer melphalan hydrochloride by IV infusion over 15–20 minutes. Complete administration within 60 minutes of reconstitution.

Infuse melphalan hydrochloride (Evomela) over 30 minutes via an injection port or a fast-running central venous catheter.

Dosage

Dosage of melphalan hydrochloride is expressed in terms of melphalan.

Adults

Multiple Myeloma

Oral

Usual initial and maintenance dosage regimen: 6 mg daily for 2–3 weeks. Withhold therapy until leukocyte and platelet counts increase (i.e., up to 4 weeks) and then initiate maintenance therapy of 2 mg daily. Adjust dosage, as required, to maintain a degree of bone marrow depression.

Alternatively, 10 mg daily for 7–10 days. Withhold therapy until platelet and leukocyte counts exceed 100,000/mm³ and 4000/mm³, respectively, and then initiate maintenance therapy of 2 mg daily. Adjust dosage, as required, to between 1–3 mg daily, depending on hematologic response.

Alternatively, 0.15 mg/kg daily for 7 days followed by a rest period of at least 14 days (or as long as 5 to 6 weeks). Maintenance therapy is initiated when the white blood cell and platelet counts are increasing, with a maintenance dose of 0.05 mg/kg/day or less, adjusted according to blood count.

Alternatively, 0.25 mg/kg daily for 4 days or 0.2 mg/kg daily for 5 days, with prednisone; administer at 4–6 week-intervals, if granulocyte and platelet counts are normal.

IV

Usual dosage: 16 mg/m² at 2-week intervals for 4 doses. After satisfactory recovery from toxicity, initiate maintenance therapy of 16 mg/m² at 4-week intervals.

Melphalan hydrochloride (Evomela) as a high-dose conditioning treatment prior to ASCT (Day 0): 100 mg/m² per day for 2 consecutive days (Day -3 and Day -2). For patients who weigh more than 130% of their ideal body weight, calculate body surface area (BSA) based on adjusted ideal body weight.

Ovarian Cancer

Oral

Usual dosage: 0.2 mg/kg daily for 5 successive days; administer at intervals of 4–5 weeks.

Dosage Modification for Toxicity

If adverse effects occur, temporarily interrupt, reduce dose, and/or permanently discontinue drug.

For oral melphalan tablets, discontinue therapy if leukocyte count falls below 3000/mm³ or platelet count falls below 100,000/mm³. May restart therapy after blood cell counts have recovered. Consider dose adjustment on the basis of blood counts at the nadir and day of treatment.

For IV melphalan hydrochloride, in some controlled clinical studies in patients with multiple myeloma, dosage reductions of 25% were employed when platelet counts were 75,000–99,999/mm³ or leukocyte counts were 3000–3999/mm³ and dosage reductions of 50% were used when platelet counts were 50,000–74,999/mm³ or leukocyte counts were 2000–2999/mm³; IV melphalan was discontinued when platelet or leukocyte counts fell below 50,000/mm³ or 2000/mm³, respectively.

Do not readminister oral or IV melphalan if a hypersensitivity reaction occurs.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

Oral

In patients with moderate to severe renal impairment, consider reducing initial dosage; however, no specific dosage recommendations.

IV

In patients with renal impairment (BUN ≥30 mg/dL), reduce dosage by 50%.

When used as a conditioning treatment (Evomela), dosage adjustment not necessary.

Geriatric Patients

No specific dosage recommendations. In general, start dose selection at low end of dosing range.

Contraindications

• Prior resistance to melphalan therapy.

• Known hypersensitivity to melphalan or any ingredient in the formulation.

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

Administer under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe bone marrow suppression with resulting infection or bleeding may occur. Hypersensitivity reactions, including anaphylaxis, have occurred. Melphalan is leukemogenic in humans. (See Boxed Warning.)

Mutagenicity and Carcinogenicity

Produces chromosomal aberrations in vitro and in vivo; considered potentially mutagenic in humans.

Sensitivity Reactions

Hypersensitivity Reactions

Acute hypersensitivity reactions, including anaphylaxis, have been reported with IV melphalan administration. Symptoms may include urticaria, pruritus, edema, and skin rash. Tachycardia, bronchospasm, dyspnea, and hypotension have also been observed. If a serious hypersensitivity reaction occurs, discontinue treatment.

Other Warnings and Precautions

Thrombocytopenia

Thrombocytopenia, which may lead to hemorrhage, occurs commonly. Frequent platelet counts are essential to determine dosage and avoid toxicity.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Consider dose adjustment on the basis of platelet counts at the nadir and day of treatment, as well as based on signs and symptoms of bleeding. Therapy may be withheld until recovery of platelet count.

Neutropenia/Leukopenia

Neutropenia/leukopenia, which may lead to infection, occurs commonly. Frequent monitoring of WBC counts essential to determine dosage and avoid toxicity.

Monitor WBC counts at baseline, during treatment, and as clinically indicated. Consider dose adjustment on the basis of WBC counts at the nadir and day of treatment. Therapy may be withheld until recovery of WBC count.

Anemia

Anemia occurs commonly. Frequent monitoring of RBC counts essential to determine dosage and avoid toxicity.

Monitor RBC counts at baseline, during treatment, and as clinically indicated. Consider dose adjustment on the basis of RBC counts. Therapy may be withheld until recovery of RBC count.

Infections

Monitor patients closely for signs and symptoms of infection and consider antimicrobials as clinically appropriate.

Secondary Malignancies

Secondary malignancies (e.g., myelodysplastic syndromes, acute leukemia) may occur. Monitor patients long-term for potential development of secondary malignancies.

GI Toxicity

Nausea, vomiting, mucositis, and diarrhea may occur. Administer prophylactic antiemetics and provide supportive care as necessary.

Hepatotoxicity

Abnormal liver function tests as well as instances of hepatitis, jaundice, and hepatic veno-occlusive disease reported. Monitor liver chemistries as appropriate.

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm. Avoid pregnancy during therapy. Advise females of reproductive potential and males with female partners of reproductive potential to use an effective method of contraception during and for a period of time after melphalan treatment.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether melphalan is distributed into human milk; breastfeeding is not recommended.

Females and Males of Reproductive Potential

Verify pregnany status prior to initiation of therapy in females of reproductive potential. Advise such females and males with female partners of reproductive potential to use effective contraception during and for a period after treatment.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

For oral melphalan, insufficient number of patients ≥65 years of age were included in studies. For IV melphalan (Evomela), no differences in safety or effectiveness observed relative to younger adults.

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment.

Renal Impairment

For oral melphalan, no specific dosage recommendations for patients with renal impairment. Consider a dose reduction in patients with renal insufficiency receiving IV melphalan for palliative treatment.

Common Adverse Effects

Adverse effects in patients receiving oral melphalan include bone marrow suppression, nausea, vomiting, diarrhea, oral ulceration, hepatic disorders, pulmonary fibrosis, interstitial pneumonitis, rash, vasculitis, alopecia, hemolytic anemia, allergic reactions.

Adverse effects (≥50%) in patients receiving IV melphalan (Evomela) include decreased neutrophil, decreased WBC counts, decreased lymphocyte counts, decreased platelet counts, diarrhea, nausea, fatigue, hypokalemia, anemia, vomiting.

General

Pretreatment Screening

• Perform a CBC with differential.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor platelet, neutrophil, and RBC counts at baseline, during treatment, and as clinically indicated.

• Monitor for signs and symptoms of infection.

• Monitor liver function tests.

• Perform long-term monitoring for development of secondary malignancies.

Premedication and Prophylaxis

• Consider administering an antiemetic prior to and during treatment with melphalan (Evomela) as a high-dose conditioning treatment.

Dispensing and Administration Precautions

• Employ safe handling and disposal precautions with melphalan since it is a hazardous medication.

• Avoid use of the abbreviation “MP” for melphalan and prednisone.

Other General Considerations

• Consult published protocols for information on dosage, method of administration, and administration of other antineoplastic agents used in combination regimens with melphalan.

Administration

Administer orally or by IV infusion. Has been administered by regional isolatedinfusion or perfusion^{† [off-label]} (e.g., for melanoma^†) and intraperitoneally^† (e.g., for advanced ovarian cancer).

Oral Administration

Administer continuously (as single daily doses) or intermittently (via various dosage regimens).

IV Administration

Administer IV only by individuals experienced in administration of the drug.

Parenteral preparations are commercially available as lyophilized powders that must be reconstituted and diluted prior to IV administration.

Consult published protocols for specific information on parenteral dosage regimens using IV melphalan for specific diseases.

Reconstitution and Dilution

Melphalan hydrochloride for injection: Reconstitute by adding 10 mL of the diluent provided by the manufacturer to a vial labeled as containing 50 mg of melphalan using a 20-gauge or larger needle to provide a solution containing 5 mg/mL. Dilute reconstituted dose further with 0.9% sodium chloride injection to a final concentration not exceeding 0.45 mg/mL.

Melphalan hydrochloride for injection (Evomela): Reconstitute by adding 8.6 mL of 0.9% sodium chloride injection to provide a solution containing 50 mg/10 mL (5 mg/mL). Dilute the required dose with an appropriate volume of 0.9% sodium chloride injection to a final concentration of 0.45 mg/mL.

Rate of Administration

Administer melphalan hydrochloride by IV infusion over 15–20 minutes. Complete administration within 60 minutes of reconstitution.

Infuse melphalan hydrochloride (Evomela) over 30 minutes via an injection port or a fast-running central venous catheter.

Dosage

Dosage of melphalan hydrochloride is expressed in terms of melphalan.

Adults

Multiple Myeloma

Oral

Usual initial and maintenance dosage regimen: 6 mg daily for 2–3 weeks. Withhold therapy until leukocyte and platelet counts increase (i.e., up to 4 weeks) and then initiate maintenance therapy of 2 mg daily. Adjust dosage, as required, to maintain a degree of bone marrow depression.

Alternatively, 10 mg daily for 7–10 days. Withhold therapy until platelet and leukocyte counts exceed 100,000/mm³ and 4000/mm³, respectively, and then initiate maintenance therapy of 2 mg daily. Adjust dosage, as required, to between 1–3 mg daily, depending on hematologic response.

Alternatively, 0.15 mg/kg daily for 7 days followed by a rest period of at least 14 days (or as long as 5 to 6 weeks). Maintenance therapy is initiated when the white blood cell and platelet counts are increasing, with a maintenance dose of 0.05 mg/kg/day or less, adjusted according to blood count.

Alternatively, 0.25 mg/kg daily for 4 days or 0.2 mg/kg daily for 5 days, with prednisone; administer at 4–6 week-intervals, if granulocyte and platelet counts are normal.

IV

Usual dosage: 16 mg/m² at 2-week intervals for 4 doses. After satisfactory recovery from toxicity, initiate maintenance therapy of 16 mg/m² at 4-week intervals.

Melphalan hydrochloride (Evomela) as a high-dose conditioning treatment prior to ASCT (Day 0): 100 mg/m² per day for 2 consecutive days (Day -3 and Day -2). For patients who weigh more than 130% of their ideal body weight, calculate body surface area (BSA) based on adjusted ideal body weight.

Ovarian Cancer

Oral

Usual dosage: 0.2 mg/kg daily for 5 successive days; administer at intervals of 4–5 weeks.

Dosage Modification for Toxicity

If adverse effects occur, temporarily interrupt, reduce dose, and/or permanently discontinue drug.

For oral melphalan tablets, discontinue therapy if leukocyte count falls below 3000/mm³ or platelet count falls below 100,000/mm³. May restart therapy after blood cell counts have recovered. Consider dose adjustment on the basis of blood counts at the nadir and day of treatment.

For IV melphalan hydrochloride, in some controlled clinical studies in patients with multiple myeloma, dosage reductions of 25% were employed when platelet counts were 75,000–99,999/mm³ or leukocyte counts were 3000–3999/mm³ and dosage reductions of 50% were used when platelet counts were 50,000–74,999/mm³ or leukocyte counts were 2000–2999/mm³; IV melphalan was discontinued when platelet or leukocyte counts fell below 50,000/mm³ or 2000/mm³, respectively.

Do not readminister oral or IV melphalan if a hypersensitivity reaction occurs.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

Oral

In patients with moderate to severe renal impairment, consider reducing initial dosage; however, no specific dosage recommendations.

IV

In patients with renal impairment (BUN ≥30 mg/dL), reduce dosage by 50%.

When used as a conditioning treatment (Evomela), dosage adjustment not necessary.

Geriatric Patients

No specific dosage recommendations. In general, start dose selection at low end of dosing range.

Specific Drugs