AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Melphalan

• Melphalan Hydrochloride

Melphalan, a nitrogen mustard-derivative alkylating agent, is an antineoplastic agent.1,2,3

Multiple Myeloma

Melphalan is used alone and as a component of various chemotherapeutic regimens in the treatment of multiple myeloma.1,2,3,114,115,116,117,123,124,125,126,127

Melphalan oral tablets are indicated for the palliative treatment of multiple myeloma and for the palliative treatment of nonresectable epithelial carcinoma of the ovary.1 Melphalan is also available in a parenteral formulation as the hydrochloride salt for use in the palliative treatment of patients with multiple myeloma who cannot take oral therapy.2 A propylene glycol-free formulation of melphalan hydrochloride (Evomela^®) is available for use as a high-dose conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma and also for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.3,15 Melphalan has been designated an orphan drug by FDA for use in the treatment of multiple myeloma.140

Clinical Experience

Melphalan has been available as a chemotherapy agent for several decades and has been used in various combination regimens for the treatment of multiple myeloma.16 Oral melphalan in combination with prednisone was historically considered the standard of care in patients with newly diagnosed multiple myeloma; such therapy resulted in increased response rates and median survival of 6 months compared with melphalan alone.16,19 High-dose chemotherapy plus HSCT is now the preferred treatment of multiple myeloma in patients younger than 65 years of age.19 For older patients and patients with clinically significant coexisting illnesses who usually do not tolerate this treatment, combination treatment with newer drugs that have shown increased rates of survival are used.19 The combination of bortezomib, melphalan, and prednisone is currently considered a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for stem-cell transplantation.19 In a randomized, open-label, phase 3 study in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy plus stem-cell transplantation, treatment with bortezomib, melphalan, and prednisone was superior to melphalan and prednisone alone with regard to time to disease progression and other outcomes.19 In another randomized, controlled, open-label, phase 3 study (ALCYONE) that was conducted in newly diagnosed patients with multiple myeloma who were ineligible for stem-cell transplantation, combination therapy with daratumumab, bortezomib, melphalan, and prednisone resulted in significantly longer progression-free survival and lower risk of disease progression or death than bortezomib, melphalan, and prednisone alone.18

Melphalan hydrochloride for injection (Evomela^®) is a propylene glycol-free formulation of melphalan indicated for use as a high-dose conditioning treatment prior to HSCT in patients with multiple myeloma and also for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate; this formulation incorporates beta cyclodextrin to enhance stability while maintaining solubility.1,15

Efficacy and safety of melphalan hydrochloride (Evomela^®) for myeloablative conditioning were evaluated in an open-label, single-arm, nonrandomized study in 61 patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT).3 The drug was administered at a dosage of 100 mg/m² daily by IV infusion over 30 minutes for 2 consecutive days prior to ASCT (day -3 and day -2).3 The overall response rate (partial response or better) improved from 79% (48 of 61) prior to the ASCT procedure to 95% (58 of 61) at 90 to 100 days post-transplant.3 There was also an increase in the number of patients with a complete response from 0 patients prior to the ASCT procedure to 10 patients at 90 to 100 days post-transplant.3 In addition, all 61 patients achieved myeloablation, neutrophil engraftment, and platelet engraftment.3

Efficacy and safety of melphalan hydrochloride (Evomela^®) in the palliative treatment of patients with muliple myeloma were evaluated in a randomized study that compared prednisone plus IV melphalan to prednisone plus oral melphalan.3 Overall response rates at 22 weeks were comparable; however, because of changes in trial design, conclusions regarding the relative activity of the 2 formulations of melphalan after week 22 cannot be made.3

Clinical Perspective

The treatment of multiple myeloma involves different combinations of drugs with different mechanisms of action, including alkylating agents, corticosteroids, anthracyclines, immunomodulatory drugs, histone deacetylase inhibitors, proteasome inhibitors, monoclonal antibodies, and high-dose chemotherapy followed by autologous stem cell transplant (ASCT).6,16 In a joint guideline published by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario in 2019, evidence-based recommendations are provided for the treatment of multiple myeloma in patients who are transplant-eligible, transplant-ineligible, and those with relapsed disease.6 For transplant-eligible patients with newly diagnosed multiple myeloma, induction therapy followed by high-dose chemotherapy and ASCT remains the standard of care.16 The guideline recommends high-dose melphalan as the recommended conditioning regimen for ASCT.6 For patients who are transplant-ineligible, several combination regimens are recommended, including a regimen containing daratumumab, bortezomib, melphalan, and prednisone.6

Ovarian Cancer

Melphalan has been used in the palliative treatment of nonresectable epithelial carcinoma of the ovary with varying results.1,105,106 In addition, tumor regression has occurred in some patients receiving intraperitoneal† administration of melphalan for the treatment of advanced ovarian cancer confined to the peritoneal cavity and/or associated with malignant ascites.101 However, platinum-based chemotherapy is currently considered the standard of care chemotherapy for the treatment of ovarian cancer.8

Melanoma

Melphalan has been used for isolated limb perfusion † or isolated limb infusion † in the treatment of patients with regionally recurrent melanoma not suitable for local or topical therapy.9,10,11 For isolated limb perfusion, melphalan is often administered in combination with either actinomycin D or tumor necrosis factor (TNF)-alfa (not currently available in the United States).9,10,11 Results of a systematic review of 22 trials involving patients with unresectable stage IIIB-IIIC metastatic melanoma revealed a median complete response rate of 47% with melphalan monotherapy, 45-65% with melphalan and actinomycin D, and up to 70% with melphalan and TNF-alfa.10 For isolated limb infusion, melphalan is also often used with actinomycin D.11 In a review of 7 studies involving patients treated with melphalan and actinomycin D via isolated limb infusion, the rates of overall response, complete response, partial response, and stable disease were 73%, 33%, 40% and 14%, respectively.11 Melphalan was designated an orphan drug by the FDA for use in hyperthermic regional limb perfusion to treat metastatic melanoma of the extremity; however, this designation has been withdrawn.140 Melphalan is also designated an orphan drug for the treatment of Stage IIB through IV melanoma.140

Amyloidosis

Melphalan has been used with prednisone in the treatment of systemic light chain amyloidosis† as a high-dose regimen followed by stem cell transplant, in combination with bortezomib and dexamethasone, and orally in combination with dexamethasone.12 The optimal therapy for systemic light chain amyloidosis remains unknown; choice of treatment is largely dependent on the extent and severity of amyloid organ involvement.12 Most patients with light-chain amyloidosis are ineligible for stem cell transplant and receive conventional chemotherapy.12 Standard conventional upfront treatment for this condition currently includes bortezomib with dexamethasone and an alkylating agent (e.g., melphalan or cyclophosphamide).12

General

Pretreatment Screening

• Perform a complete blood count (CBC) with differential.1,2,3
• Verify pregnancy status in females of reproductive potential.1,2,3

Patient Monitoring

• Monitor platelet, neutrophil, and red blood cell counts at baseline, during treatment, and as clinically indicated.1,2,3
• Monitor for signs and symptoms of infection.1,2,3
• Monitor liver function tests.1,2,3
• Perform long-term monitoring for the development of secondary malignancies.1,2,3

Premedication and Prophylaxis

• Consider administering antiemetics prior to and during treatment with melphalan (Evomela^®) as a high-dose conditioning treatment.3

Dispensing and Administration Precautions

• Employ safe handling and disposal precautions with melphalan since it is a hazardous medication.1,2,3
• Avoid use of the abbreviation “MP” for melphalan and prednisone.13

Other General Considerations

• Consult published protocols for information on the dosage, method of administration, and administration of other antineoplastic agents used in combination regimens with melphalan.1,2,3

Administration

Administer melphalan orally or by IV infusion.1,2,3 Melphalan also has been administered intraperitoneally†101 and by regional isolated perfusion or infusion† (e.g., for melanoma).9,10,11

Various preparations and formulations of melphalan are commercially available; dosage recommendations differ between the different preparations.1,2,3

Store melphalan tablets in a refrigerator (2-8°C) protected from light.1

Store melphalan hydrochloride powder for injection at controlled room temperature (20-25°C) protected from light.2

Store melphalan hydrochloride for injection (Evomela^®) at room temperature (25°C) protected from light.3 Excursions are permitted to 15-30°C.3

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration whenever solution and container permit.2,3

IV Administration

Parenteral preparations of melphalan are commercially available as lyophilized powders that must be reconstituted and further diluted prior to IV administration.2,3

Reconstitution and Dilution

Melphalan hydrochloride for injection:Reconstitute lyophilized powder 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.2 Add the diluent rapidly and shake the vial vigorously until a clear solution is obtained.2 Do not refrigerate the reconstituted solution because a precipitate may form at 5°C.2 Dilute the reconstituted dose of melphalan with 0.9% sodium chloride injection to provide a solution with a concentration not exceeding 0.45 mg/mL.2 Perform dilution of reconstituted solutions of the drug immediately because a citrate derivative of melphalan has been detected in the solution within 30 minutes of reconstitution.2 Because approximately 1% of the labeled strength of melphalan hydrolyzes every 10 minutes following dilution with 0.9% sodium chloride, administer the solution of melphalan hydrochloride soon after dilution.2

Melphalan hydrochloride for injection (Evomela^®): Reconstitute lyophilized powder by adding 8.6 mL of 0.9% sodium chloride injection to provide a solution containing 50 mg/10 mL (5 mg/mL).3 The reconstituted drug is stable for 24 hours at refrigerated temperature (5°C) and 1 hour at room temperature.3 Calculate the required volume needed for the dose and withdraw that volume from the vial(s).3 Dilute the required volume of melphalan with an appropriate volume of 0.9% sodium chloride injection to a final concentration of 0.45 mg/mL.3 The admixture solution is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution.3

Rate of Administration

Administer melphalan hydrochloride by IV infusion, usually over 15-20 minutes.2

Infuse melphalan hydrochloride (Evomela^®) over 30 minutes via an injection port or a fast-running central venous catheter.3

Dosage

Dosage of melphalan hydrochloride is expressed in terms of melphalan.2,3

Dosage of melphalan must be adjusted carefully according to the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects.1,2

Multiple Myeloma

For the treatment of multiple myeloma, various dosage schedules for oral or IV melphalan have been used.1,2,3

Oral Dosage

The manufacturer recommends an initial adult oral melphalan dosage of 6 mg given as a single daily dose for the treatment of multiple myeloma.1 Subsequent dosage should be adjusted as required based on blood counts performed approximately weekly.1 After 2-3 weeks, the drug should be discontinued for up to 4 weeks until the leukocyte and platelet counts increase, at which time an oral maintenance dosage of 2 mg daily may be instituted.1 Alternatively, some clinicians recommend an intermittent oral melphalan dosage schedule of 0.15 mg/kg daily for 7 successive days followed by a rest period of at least 14 days (or as long as 5 to 6 weeks).1 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.1 Another dosage regimen involves use of melphalan 0.25 mg/kg daily for 4 successive days (or 0.20 mg/kg/day for 5 consecutive days), administered at intervals of 4-6 weeks, with prednisone.1

Other clinicians have used oral melphalan dosages of 10 mg daily for 7-10 days.1 In these patients, maximum suppression of leukocyte and platelet counts occurred within 3-5 weeks while recovery reportedly occurred within 4-8 weeks.1 When platelet and leukocyte counts exceeded 100,000/mm³ and 4000/mm³, respectively, a continuous maintenance therapy of 2 mg daily was initiated; dosage was adjusted between 1-3 mg daily depending on hematologic response.1 The manufacturer states that it is desirable to maintain a substantial degree of bone marrow depression in order to keep the leukocyte count at 3000-3500/mm³.1

IV Dosage

The usual adult IV dosage of melphalan for the treatment of multiple myeloma is 16 mg/m² given by IV infusion once at 2-week intervals for 4 doses; then, after satisfactory recovery from toxicity, the same dose should be repeated at 4-week intervals.2

The recommended adult IV dosage of melphalan (Evomela^®) as a high-dose conditioning treatment prior to autologous stem-cell transplantation (Day 0) is 100 mg/m² per day given by IV infusion for 2 consecutive days (Day -3 and Day -2).3 For patients who weigh more than 130% of their ideal body weight, body surface area should be calculated based on adjusted ideal body weight.3

Ovarian Cancer

Oral Dosage

For the treatment of ovarian carcinoma, the usual adult dosage of melphalan is 0.2 mg/kg daily for 5 successive days, administered at intervals of 4-5 weeks, depending on hematologic response.1

Dosage Modification for Toxicity

If adverse effects occur during melphalan therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1,2

For oral melphalan tablets, discontinue therapy if the leukocyte count falls below 3000/mm³ or the platelet count falls below 100,000/mm³.1 May restart therapy after blood cell counts have recovered.1 Consider dose adjustment on the basis of blood counts at the nadir and day of treatment.1

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.2

Do not readminister oral or IV melphalan if a hypersensitivity reaction occurs.1,2,3

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1,2,3

Renal Impairment

The manufacturer states that dosage reduction may be prudent initially in patients with moderate to severe renal impairment receiving oral melphalan.1

Dosage reduction should be considered in patients with renal impairment who are receiving IV melphalan hydrochloride, since increased bone marrow suppression was observed in patients with BUN concentrations of 30 mg/dL or more.2,3 When dosage of IV melphalan is reduced by 50% in these patients, the risk of severe leukopenia and drug-related death may be reduced from about 50 to 11% and 10 to 3% of patients, respectively.2,3

When used as a conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation (Evomela^®), no dosage adjustment for renal impairment is necessary.3

Geriatric Patients

The manufacturers make no specific dosage recommendations for geriatric patients.1,2,3 In general, dosage selection for geriatric patients should usually start at the low end of the dosing range.1,2

Contraindications

• History of serious hypersensitivity reaction to melphalan.1,2,3
• Use in patients whose disease has demonstrated prior resistance to treatment.1,2

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

A boxed warning about the risks associated with use of oral and IV melphalan is included in the prescribing information for the drug.1,2,3 Melphalan should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.1,2 Severe bone marrow suppression with resulting infection or bleeding may occur.1,2,3 Controlled trials comparing IV to oral melphalan have shown more myelosuppression with the IV formulation.2,3 Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation.2,3 Melphalan is leukemogenic in humans.1,2,3

Mutagenicity and Carcinogenicity

A boxed warning about the genetic risks associated with the use of oral and IV melphalan is included in the prescribing information.1,2,3 Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans.1,2,3

Sensitivity Reactions

Hypersensitivity

Acute hypersensitivity reactions, including anaphylaxis, have been reported with IV melphalan administration.2,3 Symptoms may include urticaria, pruritus, edema, and skin rash.2,3 Tachycardia, bronchospasm, dyspnea, and hypotension have also been observed.2,3 If a serious hypersensitivity reaction occurs, discontinue treatment.2,3

Other Warnings and Precautions

Thrombocytopenia

Thrombocytopenia, which may lead to hemorrhage, occurs commonly with melphalan.1,2,3 Frequent platelet counts are essential to determine dosage and avoid toxicity. 1,2 Monitor platelet counts at baseline, during treatment, and as clinically indicated.1,2,3 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.1,2 Therapy may be withheld until recovery of platelet count. 1,2,3

Neutropenia/Leukopenia

Neutropenia/leukopenia, which may lead to infection, occurs commonly with melphalan.1,2,3 Frequent white blood cell counts (WBCs) are essential to determine dosage and avoid toxicity.1,2 Monitor WBCs at baseline, during treatment, and as clinically indicated.1,2,3 Dose adjustment on the basis of WBCs at the nadir and day of treatment should be considered.1,2 Therapy may be withheld until recovery of WBCs.1,2,3

Anemia

Anemia occurs commonly with melphalan.1,2,3 Frequent red blood cell (RBC) counts are essential to determine dosage and avoid toxicity.1,2 Monitor RBCs at baseline, during treatment, and as clinically indicated.1,2,3 Dose adjustment on the basis of RBCs should be considered.1,2 Therapy may be withheld until recovery of RBCs.1,2,3

Infections

Monitor patients receiving melphalan closely for signs and symptoms of infection and consider antimicrobials as clinically appropriate.1,2,3

Secondary Malignancies

Secondary malignancies (eg, myelodysplastic syndromes, acute leukemia) have been reported in patients with multiple myeloma administered melphalan-containing regimens.1,2,3 Weigh the potential benefits of therapy against the possible risk of a secondary malignancy.1,2,3 Monitor patients long-term for the potential development of secondary malignancies.1,2,3

GI Toxicity

Nausea, vomiting, mucositis, and diarrhea may occur with melphalan therapy.1,2,3 Administer prophylactic antiemetics and provide supportive care as necessary.3

Hepatotoxicity

Abnormal liver function tests as well as instances of hepatitis, jaundice, and hepatic veno-occlusive disease have been reported with melphalan therapy.3 Monitor liver function tests as appropriate.1,2,3

Fetal/Neonatal Morbidity and Mortality

Melphalan can cause fetal harm when administered to pregnant females based on its mechanism of action and findings in animal studies.1,2,3 Although there are no adequate and controlled studies to date using melphalan in pregnant females, the drug has been shown to be teratogenic and embryotoxic in rats.1,2,3

Pregnancy should be avoided during melphalan therapy.1,2,3 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.3 If melphalan is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1,2,3

Specific Populations

Pregnancy

Melphalan may cause fetal harm if administered to pregnant women based on its mechanism of action and results of animal studies.1,2,3

Lactation

It is not known whether melphalan is distributed into milk in humans.1,2,3 Because of the potential for adverse reactions to melphalan in breast-fed infants, breastfeeding is not recommended.3

Females and Males of Reproductive Potential

Prior to initiation of melphalan therapy, verify pregnancy status of females of reproductive potential.1,2,3 Such females and males with female partners of reproductive potential should be advised to use effective contraception during and for a period after treatment.3

Ovarian suppression and amenorrhea may occur during melphalan therapy in premenopausal women.1,2,3 Reversible and irreversible suppression of testicular function also have been reported in patients receiving the drug.1,2,3

Pediatric Use

Safety and efficacy of melphalan have not been established in pediatric patients.1,2,3

Geriatric Use

Studies of oral melphalan did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger subjects.1 In the single-arm pivotal study of IV melphalan (Evomela^®), 30% of patients were 65 years of age and older; no differences in safety or effectiveness were observed between these geriatric patients and younger adults.3 However, an increased incidence of engraftment syndrome was observed in older versus younger patients.3

Hepatic Impairment

Melphalan degradation does not involve hepatic metabolism.14 The manufacturers make no specific dosage recommendations for patients with hepatic impairment.1,2,3

Renal Impairment

The contribution of renal impairment to melphalan clearance appears to be low.1,2,3 For oral melphalan, the manufacturer makes no specific dosage recommendations in patients with renal impairment.1 A dose reduction should be considered in patients with renal insufficiency receiving IV melphalan for palliative treatment of multiple myeloma.2,3

Common Adverse Effects

Adverse effects reported 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, and allergic reactions.1

Adverse effects reported in at least 50% of patients receiving IV melphalan (Evomela^®) include decreased neutrophil, white blood cell, lymphocyte, and platelet counts, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting.3

Drug interaction information involving melphalan is limited since degradation of the drug does not involve hepatic metabolism.1,14

Carmustine

IV melphalan may reduce the threshold for carmustine-induced pulmonary toxicity.2,3

Cisplatin

Concomitant administration of cisplatin may affect the pharmacokinetics of melphalan secondary to cisplatin-induced renal impairment, which may result in decreased clearance of melphalan.2

Cyclosporine

Melphalan may increase cyclosporine-induced nephrotoxicity.2,3 Severe renal failure has been reported in patients receiving a single dose of IV melphalan followed by usual oral dosages of cyclosporine.2,3

Description

Melphalan is an alkylating agent that exhibits cytotoxic effects due to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine.1,2,3 Similar to other bifunctional alkylating agents, melphalan is active against both resting and rapidly dividing tumor cells.1,2,3

Following oral administration, absorption of melphalan is extremely variable with respect to both time to initial appearance in plasma (range: 0- 6 hours) and maximum serum concentration.1 The mean absolute bioavailability of oral melphalan is also highly variable (range: 56% to 93%).1 This inconsistency may be due to incomplete intestinal absorption, variable “first pass” hepatic metabolism, or rapid hydrolysis.1 Administration of oral melphalan with a high fat meal may decrease exposure by 36-54%.1 Following IV administration, serum melphalan concentrations decrease rapidly in a biexponential manner and the drug is distributed in whole body water.2,3,14 Melphalan distributes into CSF in low concentrations.1,2,3 The drug is reportedly variably bound to plasma proteins (range: 53- 92%), mainly albumin, and to a lesser extent (about 20%) to α1-acid glycoprotein (α1-AGP).1,2 About 30% of melphalan is irreversibly bound to plasma proteins.1,2,3 Interactions of melphalan with immunoglobulins have been found to be negligible.1,2

Following administration of a single oral dose, the terminal plasma half-life of melphalan was 1.5 hours.1 Following IV administration of melphalan hydrochloride in adult patients, the half-life of melphalan was about 10 minutes in the initial distribution phase (t½α) and about 75 minutes in the terminal elimination phase (t½β).2,3 Melphalan is apparently eliminated from plasma mainly by spontaneous hydrolysis, forming the monohydroxy and dihydroxy derivatives of the drug; no other metabolites have been identified in humans.1,3 Following IV administration of melphalan hydrochloride, total body clearance of the drug averages 7-9 mL/minute per kg in adult patients, although considerable interindividual variation in body clearance exists.2,3 In adult patients, total body clearance of melphalan may be decreased following multiple IV doses (e.g., 0.5 mg/kg every 6 weeks).2,3 Approximately 10% of a single oral dose of melphalan is excreted in urine unchanged within 24 hours.1 Although renal elimination of melphalan appears to be low, results of a pharmacokinetic study indicate that there may be a direct correlation between renal function and the elimination rate constant of the drug, while a negative correlation may exist between AUC of the drug and renal function.1

Advice to Patients

• Inform patients that bleeding or infection may occur with therapy.1,2,3 Instruct patients to report signs or symptoms of bleeding or infection to a clinician.1,2,3
• Advise patients that an allergic reaction can occur with therapy.1,2,3 Instruct patients to report signs or symptoms of an allergic reaction immediately.1,2,3
• Inform patients that secondary malignancies may occur.1,2,3
• Advise patients that nausea, vomiting, mouth sores/pain, and diarrhea may occur with therapy.1,2,3 Instruct patients to report any of these symptoms to their clinician.1,2,3
• Inform patients of the importance of monitoring liver function tests during therapy.1,2,3
• Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,2,3 Instruct females of reproductive potential and males with female partners of reproductive potential to use an effective method of contraception during and for a period after therapy.3 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1,2,3 Inform women that breastfeeding is not recommended during melphalan therapy.1,2,3
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1,2,3
• Inform patients of other important precautionary information.1,2,3

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Alvogen, Inc. Melphalan tablets prescribing information. Morristown, NJ; 2019 Mar.

2. Fresenius Kabi. Melphalan hydrochloride for injection prescribing information. Lake Zurich, IL: 2016 Aug.

3. Spectrum Pharmaceuticals, Inc. Evomela® (melphalan) for injection, for intravenous use prescribing information. Irvine, CA; 2016 Mar.

5. . Richardson PG, Oriol A, Larocca A, et al. . Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol . 2021; 39:757-67.

6. Mikhael J, Ismaila N, Cheung MC, et al. . Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol . 2019; 37:1228-63.

7. Piver MS.. Treatment of ovarian cancer at the crossroads: 50 years after single-agent chemotherapy. Oncology (Williston Park) . 2006; 20:1156, 58.

8. . Colombo N, Sessa C, du Bois A, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol . 2019; 30:672-705.

9. Noorda EM, Vrouenraets BC, Nieweg OE, et al. Isolated limb perfusion for unresectable melanoma of the extremities. . Arch Surg . 2004; 139:1237-42.

10. Moreno-Ramirez D, de la Cruz-Merino L, Ferrandiz L, et al. Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety. Oncologist. . 2010; 15:416-27.

11. Kroon HM, Huismans AM, Kam PCA, et al. Isolated limb infusion with melphalan and actinomycin D for melanoma: a systematic review. J Surg Oncol . 2014; 109:348-51.

12. Milani P, Palladini G. Conventional therapy for amyloid light-chain amyloidosis. Acta Haematol . 2020; 143:365-72.

13. Davis NM. Medical abbreviations that have contradictory of ambiguous meanings. From Institute for Safe Medication Practices website. Accessed 2021 Oct 19.

14. Esma F, Salvini M, Troia R, et al. Melphalan hydrochloride for the treatment of multiple myeloma. Expert Opin Pharmacother . 2017; 18:1127-36.

15. Aljitawi OS, Hari P. Propylene glycol-free melphalan as conditioning regimen for autologous transplantation in myeloma. Int J Hematol Oncol. 2016 May;5(1):5-10. Epub 2016 May 31. [PubMed 30302199]

16. Poczta A, Rogalska A, Marczak A. Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies-Current Research and Clinical Approaches. J Clin Med. 2021 Apr 23;10(9):1841. [PubMed 33922721]

17. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020 May;95(5):548-567. Erratum in: Am J Hematol. 2020 Nov;95(11):1444. [PubMed 32212178]

18. Mateos MV, Dimopoulos MA, Cavo M et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. [PubMed 29231133]

19. San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. [PubMed 18753647]

101. Howell SB, Pfeifle CE, Olshen RA. Intraperitoneal chemotherapy with melphalan. Ann Intern Med . 1984; 101:14-8. [PubMed 6732077]

105. Wadler S, Yeap B, Vogl S et al. Randomized trial of initial therapy with melphalan versus cisplatin-based combination chemotherapy in patients with advanced ovarian carcinoma: initial and long term results—Eastern Cooperative Oncology Group Study E2878. Cancer . 1996; 77:733-42. [PubMed 8616766]

106. Hasan J, Jayson GC. Oral melphalan as a treatment for platinum-resistant ovarian cancer. Br J Cancer. 2003 Jun 16;88(12):1828-30. [PubMed 12799622]

114. Cooper MR, McIntyre OR, Propert KJ et al. Single, sequential, and multiple alkylating agent therapy for multiple myeloma: a CALGB study. J Clin Oncol . 1986; 4:1331-9. [PubMed 3528403]

115. Cornwell GG III, Pajak TF, Kochwa S et al. Vincristine and prednisone prolong the survival of patients receiving intravenous or oral melphalan for multiple myeloma: Cancer and Leukemia Group B experience. J Clin Oncol . 1988; 6:1481-90. [PubMed 3047338]

116. Harley JB, Pajak TF, McIntyre OR et al. Improved survival of increased-risk myeloma patients on combined triple-alkylating-agent therapy: a study of the CALGB. Blood . 1979; 54:13-22.

117. Osterborg A, Ahre A, Björkholm M et al. Oral versus intravenous melphalan and prednisone treatment in multiple myeloma stage II: a randomized study from the Myeloma Group of Central Sweden. Acta Oncol . 1990; 29:727-31. [PubMed 2223143]

123. Dunbar CE, Nienhuis AW. Multiple myeloma: new approaches to therapy. JAMA . 1993; 269:2412-6. [PubMed 7683062]

124. Österborg A, Björkholm M, Björeman M et al. Natural interferon-α in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the myeloma group of central Sweden. Blood . 1993; 81:1428-34. [PubMed 8453092]

125. MacLennan ICM, Chapman C, Dunn J et al. Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet . 1992; 339:200-5. [PubMed 1346171]

126. Gregory WM, Richards MA, Malpas JS. Combined chemotherapy versus melphalan and prednisolone for treatment of myelomatosis. Lancet . 1992; 339:1353-4. [PubMed 1350010]

127. Clarke M, Gray R, Dunn J et al. Combination chemotherapy for myelomatosis. Lancet . 1992; 340:433. [PubMed 1353589]

140. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Accessed 2021 Oct 25. [Web]