Melphalan Hydrochloride – Uses, Dosage, Side Effects, Interaction

Melphalan Hydrochloride is a bifunctional alkylating agent and phenylalanine derivative of nitrogen mustard. Melphalan hydrochloride is converted into highly reactive ethylenimmonium intermediates that induce covalent guanine N7-N7 intra- and inter-crosslinks and alkylation of adenine N3 of DNA. This agent also alkylates RNA and protein structures. As a result RNA transcription and protein synthesis are inhibited, ultimately leading to cell growth arrest and/or death.

Mechanism of Action

Melphalan attaches alkyl groups to the N-7 position of guanine and the N-3 position of adenine, leading to the formation of mono adducts, and DNA fragmenting when repair enzymes attempt to correct the error. It can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription. Finally, melphalan can induce a number of different mutations.

or

Melphalan flufenamide is a more lipophilic prodrug of melphalan, which allows it to be more readily uptaken by cells. It is likely taken up into malignant cells by passive diffusion, where it is hydrolyzed by aminopeptidase N. The expression of aminopeptidases, along with other hydrolytic enzymes, is upregulated in many malignant cells, making the hydrolysis reaction to melphalan more favorable in a malignant cell. Increased concentrations of free melphalan in malignant cells lead to rapid irreversible DNA damage and apoptosis, reducing the potential for the development of resistance. Free melphalan is a nitrogen mustard derivative alkylating agent. Melphalan attaches alkyl groups to the N-7 position of guanine and the N-3 position of adenine, leading to the formation of mono adducts, and DNA fragmenting when repair enzymes attempt to correct the error. It can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription. Finally, melphalan can induce a number of different mutations. While melphalan induces phosphorylation of the DNA damage marker γ-H2AX in melphalan-sensitive cells at 6 hours, melphalan flufenamide induces γ-H2AX at 2 hours. Melphalan flufenamide is also able to induce γ-H2AX in melphalan-resistant cells.

Indication

  • For the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Has also been used alone or as part of various chemotherapeutic regimens as an adjunct to surgery in the treatment of breast cancer, alone or in combination regimens for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma of the extremities, as well as for the treatment of amyloidosis with prednisone.
  • High-dose of Phelinun used alone or in combination with other cytotoxic medicinal products and/or total body irradiation is indicated in the treatment of: multiple myeloma, malignant lymphoma (Hodgkin, non-Hodgkin lymphoma), acute lymphoblastic, and myeloblastic leukemia, childhood neuroblastoma, ovarian cancer, mammary adenocarcinoma.
  • Phelinun in combination with other cytotoxic medicinal products is indicated as reduced intensity conditioning (RIC) treatment prior to allogeneic hematopoietic stem cell transplantation (also HSCT) in malignant hematological diseases in adults.
  • Phelinun in combination with other cytotoxic medicinal products is indicated as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation in hematological diseases in the pediatric population as Myeloablative conditioning (MAC) treatment in case of malignant hematological diseases RIC treatment in case of non-malignant hematological diseases.
  • Melphalan flufenamide is indicated in combination with [dexamethasone] to treat adults with relapsed or refractory multiple myeloma who have received ≥4 therapies and are refractory to at least one proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. The FDA has withdrawn the drug from the market for this indication following phase 3 trial data showing decreased overall survival.
  • Pepaxti is indicated, in combination with dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least three prior lines of therapies, whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy. For patients with a prior autologous stem cell transplantation, the time to progression should be at least 3 years from transplantation
  • Multiple Myeloma (MM)
  • Unresectable Ovarian Cancer (Epithelial)
  • Conditioning regimens for allogeneic stem cell transplantation therapy

Use in Cancer

Melphalan hydrochloride is approved to treat:

  • Multiple myeloma.
    • It is used for palliative treatment in patients who cannot take melphalan by mouth. This use is approved for the Alkeran and Evomela brands.
    • It is used as a conditioning treatment to prepare patients for a stem cell transplant. This use is approved for the Evomela brand.

Melphalan hydrochloride is also being studied in the treatment of other types of cancer.

Melphalan is also available in a tablet form. For more information, see the Drug Information Summary for Melphalan.

Contraindication

  • a bad infection
  • a type of blood disorder where the red blood cells burst called hemolytic anemia
  • decreased function of bone marrow
  • anemia
  • decreased blood platelets
  • low levels of white blood cells
  • low levels of granulocytes, a type of white blood cell
  • inflammation of the blood vessels
  • hepatic veno-occlusive disease, a type of liver disease
  • bleeding
  • a type of inflammation of the lung called interstitial pneumonitis
  • a condition where there is formation of fibrous tissue in the lung called pulmonary fibrosis
  • damage to the liver and inflammation
  • decreased kidney function
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: 2 mg; 50 mg

Multiple Myeloma

ORAL:
A typical oral dosage regimen is:

  • 6 mg orally once daily; after 2 to 3 weeks therapy should be discontinued for up to 4 weeks and the blood count followed; when white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted

Alternate Oral Regimens:

  • Osserman and Takatsuki have used an initial course of 10 mg/day for 7 to 10 days. They report that maximal suppression of the leukocyte and platelet counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks. Continuous orally maintenance therapy with 2 mg/day is instituted when the white blood cell count is greater than 4000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. The dosage is adjusted to between 1 and 3 mg/day depending on the hematological response. It is desirable to try to maintain a significant degree of bone marrow depression to keep the leukocyte count in the range of 3000 to 3500 cells/mcL.
  • Hoogstraten et al have started therapy with 0.15 mg/kg/day for 7 days followed by a rest period of at least 14 days, but it may be up to 5 to 6 weeks. Maintenance therapy is started when the white blood cell and platelet counts are rising. The maintenance dose is 0.05 mg/kg/day or less and is adjusted according to the blood count.
  • One study by Alexanian et al has shown that using this drug in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. One regimen has been to administer courses of this drug at 0.25 mg/kg/day for 4 consecutive days (or, 0.2 mg/kg/day for 5 consecutive days) for a total dose of 1 mg/kg/course. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte and platelet count have returned to normal levels.
  • The entire oral dose may be given at one time.
  • Numerous oral regimes have been used. Scientific literature and/or institutional protocol should be consulted for further information.
  • Oral administration of this drug results in variable absorption; dosage may need to be cautiously increased until myelosuppression is seen to ensure that therapeutic levels have been reached.
  • The administration of this drug with prednisone is more effective than this drug as monotherapy. The combination is usually given on an intermittent basis, although the superiority of this technique over continuous therapy has not been established.
  • Evidence suggests that one-third to one-half of the patients with multiple myeloma show a favorable response to administration of this drug.
  • Experience with oral administration suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if therapy is abandoned prematurely.
  • There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.

IV (when oral therapy is not appropriate):

  • 16 mg/m2 as a single IV infusion over 15 to 20 minutes every 2 weeks for 4 doses; then, after adequate recovery from toxicity, at 4-week intervals
  • Evidence suggests that one-third to one-half of the patients with multiple myeloma show a favorable response to administration of this drug.
  • Dose adjustment based on blood cell counts at the nadir and day of therapy should be considered.
  • There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.
  • Consult local institutional guidelines for alternate dosing options.
  • Oral: For the palliative treatment of multiple myeloma.
  • IV: For the palliative treatment of multiple myeloma when oral therapy is not appropriate.

Ovarian Cancer

  • Common regimen: 0.2 mg/kg orally daily for 5 days as a single course; courses are repeated every 4 to 5 weeks depending upon hematologic tolerance
  • There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.
  • Consult local institutional guidelines for alternate dosing options.
  • For the palliation of nonresectable epithelial carcinoma of the ovary.

Renal Dose Adjustments

  • In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially.
  • Patients with azotemia should be closely observed to make dosage reductions, if required, as soon as possible.

IV:
A reduction of up to 50% should be considered in patients with renal insufficiency (BUN greater than or equal to 30 mg/dL).

ORAL:
A recommendation as to whether dosage reduction should be made routinely in patients with renal insufficiency cannot be made because:

  • There is considerable inherent patient-to-patient variability in the systemic availability of this drug in patients with normal renal function.
  • Only a small amount of the administered dose appears as parent drug in the urine of patients with normal renal function.

or

Dosage Intra-arterial
Malignant melanoma, Soft tissue sarcoma
  • Adult: As melphalan hydrochloride: Upper extremity perfusions: 0.6-1 mg/kg. Lower extremity perfusions: 0.8-1.5 mg/kg (in melanoma) or 1-1.4 mg/kg (in sarcoma).
  • Elderly: Initiate treatment at the lower end of the dosing range.
Intravenous
Multiple myeloma
  • Adult: As melphalan hydrochloride: 0.4 mg/kg (16 mg/m2) repeated at appropriate intervals (e.g. once every 4 weeks) provided there has been a recovery of the peripheral blood count during this period. A high-dose regimen: 100-200 mg/m2, to be followed by hematopoietic stem cell rescue if doses are >140 mg/m2. As melphalan flufenamide: In patients with relapsed or refractory multiple myeloma who have received ≥4 prior lines of therapy and whose disease is refractory to ≥1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody: 40 mg over 30 minutes on Day 1 of each 28-day treatment cycle, in combination with dexamethasone. Continue until disease progression or unacceptable toxicity. Dose reduction or modifications may be required according to individual safety or tolerability (refer to detailed product guidelines).
  • Elderly: Initiate treatment at the lower end of the dosing range.
Intravenous
Ovarian adenocarcinoma
  • Adult: As melphalan hydrochloride: Monotherapy: 1 mg/kg (approx 40 mg/m2) given at intervals of 4 weeks. In combination with other cytotoxic drugs: 0.3-0.4 mg/kg (12-16 mg/m2) at intervals of 4-6 weeks
  • Elderly: Initiate treatment at the lower end of the dosing range.
Intravenous
Advanced neuroblastoma
  • Child: As melphalan hydrochloride: High-dose regimen: 100-240 mg/m2 (may be divided equally over 3 consecutive days) followed by hematopoietic stem cell rescue if doses are >140 mg/m2.
Oral
Ovarian adenocarcinoma
  • Adult: 0.2 mg/kg daily for 5 days, repeated every 4-8 weeks, or as soon as the bone marrow has recovered.
  • Elderly: Initiate treatment at the lower end of the dosing range.
Oral
Breast cancer
  • Adult: 0.15 mg/kg or 6 mg/m2 daily for 5 days, repeated every 6 weeks. Dose reduction may be needed if bone marrow toxicity was observed.
  • Elderly: Initiate treatment at the lower end of the dosing range.
Oral
Polycythemia vera
  • Adult: Remission induction: 6-10 mg daily for 5-7 days, then 2-4 mg daily until satisfactory disease control is achieved. Maintenance: 2-6 mg once weekly, with careful hematological control and dosage adjustment based on blood counts.
  • Elderly: Initiate treatment at the lower end of the dosing range.

Oral
Multiple myeloma

  • Adult: Usual dosage regimens: Regimen 1: 0.15 mg/kg daily in divided doses for 4 days, repeated at 6-week intervals, usually in combination with a corticosteroid. Regimen 2: 6 mg once daily for 2-3 weeks, followed by up to 4 weeks rest with careful monitoring of blood counts. A maintenance dose of 2 mg daily may be given if WBC and platelet counts are rising. Several regimens have been used; refer to detailed product-specific guidelines. Delay or adjust dose if necessary. Dosage may need to be cautiously increased until myelosuppression is observed, to ensure that potentially therapeutic levels have been reached.
  • Elderly: Initiate treatment at the lower end of the dosing range.

Side Effects

The Most Common

  • nausea
  • vomiting
  • loss of appetite or weight
  • sores in the mouth and throat
  • missed menstrual periods (in girls and women)
  • joint, muscle, or back pain
  • rash
  • hives
  • itching
  • difficulty breathing or swallowing
  • pale skin
  • excessive tiredness
  • fainting
  • fast, irregular, or pounding heartbeat
  • yellowing of the skin or eyes
  • pain in the upper right part of the stomach
  • dark colored urine
  • unusual lumps or masses

More Common

  • low white blood cell counts–fever, chills, cough, pain or burning when you urinate.
  • low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet;
  • easy bruising, unusual bleeding, purple or red spots under your skin;
  • sores or white patches in or around your mouth, trouble swallowing or talking, dry mouth, bad breath, altered sense of taste;
  • severe ongoing nausea, vomiting, or diarrhea;
  • new or worsening cough, fever, trouble breathing;
  • unusual lumps or masses;
  • missed menstrual periods;
  • inflammation of your blood vessels–warmth or tingling, skin rash, fever, headache, body aches, night sweats, weight loss, feeling or weak or tired;
  • liver problems–loss of appetite, stomach pain (upper right side), dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
  • low potassium level–leg cramps, constipation, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling.
  • low blood cell counts;
  • mouth sores;
  • tiredness;
  • low potassium levels; or
  • hair loss.
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Rare

  • Nausea
  • Bone marrow suppression, including
  • Decreased white blood cell count causing the increased risk of infection
  • Decreased platelet count causing an increased risk of bleeding
  • Severe allergic reactions
  • Pulmonary fibrosis (scarring of lung tissue) including fatal outcomes (usually only with prolonged use)
  • Hair loss
  • Interstitial pneumonitis
  • Rash
  • Itching
  • Irreversible bone marrow failure due to melphalan not being withdrawn early enough
  • Cardiac arrest

Drug Interaction

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Pregnancy and Lactation

US FDA pregnancy category: Not Assigned

Pregnancy

There are no animal studies to evaluate the risk of exposure to the mother or the unborn child. This drug is genotoxic and has shown to be toxic to actively dividing animal cells. This drug has the potential to be teratogenic and cause embryo-fetal lethality. Based on animal toxicology studies, this drug may impair fertility in males and cause irreversible testicular suppression. There are no controlled data in human pregnancy.

Lactation

This drug should not be used during breastfeeding and for at least 1 week following the last dose. The effects on the nursing infant and milk production are unknown.

How should this medicine be used?

Melphalan comes as a tablet to take by mouth. It is usually taken on an empty stomach once a day. The length of treatment depends on the types of drugs you are taking, how well your body responds to them, and the type of cancer you have. Take melphalan at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take melphalan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may need to delay your treatment or adjust your dose of melphalan depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment. Do not stop taking melphalan without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking melphalan,

  • tell your doctor and pharmacist if you are allergic to melphalan, any other medications, or any of the ingredients in melphalan tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: carmustine (BICNU, BCNU), cimetidine (Tagamet), cisplatin (Platinol AQ), cyclosporine (Sandimmune, Gengraf, Neoral), or interferon alfa (Intron A, Infergen, Alferon N).
  • tell your doctor if you have taken melphalan before, but your cancer did not respond to the medication. Your doctor will probably tell you not to take melphalan.
  • tell your doctor if you have received radiation therapy or other chemotherapy recently or if you have or have ever had kidney disease.
  • you should know that melphalan may interfere with the normal menstrual cycle (period) in women and may temporarily or permanently stop sperm production in men. Melphalan may cause infertility (difficulty becoming pregnant); however, you should not assume that you cannot get pregnant or that you cannot get someone else pregnant. Women who are pregnant or breast-feeding should tell their doctors before they begin taking this drug. You should not plan to have children while receiving chemotherapy or for a while after treatments. (Talk to your doctor for further details.) Use a reliable method of birth control to prevent pregnancy. Melphalan may harm the fetus.
  • do not have any vaccinations without talking to your doctor.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Melphalan
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Melphalan-hydrochloride
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Melphalan-flufenamide
  4. https://medlineplus.gov/druginfo/meds/a682220.html
  5. https://en.wikipedia.org/wiki/Melphalan
  6. https://go.drugbank.com/drugs/DB01042
  7. https://www.drugs.com/mtm/melphalan-oral-injection.html
  8. https://www.cancer.gov/about-cancer/treatment/drugs/melphalan-hydrochloride
  9. https://www.webmd.com/drugs/2/drug-5234/melphalan-oral/details/list-contraindications
  10. Melphalan [USAN:USP:INN:BAN:JAN]
    ChemIDplus Chemical Information Classification
  11. LICENSE
    Creative Common’s Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
  12. CompTox Chemicals Dashboard Chemical Lists
  13. NCI Thesaurus Tree
  14. MELPHALAN
    CCSbase Classification
  15. LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    NORMAN Suspect List Exchange Classification
  16. IARC Classification
  17. PubChem
  18. LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
  19. Antineoplastic Agents, Alkylating
  20. LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    Therapeutic category of drugs in Japan
    Anatomical Therapeutic Chemical (ATC) classification
    Drugs listed in the Japanese Pharmacopoeia
  21. NCBI