Melphalan: Benefits, Dosage, and Side Effects

What Exactly Is Melphalan?

Melphalan is a cancer‑fighting medicine used in chemotherapy. It has been used for many years, but a newer form received FDA (Food and Drug Administration) approval on August 14, 2023. In this newer method, Melphalan chemotherapy is delivered directly to the liver using a special hepatic delivery system. This allows doctors to target liver tumours more precisely while reducing exposure to the rest of the body.

This targeted treatment is approved for adult patients with uveal melanoma who have unresectable liver metastases involving less than 50 % of the liver. It is especially helpful when cancer has not widely spread outside the liver.

Apart from liver‑directed therapy, Melphalan uses also include treatment of multiple myeloma, a cancer of the bone marrow. Melphalan injection is administered to patients who are unable to take the medication orally. It is also widely used as bone marrow transplant conditioning, where it destroys diseased bone marrow cells before a stem cell transplant.

Drug Group

Melphalan belongs to a group of cancer medicines called alkylating agents. These drugs damage cancer cell DNA (deoxyribonucleic acid) and stop cancer cells from growing and dividing. Because of this action, alkylating agent chemotherapy is effective against fast‑growing cancers.

Available Doses and Dosage Forms

Melphalan for injection is supplied as five small, single‑use, clear glass vials. Each vial contains 50 mg of dry powder that looks white to pale yellow. Before use, the powder must be mixed with a special liquid provided with the kit. The prepared solution is then given to the patient under medical supervision.

For Patients:

What Is Multiple Myeloma?

Multiple myeloma is a rare type of blood cancer that affects plasma cells. Plasma cells are a kind of white blood cell that normally help your body fight infections by making antibodies. In multiple myeloma, these plasma cells become abnormal and multiply excessively. Instead of making healthy antibodies, they produce faulty proteins called M-proteins.

These abnormal cells crowd out healthy blood cells and can damage your bones and kidneys. As a result, you may experience symptoms such as weakness, frequent infections, bone pain, anemia, and kidney problems. Plasma cell cancer therapy often includes Melphalan chemotherapy to help control the disease.

How Does Melphalan Chemotherapy Work?

• Melphalan works by damaging the DNA inside cancer cells. DNA carries the instructions that tell cells how to grow and divide. When this DNA is damaged, cancer cells cannot survive.

• Cancer cells grow and divide rapidly and are poor at repairing DNA damage. Because of this, Melphalan chemotherapy affects cancer cells more than normal cells.

• Over time, these damaged cancer cells die, which helps slow cancer growth and prevents it from spreading further in your body.

What Should You Tell the Doctor Before Taking Melphalan?

Before starting Melphalan chemotherapy, it is important to tell your doctor if:

• You are allergic to Melphalan or any of its ingredients.

• Are you taking any other medicines, including prescription drugs, vitamins, or herbal supplements?

• You have received Melphalan before, and it did not work for you.

• You have recently had or are planning to receive any vaccinations.

• This medicine can also harm an unborn baby. If you are pregnant, planning to become pregnant, or breastfeeding, tell your doctor right away. Reliable birth control should be used during treatment and for a period after therapy, as advised by your healthcare provider.

How Is Melphalan Dosage Given?

• Melphalan injection is administered by a trained healthcare professional into a vein. The infusion usually takes about 15 to 30 minutes.

• For multiple myeloma treatment, if you cannot take Melphalan tablets, you may receive injections every two weeks for four doses, followed by monthly doses.

• Before a bone marrow transplant, Melphalan may be given once daily for two days to destroy cancer cells and prepare the bone marrow for the transplant.

• If you develop Melphalan side effects, your doctor may delay your treatment or adjust the Melphalan dosage to keep you safe.

What Side Effects Are Associated With Melphalan?

Some side effects are common and usually manageable. Inform your doctor if they become severe or do not improve:

• Heartburn.

• Missed periods (in women).

• Stomach pain.

• Nausea or vomiting.

• Hair loss.

• Mouth or throat sores.

• Changes in taste.

• Diarrhea or constipation.

• Loss of appetite or weight.

Some side effects can be serious and need urgent medical care:

• Shortness of breath.

• Unusual lumps or swelling.

• Itching or rash.

• Swelling of the face, lips, tongue, or throat.

• Blurred vision.

• Yellowing of skin or eyes.

• Dizziness or fainting.

• Injection site pain, redness, swelling, blisters, or sores.

• Trouble breathing or swallowing.

• Pale skin.

• Fast or irregular heartbeat.

• Pain in the upper right abdomen.

• Dark urine.

• Extreme tiredness or weakness.

Missed Dose:

Melphalan should be taken exactly as scheduled. If you miss an appointment or are unable to attend treatment, contact your doctor or healthcare provider as soon as possible.

Overdose:

An overdose is a medical emergency. Get immediate medical help if any of the following occur:

• Vomiting blood.

• Severe nausea or vomiting.

• Severe diarrhea.

• Reduced alertness.

• Seizures.

• Mouth or throat sores.

• Unusual bleeding or bruising.

• Blood in stool or black-colored stools.

Storage:

Melphalan injection should be stored at room temperature, between 20°C and 25°C. Short exposure to slightly higher or lower temperatures is acceptable. Keep the medicine protected from light and handle it carefully, as it is considered a potentially harmful drug.

For Doctors

Who Should Avoid or Use Melphalan Carefully?

Indications:

Melphalan injection, used as part of a hepatic delivery system (kit-based), was indicated for adult patients with uveal melanoma who had unresectable liver metastases involving less than 50 % of the liver. Patients were eligible if there was no extrahepatic disease or if extrahepatic disease was limited only to the bones. Metastases involving the lungs, lymph nodes, or subcutaneous tissues were allowed only if these lesions had already been surgically removed or treated with radiation therapy.

Contraindications:

Melphalan injection was contraindicated in patients with a history of severe allergic reactions to Melphalan. This included anaphylaxis, which is a life-threatening allergic response.

Dosing Considerations:

• Melphalan injection was recommended only for individuals who weighed 70 pounds or more when used with the hepatic delivery system. This restriction existed because catheter placement into the hepatic artery could be difficult in patients with lower body weight.

• The drug was administered by direct infusion into the hepatic artery using the delivery system provided in the kit. The full administration procedure was followed according to the manufacturer’s instructions for use.

• Patients could receive Melphalan injection once every six to eight weeks, with a maximum of six treatment cycles.

• The dose was calculated as 3 mg per kilogram of ideal body weight, and the maximum allowable dose per treatment was 220 mg.

Melphalan for Injection: Kit Description

Each kit contained five single-dose glass vials, each with 50 mg of lyophilized Melphalan powder. The powder appeared white to pale yellow and was reconstituted using the supplied diluents before administration.

Dosing Considerations:

• Those individuals who weigh 35 kilograms or more should only use Melphalan injection in the hepatic delivery system.

• This is because individuals who weigh less may have trouble getting the catheter inserted. The Melphalan injection in the kit is administered by inserting a needle into the hepatic artery.

• The instructions for the use manual should be referred to for the entire process.

• An individual can receive this injection every six to eight weeks, but no more than six times.

• According to a precise calculation, a person should take Melphalan injection at a dosage of 3 milligrams for every kilogram of their optimum body weight. The maximum one should provide in a single dose is 220 milligrams.

Melphalan for Injection: The kit contains five single-dose, transparent glass injection vials containing 50 milligrams of lyophilized white to light yellow powder for reconstitution with the included diluents.

Mechanism of Action:

Melphalan belonged to the class of alkylating agents. It exerted its anticancer effect by damaging DNA within tumor cells. The drug formed cross-links between DNA strands, mainly by binding to the N7 position of guanine. This DNA damage interfered with cell replication and led to cell death. Melphalan was effective against both actively dividing cells and resting tumor cells.

Pharmacodynamics:

Studies assessing the cardiac effects of Melphalan injection showed a mild increase in heart rate-corrected QT interval. On average, QT intervals increased by about 8 milliseconds after treatment. Patients who received 200 mg/m² also showed an average increase in heart rate of 7.5 beats per minute compared to baseline values.

Pharmacokinetics:

• Absorption - There are two stages of absorption after injecting Melphalan. The first stage lasts for around 10 minutes and is rapid, while the second stage is slower and lasts for about 75 minutes. The rate at which the body can eliminate this medication from the blood varies but is normally between seven and nine milliliters per minute per kilogram (ml/min/kg) of body weight.

• Distribution - Melphalan is transported throughout the body after entering the circulation. It can pass across cell membranes, including the blood-brain barrier. Its distribution may be impacted by the ability of Melphalan to attach to blood proteins, notably albumin ( 40 to 60 percent).

• Metabolism - Melphalan is mostly removed from the plasma by chemical hydrolysis into inactive monohydroxy melphalan and dihydroxy melphalan.

• Excretion - Melphalan and its metabolites are mostly eliminated through the kidneys. Both its unmodified form and its metabolites are eliminated in the urine.

Toxicity (Carcinogenesis and Mutagenesis)

Adequate long-term studies on the carcinogenic potential of Melphalan were limited. Animal studies showed that repeated Melphalan exposure led to lung tumors or cancer and abdominal sarcomas in rodents. Other studies demonstrated chromosomal damage in bone marrow cells, suggesting a possible mutagenic and carcinogenic risk. These findings indicated potential long-term risks, though further research was required.

Clinical Studies (Safety and Efficacy)

• Most adverse effects reported with Melphalan injection were temporary and manageable. No unexpected toxic effects were observed.

• All patients experienced myeloablation, meaning suppression of bone marrow activity. This effect was expected and intentional in high-dose chemotherapy settings to allow for stem cell transplantation or elimination of malignant cells.

• High response rates were achieved, and successful engraftment of neutrophils and platelets occurred in most patients.

Warnings and Precautions

• Bone Marrow Suppression: Melphalan caused significant bone marrow suppression, leading to low blood cell counts. Before initiating the treatment, stem cells needed to be kept ready. Blood counts were closely observed, and infections, anemia, and bleeding, if noted, were treated appropriately.

• Gastrointestinal Toxicity: Common side effects like nausea, vomiting, diarrhea, and mouth ulcers were noted. Preventive antiemetics (prevent vomiting) and supportive care were recommended.

• Hypersensitivity: About 2 % of patients experienced allergic reactions, including rash, itching, swelling, bronchospasm, or anaphylaxis. Treatment was stopped immediately in severe cases.

• Hepatotoxicity: Abnormal liver function tests, hepatitis, jaundice, and veno-occlusive disease were reported. Liver function needs regular monitoring.

• Secondary Malignancies: Melphalan could damage chromosomes and increase the risk of secondary cancers, such as leukemia. The risks had to be balanced against treatment benefits.

• Infertility: Melphalan could cause permanent or temporary infertility in both men and women.

• Embryo-Fetal Toxicity: Melphalan could harm a developing fetus. Pregnancy had to be avoided during and after treatment.

Drug Interactions

Formal interaction studies were not conducted. However, kidney damage was reported when Melphalan was combined with cyclosporine. Lung toxicity was increased when combined with BCNU, and severe intestinal injury was reported in children receiving nalidixic acid with Melphalan.

Specific Considerations:

Pregnancy:

• Melphalan can seriously harm an unborn baby if it is given during pregnancy. It may cause birth defects or even lead to the loss of the pregnancy.

• The drug can damage genetic material, which increases the risk of abnormal development of the fetus. Studies in animals have shown that even low doses of melphalan can cause serious birth defects.

• Because of these risks, Melphalan should be avoided during pregnancy, and women should be clearly informed about the dangers to the unborn baby before starting treatment.

Breastfeeding Mothers:

It is not known whether melphalan passes into breast milk. However, many medicines can enter breast milk and may harm a nursing infant. For this reason, breastfeeding should be stopped while receiving melphalan treatment to protect the baby’s health.

Children:

Melphalan has not been adequately studied in children. Since clinical trials did not include pediatric patients, the safety and effectiveness of this drug in children are not established. Therefore, its use in children is generally avoided unless clearly necessary.

Older Adults:

Melphalan works similarly in older and younger adults, and overall safety and effectiveness are comparable. However, older patients have a higher chance of developing a condition called engraftment syndrome, which can occur after bone marrow or stem cell treatment. Studies have shown that this condition is more common in patients aged 65 years and above, so careful monitoring is needed in elderly patients.

Patients With Kidney Problems:

Patients with kidney disease usually do not need a dose reduction when melphalan is used as part of conditioning therapy. However, when melphalan is used for symptom control or palliative treatment, lowering the dose may be safer, especially in those with poor kidney function. Patients with high blood urea nitrogen (BUN) levels are at higher risk of severe bone marrow suppression. The dosage may be reduced by half to reduce the risk of severe bone marrow complications.

Conclusion:

Melphalan is an established safe therapy in cancer therapy, particularly with multiple myeloma. It helps slow disease progression and manage symptoms by destroying cancer cell DNA. Its application should be done with caution and close observation, since the gains may be offset by potential side effects.

A cancer specialist’s guidance is essential to decide if this therapy suits a patient’s overall health and treatment goals.

Key Takeaways

• Melphalan can play an important role in controlling certain cancers, but it is not a cure.

• Its effectiveness depends mainly on the cancer type, stage, and the patient’s condition.

• Thoughtful selection and expert supervision help achieve the best possible outcomes.