Pepaxti (Melflufen)
Melphalan flufenamide – Alkylating Agent for Multiple Myeloma
Quick Facts About Pepaxti
Key Takeaways About Pepaxti
- Pepaxti is a peptide-drug conjugate that delivers concentrated alkylating activity directly inside myeloma cells, potentially overcoming drug resistance.
- It is used in combination with dexamethasone for patients with relapsed or refractory multiple myeloma after at least three prior lines of treatment.
- Severe bone marrow suppression (thrombocytopenia, neutropenia, anaemia) is expected and requires regular blood count monitoring throughout treatment.
- The drug is given as a 30-minute IV infusion once every 28 days, with the dose determined by body weight.
- Secondary malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) have been reported; patients require long-term follow-up.
What Is Pepaxti and What Is It Used For?
Pepaxti contains the active substance melphalan flufenamide (also known as melflufen), a first-in-class peptide-drug conjugate that belongs to the alkylating agent family of anticancer medicines. It was developed to address the significant unmet medical need for patients with heavily pretreated multiple myeloma – a cancer of the plasma cells in the bone marrow.
Multiple myeloma is the second most common blood cancer, characterised by the uncontrolled proliferation of malignant plasma cells in the bone marrow. These abnormal cells produce large amounts of a single type of antibody (monoclonal protein or M-protein), which can damage the kidneys, weaken the bones, suppress the immune system, and cause anaemia. While modern treatments have significantly improved survival outcomes, most patients eventually relapse and require additional lines of therapy.
Pepaxti is specifically indicated for adult patients who have received at least three prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor (such as bortezomib or carfilzomib), one immunomodulatory agent (such as lenalidomide or pomalidomide), and one anti-CD38 monoclonal antibody (such as daratumumab). These patients are considered to have triple-class refractory disease and typically have limited treatment options available.
How Does Pepaxti Work?
The unique mechanism of action of Pepaxti distinguishes it from conventional alkylating agents. Melphalan flufenamide is a highly lipophilic (fat-soluble) peptide-drug conjugate, which allows it to enter cells rapidly through passive diffusion across the cell membrane. Once inside the cell, aminopeptidases – enzymes that are overexpressed in myeloma cells – cleave the peptide bond, releasing the alkylating metabolites desethyl-melphalan flufenamide and melphalan at high intracellular concentrations.
This targeted delivery mechanism is particularly important because myeloma cells express significantly higher levels of aminopeptidases compared to normal cells. As a result, the cytotoxic metabolites accumulate preferentially within myeloma cells, achieving intracellular drug concentrations that are substantially higher than those achievable with conventional melphalan. This can potentially overcome certain forms of drug resistance that limit the effectiveness of traditional alkylating agents.
The alkylating metabolites work by forming covalent bonds with DNA strands, creating cross-links that prevent the DNA from being properly replicated during cell division. This DNA damage triggers programmed cell death (apoptosis) in the myeloma cells. In preclinical studies, melflufen demonstrated cytotoxic activity against myeloma cell lines that were resistant to other alkylating agents, including conventional melphalan.
What Should You Know Before Taking Pepaxti?
Your treating oncologist or haematologist will carefully evaluate whether Pepaxti is appropriate for you based on your medical history, current health status, and the nature of your myeloma disease. Several important factors need to be considered before treatment begins.
Contraindications
You must not receive Pepaxti if you:
- Are allergic (hypersensitive) to melphalan flufenamide or any of the other ingredients in the medicine
- Are breastfeeding – it is not known whether melphalan flufenamide passes into breast milk, and a risk to the breastfed infant cannot be excluded
Warnings and Precautions
Talk to your doctor before receiving Pepaxti if you have any of the following conditions, as they may require special monitoring or dose adjustments:
Thrombocytopenia (low platelet count): Pepaxti causes severe thrombocytopenia in most patients. Low platelet counts increase the risk of bleeding, which can be life-threatening. Your doctor will monitor your platelet count closely and may delay treatment or reduce the dose if your platelets are too low. You should report any unusual bruising, bleeding gums, nosebleeds, blood in the urine or stool, or prolonged bleeding from cuts.
Neutropenia (low neutrophil count): Severe neutropenia significantly increases the risk of serious infections. Febrile neutropenia (fever with very low neutrophil counts) is a medical emergency requiring immediate treatment with antibiotics. Your doctor may prescribe growth factor support (G-CSF) to help your bone marrow recover more quickly between treatment cycles.
Anaemia (low red blood cell count): Most patients will experience anaemia during treatment, which can cause fatigue, weakness, shortness of breath, and dizziness. Blood transfusions may be necessary. Erythropoiesis-stimulating agents may also be considered.
Infections: Due to the immunosuppressive nature of Pepaxti, patients are at increased risk of developing serious infections, including pneumonia, sepsis, and opportunistic infections. Contact your doctor immediately if you develop a fever, chills, cough, sore throat, or any other signs of infection.
Bleeding: In addition to the increased bleeding risk from thrombocytopenia, Pepaxti can cause other bleeding complications. Report any unusual bleeding or bruising to your healthcare team immediately.
Blood clots (thromboembolic events): Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients treated with Pepaxti. Seek immediate medical attention if you experience leg swelling, leg pain, chest pain, or sudden shortness of breath.
Secondary malignancies: Treatment with alkylating agents, including Pepaxti, is associated with an increased risk of developing secondary malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). These conditions may develop months to years after treatment. Long-term follow-up is recommended.
Kidney impairment: Pepaxti and its metabolites are partially excreted through the kidneys. Renal function should be monitored before each cycle. Dose adjustment may be necessary in patients with reduced kidney function. Pepaxti has not been studied in patients on dialysis.
Drug Interactions
Inform your doctor about all medicines you are currently taking, have recently taken, or might take. While formal drug interaction studies with Pepaxti are limited, the following interactions should be considered:
- Live vaccines: Vaccination with live or live-attenuated vaccines must be avoided during treatment with Pepaxti, as the immunosuppressed state may lead to uncontrolled vaccine virus replication and serious infection. Inactivated vaccines may be less effective during treatment.
- Other myelosuppressive agents: Concomitant use of other medicines that suppress bone marrow function may increase the risk and severity of myelosuppression.
- Nalidixic acid: Concurrent administration with nalidixic acid has been associated with an increased risk of haemorrhagic enterocolitis and death in the context of high-dose melphalan therapy, and should be avoided.
- Ciclosporin: The combination may result in renal impairment due to cumulative nephrotoxic effects.
Pregnancy and Breastfeeding
Melphalan flufenamide may impair fertility in both men and women. Male patients should consider sperm preservation before starting treatment, as the drug may cause irreversible infertility. Women of childbearing potential should discuss fertility preservation options with their healthcare team before beginning therapy.
Breastfeeding must be discontinued before starting Pepaxti treatment. It is not known whether melphalan flufenamide or its metabolites are excreted in human breast milk, and a risk to the breastfed infant cannot be excluded.
Vaccination Considerations
Patients receiving Pepaxti must not receive live or live-attenuated vaccines due to the risk of vaccine-related infection. If vaccination is necessary, only inactivated vaccines should be used, although their efficacy may be reduced due to immunosuppression. Discuss all vaccination plans with your oncologist. Household contacts of Pepaxti-treated patients should also avoid live vaccines where possible, or take precautions to avoid transmission.
What Is the Correct Dosage of Pepaxti?
Pepaxti is a hospital-administered medicine that must be prepared and given by healthcare professionals experienced in the use of anticancer agents. The powder must be reconstituted and then diluted before intravenous administration. Treatment should continue until disease progression or unacceptable toxicity occurs.
Adults weighing more than 60 kg
Dose: 40 mg intravenously once every 28 days
Administration: Infused over approximately 30 minutes
Adults weighing 60 kg or less
Dose: 30 mg intravenously once every 28 days
Administration: Infused over approximately 30 minutes
Dexamethasone (combination)
Dose: 40 mg orally on days 1, 8, 15 and 22 of each 28-day cycle
For patients over 75 years: consider 20 mg dexamethasone on the same schedule
Dose Adjustments
Your doctor may need to delay treatment, reduce the dose, or permanently discontinue Pepaxti based on your blood count results and other side effects. The following general principles apply:
| Toxicity | Criteria | Action |
|---|---|---|
| Thrombocytopenia | Platelet count < 50,000/µL on Day 1 | Delay treatment until platelets ≥ 50,000/µL; consider dose reduction |
| Neutropenia | ANC < 1,000/µL on Day 1 | Delay treatment until ANC ≥ 1,000/µL; consider G-CSF support |
| Febrile neutropenia | Grade 3–4 febrile neutropenia | Delay treatment; reduce dose by one level; add G-CSF prophylaxis |
| Anaemia | Haemoglobin < 8 g/dL | Consider transfusion support; delay if symptomatic; consider dose reduction |
| Renal toxicity | Serum creatinine ≥ 2x baseline or CrCl < 30 mL/min | Delay treatment; reassess renal function; consider discontinuation |
Dose reductions should follow a stepwise approach. For patients receiving 40 mg, the first dose reduction is to 30 mg and the second dose reduction is to 20 mg. For patients receiving 30 mg, the first dose reduction is to 20 mg. If further dose reduction below 20 mg is required, Pepaxti should be permanently discontinued.
Missed Dose
If a scheduled dose is missed or delayed, it should be administered as soon as possible. The next dose should then be given at the appropriate interval (28 days) from the rescheduled dose. Two doses should never be given at the same time to make up for a missed dose.
Overdose
As Pepaxti is administered by healthcare professionals in a controlled clinical setting, overdose is unlikely but could result in severe, potentially life-threatening myelosuppression. There is no specific antidote for melphalan flufenamide overdose. In the event of an overdose, the patient should be closely monitored for signs and symptoms of adverse reactions, particularly bone marrow suppression, and supportive care should be provided as clinically indicated. This may include blood transfusions, growth factor support, and antimicrobial prophylaxis.
What Are the Side Effects of Pepaxti?
- High fever (38.5°C/101.3°F or above), chills, or signs of severe infection
- Unusual or heavy bleeding, blood in urine or stool, or vomiting blood
- Sudden chest pain, shortness of breath, or leg swelling (signs of blood clot)
- Severe headache, confusion, or visual disturbances
- Signs of a severe allergic reaction: rash, itching, swelling of face or throat, difficulty breathing
Like all medicines, Pepaxti can cause side effects, although not everybody gets them. Most side effects are related to the drug's effect on the bone marrow and immune system. Your oncology team will monitor you closely and provide supportive care as needed.
Very Common (may affect more than 1 in 10 people)
- Thrombocytopenia (low platelet count)
- Neutropenia (low neutrophil count)
- Anaemia (low red blood cell count)
- Pneumonia (lung infection)
- Upper respiratory tract infection
- Diarrhoea
- Nausea
- Pyrexia (fever)
- Cough
- Dyspnoea (shortness of breath)
- Fatigue
- Asthenia (weakness)
Common (may affect up to 1 in 10 people)
- Sepsis (blood infection)
- Febrile neutropenia (fever with low white blood cells)
- Lymphopenia (low lymphocyte count)
- Leukopenia (low total white blood cell count)
- Decreased appetite
- Hypokalaemia (low potassium)
- Hyperuricaemia (high uric acid)
- Headache
- Dizziness
- Dyspnoea on exertion
- Epistaxis (nosebleeds)
- Vomiting
- Deep vein thrombosis (DVT)
- Bruising (contusion)
Uncommon (may affect up to 1 in 100 people)
- Septic shock
- Pulmonary embolism (blood clot in lung)
- Myelodysplastic syndrome (MDS)
- Acute myeloid leukaemia (AML)
The severity and duration of bone marrow suppression typically worsen with successive treatment cycles. Thrombocytopenia is usually the most pronounced and dose-limiting haematological toxicity. Platelet nadirs (lowest point) typically occur around day 15 of each 28-day cycle, with recovery by the start of the next cycle in most patients. However, recovery may be delayed, particularly in later treatment cycles.
Infections are a significant concern due to the prolonged neutropenia caused by Pepaxti. Pneumonia and upper respiratory tract infections are the most commonly reported infections. Patients should be advised to report any signs of infection promptly and should avoid contact with individuals who have active infections whenever possible.
How Should You Store Pepaxti?
Pepaxti is a hospital-administered medicine, and its storage is the responsibility of the hospital pharmacy. However, understanding the storage requirements helps patients appreciate the careful handling this medicine requires:
- Temperature: Store in a refrigerator at 2–8°C (36–46°F)
- Light protection: Keep the vial in the original outer carton to protect from light
- Do not freeze: The product must not be frozen
- After reconstitution: The reconstituted solution should be used within a specified time frame as detailed in the prescribing information. Chemical and physical in-use stability has been demonstrated for limited hours under controlled conditions.
- After dilution: The diluted solution for infusion should be administered promptly. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
As with all medicines, Pepaxti should be kept out of the sight and reach of children. Do not use this medicine after the expiry date stated on the carton and vial label. Healthcare professionals should follow cytotoxic handling procedures for preparation and disposal of this medicine.
What Does Pepaxti Contain?
Understanding the composition of your medicine can help you discuss any concerns with your healthcare team, particularly if you have known allergies or intolerances to specific ingredients.
| Component | Details |
|---|---|
| Active substance | Melphalan flufenamide 20 mg (as hydrochloride) |
| Excipient | Sucrose |
| Physical form | White to off-white lyophilised powder |
| Container | Type I glass vial with bromobutyl rubber stopper and aluminium seal |
| After reconstitution | Clear, colourless solution |
| Manufacturer | Oncopeptides AB, Stockholm, Sweden |
Melphalan flufenamide hydrochloride is the salt form of the active substance used in the pharmaceutical formulation. The molecular structure consists of a melphalan moiety linked to a para-fluoro-L-phenylalanine ethyl ester via a peptide bond. This lipophilic peptide-drug conjugate design is what allows the drug to rapidly enter cells and achieve high intracellular concentrations of active alkylating metabolites.
Sucrose is the only excipient and serves as a lyoprotectant and bulking agent to maintain the stability and structure of the lyophilised powder during storage. Patients with rare hereditary problems of fructose intolerance should be aware of the sucrose content, although the amount administered per dose is small.
Frequently Asked Questions
Pepaxti (melphalan flufenamide) is used in combination with dexamethasone to treat adult patients with multiple myeloma – a type of blood cancer affecting plasma cells in the bone marrow. It is specifically approved for patients whose cancer has returned or stopped responding after at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. It represents a treatment option for patients with limited remaining therapeutic choices.
Pepaxti is given as an intravenous (IV) infusion over approximately 30 minutes. It is administered once every 28 days (4 weeks) at a hospital or clinic by healthcare professionals experienced in anticancer therapy. The powder must be reconstituted and diluted before administration. Patients typically need to attend the clinic for blood tests before each cycle and for the infusion itself.
The most serious side effects of Pepaxti include severe bone marrow suppression (myelosuppression), which can lead to life-threatening infections, serious bleeding, and severe anaemia requiring transfusions. Other serious risks include sepsis, pulmonary embolism, deep vein thrombosis, and the development of secondary malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Regular blood count monitoring is essential to detect and manage these complications early.
No, Pepaxti must not be used during pregnancy. Based on its mechanism of action as an alkylating agent that damages DNA, it is expected to cause foetal harm. Women of childbearing potential must use effective contraception during treatment and for 6 months after the last dose. Male patients must also use contraception during treatment and for 3 months after the last dose. A pregnancy test must be confirmed negative before starting treatment. If pregnancy occurs during treatment, inform your doctor immediately.
Pepaxti has a unique mechanism that distinguishes it from other myeloma treatments. As a peptide-drug conjugate, it is designed to rapidly enter cells and then be activated inside them by aminopeptidases, which are overexpressed in myeloma cells. This results in much higher intracellular concentrations of the active alkylating agent compared to conventional melphalan. This targeted delivery may help overcome certain forms of drug resistance. Unlike oral medications, Pepaxti is administered as an IV infusion, ensuring complete and predictable drug delivery.
Comprehensive monitoring is essential during Pepaxti treatment. Complete blood counts (including platelets, neutrophils, and haemoglobin) must be checked at baseline, weekly during the first two cycles, and at least every two weeks in subsequent cycles. Renal function tests (serum creatinine, estimated GFR) should be assessed before each cycle. Liver function tests should also be monitored periodically. Your doctor will watch for signs of infection, bleeding, thrombosis, and secondary malignancies throughout treatment and during follow-up.
References
- European Medicines Agency (EMA). Pepaxti (melphalan flufenamide) – EPAR summary for the public. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/pepaxti
- Richardson PG, Oriol A, Larocca A, et al. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. Journal of Clinical Oncology. 2021;39(7):757–767. doi:10.1200/JCO.20.02259
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 3.2025.
- World Health Organization (WHO). Model List of Essential Medicines. 23rd Edition, 2023.
- Mateos MV, Bladé J, Bringhen S, et al. Melflufen in relapsed or refractory multiple myeloma: the OCEAN trial. The Lancet Haematology. 2023;10(3):e191–e201.
- National Institute for Health and Care Excellence (NICE). Technology Appraisals: Multiple Myeloma treatments. Available at: https://www.nice.org.uk
- Wickström M, Nygren P, Larsson R, et al. Melflufen – a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8(39):66641–66655.
Editorial Team
This article was written and reviewed by the iMedic Medical Editorial Team, comprising specialist physicians in oncology, haematology, and clinical pharmacology. All content follows the GRADE evidence framework and adheres to international clinical guidelines.