Melphalan Flufenamide

Melphalan flufenamide is a peptide-conjugated alkylating drug, made of a dipeptide and an alkylating moiety of the nitrogen mustard group. Its lipophilic structure lets it enter cells rapidly, where it is cleaved to the active alkylating metabolite melphalan.

Mechanism of Action

• Cell entry: the lipophilic intact peptide conjugate is distributed rapidly into cells by passive transport.
• Intracellular activation: esterases and peptidases bind it and convert it to melphalan. Aminopeptidase activity is raised in many malignant cells, which favours the release of melphalan inside tumour cells.
• DNA damage: as with other nitrogen mustards, cross-linking of DNA underlies the antitumour activity. In cellular assays it inhibited proliferation and induced apoptosis of haematopoietic tumour cells. In laboratory work it produced DNA-damage signals faster than melphalan itself, and also in melphalan-resistant cells.
• p53 status: cytotoxic activity was retained in myeloma cells with absent or impaired p53 function.
• Dexamethasone: the two medicines showed synergistic cytotoxicity in melphalan-resistant and non-resistant myeloma cell lines.
• Cardiac electrophysiology: at the approved dose there was no clinically relevant effect on the PR interval, QRS interval or QTc interval.

Pharmacokinetics

• Absorption: after a 40 mg dose, melphalan flufenamide reached an average peak plasma concentration of 159 ng/mL during the 30-minute infusion. The active metabolite melphalan peaked 4–15 minutes after the end of the infusion (peak 432 ng/mL, AUC 873 ng·h/mL after a single dose). Peripheral and central venous infusion are bioequivalent. Exposure rises roughly in proportion to dose over 25–130 mg.
• Distribution: melphalan flufenamide leaves the plasma quickly by distribution to peripheral tissues. Volume of distribution is 35 L for melphalan flufenamide and an apparent 76 L for melphalan.
• Metabolism: in tissues, to desethyl-melphalan flufenamide and to melphalan; there is no appreciable conversion to melphalan in plasma. Melphalan is mainly hydrolysed spontaneously to monohydroxy- and dihydroxy-melphalan.
• Elimination: half-life is 2.1 minutes for melphalan flufenamide and 70 minutes for melphalan; clearance is 692 L/h and 23 L/h respectively. Renal and hepatic excretion of the unchanged compound is negligible.
• Special populations: age and sex had no effect on melphalan exposure. Melphalan AUC was on average 6% higher in mild renal impairment, 18% higher in moderate impairment with eGFR 45–60 and 32% higher with eGFR 30–45 mL/min/1.73 m² than with normal renal function. Mild hepatic impairment made no difference; the effect of moderate or severe impairment is not known. At 60 kg body weight, peak concentration was on average 36% higher and AUC 31% higher than at 95 kg.

Pepaxti is indicated, in combination with dexamethasone, for the treatment of adults with multiple myeloma:

• who have received at least three prior lines of therapy;
• whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent and one anti-CD38 monoclonal antibody;
• and who have shown 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.

• Hypersensitivity to melphalan flufenamide or to any of the excipients.
• Breastfeeding.

The safety data cover 491 patients with multiple myeloma (13 treated alone and 478 with dexamethasone), including 147 with triple-class refractory disease. The most frequent reactions are thrombocytopenia (83%), neutropenia (72%), anaemia (66%), nausea (21%), diarrhoea (19%) and pyrexia (19%). The most frequent serious reactions are pneumonia (11%), thrombocytopenia (5%) and respiratory tract infection (4%).

Very common (≥1/10): pneumonia, respiratory tract infection, thrombocytopenia, neutropenia, anaemia, dyspnoea, cough, diarrhoea, nausea, pyrexia, fatigue, asthenia.

Common (≥1/100 to <1/10): sepsis, febrile neutropenia, leukopenia, lymphopenia, decreased appetite, hypokalaemia, hyperuricaemia, headache, dizziness, deep vein thrombosis, haematoma, exertional dyspnoea, epistaxis, vomiting.

Uncommon (≥1/1,000 to <1/100): septic shock, myelodysplastic syndrome, acute myeloid leukaemia, pulmonary embolism.

Selected reactions in more detail:

• Thrombocytopenia: grade 3 or 4 in 74% of patients, in 33% during the first cycle, with a median time to onset of 43 days. It led to dose delay, dose reduction and discontinuation in 41%, 23% and 12% of patients.
• Bleeding: any grade in 21% of patients, grade 3 in 2% and grade 4 in under 1%. Epistaxis (6%) and unspecified haematoma (2%) were the most frequent.
• Neutropenia: grade 3 or 4 in 66% of patients, in 38% during the first cycle, with a median time to onset of 22 days. Febrile neutropenia occurred in 4%. Clinically significant infections (grade 3 or higher) occurred in 8% of patients with concurrent grade 3–4 neutropenia.
• Infections: any infection in 52% of patients, mostly pneumonia and other respiratory tract infections; the most severe can be fatal.
• Anaemia: grade 3 in 41% of patients and grade 4 in 1%.
• Second primary malignancies: myelodysplastic syndrome and acute myeloid leukaemia were uncommon in clinical studies.

No interaction studies have been performed with melphalan flufenamide. On the available in vitro and clinical data, the risk of pharmacokinetic or pharmacodynamic interactions is low.

• Dexamethasone: the intended combination partner (see Administration and Dosage).
• Live attenuated vaccines: a risk of severe illness, which may be fatal, has been described with the metabolite melphalan, and is higher in patients already immunosuppressed by their disease. Use an inactivated or mRNA-based vaccine where one exists.
• Lenalidomide or thalidomide: Pepaxti is not indicated in combination with them (see Mutagenicity and Second Malignancies).

Treatment must be initiated and supervised by physicians experienced in the treatment of multiple myeloma. Pepaxti is for intravenous use only. It is reconstituted and diluted by a healthcare professional, and infusion of the diluted solution must begin within 60 minutes of the start of reconstitution, or the solution must be placed in a refrigerator within 30 minutes of the start of reconstitution. It is given as a 30-minute infusion through a peripheral vein or a central venous access device such as a PICC or tunnelled central venous catheter. If given peripherally, the veins should be alternated. In case of extravasation, stop the infusion immediately and use a central venous line.

Recommended Dose

• Pepaxti: 40 mg on Day 1 of each 28-day cycle. For patients weighing 60 kg or less, the starting dose is 30 mg. Treatment continues until disease progression or unacceptable toxicity.
• Dexamethasone: 40 mg orally on Days 1, 8, 15 and 22 of each 28-day cycle; 20 mg for patients aged 75 years and older.
• Supportive medicines: prophylactic antimicrobials should be considered to reduce the risk of infection, and anti-emetics should be given before and during treatment at the physician’s discretion.

Dose Modification for Adverse Reactions

• Withhold Pepaxti if the neutrophil count is below 1 × 10⁹/L or the platelet count is below 50 × 10⁹/L on an intended dosing day. Monitor the count weekly until neutrophils are 1 × 10⁹/L or higher, or platelets 50 × 10⁹/L or higher, then resume at one dose level lower.
• Dose levels above 60 kg: 40 mg, then 30 mg, 20 mg and 15 mg. At 60 kg or less: 30 mg, then 20 mg and 15 mg. Permanently discontinue if the patient cannot tolerate 15 mg.
• Non-haematological reactions, grade 2: consider withholding until resolved to grade 1 or baseline, and consider resuming one dose level lower.
• Non-haematological reactions, grade 3 or 4: withhold until resolved to grade 1 or baseline, and consider resuming one dose level lower.

Special Populations

• Elderly: no dose adjustment (the dexamethasone dose is lower from 75 years).
• Renal impairment: no adjustment if eGFR is above 45 mL/min/1.73 m²; 30 mg is recommended for eGFR 30–45; there are insufficient data below 30.
• Hepatic impairment: no adjustment in mild impairment; insufficient data in moderate or severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Thrombocytopenia

Platelet counts are monitored at baseline, during treatment and as clinically indicated, more often in the first two months. Pepaxti must not be given if platelets are below 50 × 10⁹/L; withhold until they reach 50 × 10⁹/L or more (without recent transfusion) and resume one dose level lower. Transfusion may be considered. Patients should report any bleeding or bruising.

Neutropenia and Infections

Neutrophil counts are monitored in the same way. Pepaxti must not be given if the count is below 1 × 10⁹/L. Growth factors and/or prophylactic antimicrobials may be considered. Infections, including grade 3 or higher pneumonia and upper respiratory tract infection, can occur, so patients should be watched closely and report signs of infection.

Anaemia

Red blood cell counts are monitored at baseline, during treatment and as clinically indicated, more often in the first two months. Transfusion and/or erythropoietin may be considered.

Gastrointestinal Events

Nausea and diarrhoea are very common and vomiting is common. Prophylaxis with anti-emetics should be considered before and during the infusion.

Thromboembolic Events

Venous thromboembolic events have been seen with Pepaxti and dexamethasone. Patients with known risk factors, including prior thrombosis, should be closely monitored. Prophylaxis is decided after careful assessment of each patient’s risk, including thrombocytopenia, and anti-thrombotic prophylaxis can be considered in high-risk patients.

Extravasation

Melphalan flufenamide can cause local tissue damage if it leaks out of the vein.

Mutagenicity and Second Malignancies

Melphalan, the metabolite, is mutagenic in animals and has caused chromosome aberrations in patients. Acute myeloid leukaemia and myelodysplastic syndromes have occurred, and the leukaemogenic risk must be weighed against the benefit; patients are monitored closely before and during treatment. Alkylating agents are linked to second primary malignancies, and melphalan with lenalidomide and prednisone (and, less so, thalidomide and prednisone) raises the risk of solid second tumours in elderly patients with newly diagnosed myeloma. Pepaxti is not indicated in combination with lenalidomide or thalidomide.

Prior Autologous Stem Cell Transplantation

Pepaxti is not recommended in patients who progressed within 36 months after an autologous stem cell transplantation. In post-hoc analyses of the randomised OCEAN trial, such patients survived for a shorter time on melphalan flufenamide and dexamethasone than on the pomalidomide and dexamethasone comparator.

Conditioning Before Transplantation

The efficacy and safety of doses needed for myeloablation have not been studied. Pepaxti should not be used as conditioning treatment before stem cell transplantation.

Renal Impairment

Patients with renal impairment may have marked bone marrow suppression and should be monitored closely.

Live Vaccines

See Drug Interactions: use an inactivated or mRNA-based vaccine where one exists.

Pregnancy, Breastfeeding and Fertility

• Contraception: male and female patients should use effective, reliable contraception until six months after treatment ends.
• Pregnancy: there are no human data. Animal studies with melphalan showed reproductive toxicity, and because of its genotoxic properties and structural similarity to known teratogens, melphalan flufenamide may cause congenital malformations. It should not be used in pregnancy unless the woman’s condition requires it.
• Breastfeeding: contraindicated, because of its genotoxic properties.
• Fertility: it is expected to suppress ovarian function in premenopausal women, causing amenorrhoea in many. Animal studies showed adverse effects on spermatogenesis, so male fertility may be affected temporarily or permanently; storing semen before treatment is advised.

Effect on Driving

Pepaxti has a moderate influence on the ability to drive and use machines. Dizziness and nausea may affect it.

Store the vials in a refrigerator at 2–8 °C, in the original package to protect from light. Do not freeze. The vials are transported and held under cold-chain conditions until they are prepared by the healthcare professional. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vial: 4 years.
• Diluted solution: use immediately. If not used immediately, it can be kept in a refrigerator (2–8 °C) for up to 6 hours before administration; do not freeze. If refrigerated, let the solution reach room temperature (20–25 °C) for no more than 30 minutes before administration. The diluted solution may be kept at room temperature for up to 1.5 hours, including infusion time.

Prescription only (Rx), subject to restricted medical prescription: treatment must be started and supervised by physicians experienced in treating multiple myeloma. Pepaxti is reconstituted, diluted and infused by healthcare professionals, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions (2–8 °C).