Melphalan flufenamide

What is melphalan flufenamide (melflufen, Pepaxti®)?

Melphalan flufenamide is a drug used to treat myeloma (also known as multiple myeloma), manufactured by Oncopeptides AB. You may hear it called by its brand name, Pepaxti®, or by the name “melflufen”.
Melflufen is authorised for use in the European Union since August 2022.
Melflufen together with dexamethasone is indicated for treating myeloma patients who have received at least three prior lines of therapy and are refractory (i.e. no longer responding) to at least one proteasome inhibitor, one immunomodulatory agent and one anti-CD38 monoclonal antibody. Also, patients being administered melflufen have progressed on or after their previous treatment line. Patients who have received an autologous stem cell transplant should have had three years or more after the transplantation without their disease worsening.

How does melphalan flufenamide work?

Melflufen is a medicine called a peptide drug conjugate –consisting of a cytotoxic agent, which is capable of killing cells (called melphalan) and a peptide (a small protein). Melphalan is an older chemotherapy drug commonly used to treat myeloma. Melflufen is a modified version of melphalan. Specifically, adding a peptide to melphalan helps the melphalan more rapidly and efficiently find and enter myeloma cells, resulting in a more effective drug.

Once melflufen is inside myeloma cells, it is broken down into its active form, releasing the chemotherapy drug melphalan. Melphalan then changes the structure of the DNA, which prevents the cells from replicating, and ultimately kills the myeloma cell. 

What are the benefits of melphalan flufenamide?

The safety and efficacy of melflufen were evaluated in the phase II HORIZON study in 157 relapsed/refractory myeloma patients who were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Of the 157 patients enrolled, 29% of those who received treatment had a response (a reduction in signs and symptoms of myeloma). In addition, the progression-free survival (the time from treatment to the progression of disease or death) was 4.2 months and overall survival (the median time patients lived after treatment) was 11.6 months.

Additionally, the phase III OCEAN trial investigated treatment with melflufen in 495 relapsed/refractory myeloma patients who received 2-4 lines of prior therapy and were refractory to lenalidomide. This study compared the efficacy of pomalidomide with melflufen. The results show that treatment with melflufen lengthens the time before disease progression or death compared to pomalidomide.

Although melflufen is authorised in the European Union, it is important to note that in 2021, the United States (US) Food and Drug Administration (FDA) first approved melflufen but later suspended enrolment in all ongoing melflufen trials in the US. The reason behind this decision was that results from the OCEAN trial showed that patients in the melflufen group were 10% more likely to die compared to patients in the pomalidomide group. Further analysis demonstrated that the overall survival of patients was higher in the melflufen group where patients who had their disease worsening in less than 3 years after a stem cell transplant were excluded from the analysis. This is why the EMA recommends melflufen not to be given to patients who had their disease worsening within 3 years after receiving a stem cell transplant. Melflufen is no longer available in the US.

How is melphalan flufenamide given?

Melflufen is administered through an infusion (drip) for over 30 minutes into a vein and is usually given once every 28 days. The specific dose of melflufen may vary depending on your body weight, any side effects that you may experience and your response to the medication.

Patients receiving melflufen will also receive dexamethasone (40 mg by mouth, or 20mg by mouth, if older than 75) on days 1, 8, 15 and 22 of each 28-day cycle.

What are the side-effects of melphalan flufenamide?

The safety of melflufen has been evaluated in 497 patients. The most frequent blood abnormalities were:

• thrombocytopenia (decreased platelets, needed for blood clotting; 83%),
• neutropenia (decreased neutrophils, a type of immune/white blood cell; 72%),
• anaemia (decreased red blood cells; 66%)

Changes in blood levels can be seen throughout treatment and will likely require frequent monitoring. Taking melflufen may increase your risk of infection, and therefore you may be advised to take precautions to prevent infection such as handwashing, wearing a mask and avoiding large crowds. Your doctor may also recommend that you be up to date on vaccinations before treatment. In addition, you may be advised to take precautions to limit your risk of falling (e.g., removing trip hazards from your home), as low platelets can increase your risk of bleeding.

As well as changes in the blood, the other most frequent side effects seen with melflufen were:

• Nausea (21%)
• Diarrhoea (19%)
• Fever (19%)
• Fatigue
• Weakness
• Cough
• Shortness of breath (dyspnoea)

Melflufen can also commonly cause the following side effects which may affect up to 1 in 10 people:

• Headache
• Dizziness
• Vomiting
• Low potassium level
• Decreased appetite

The most frequent serious side effects that have been observed with  melflufen   were pneumonia (11%), respiratory tract infection (4%) and thrombocytopenia (5%).

Side effects related to melflufen can occur at any time throughout treatment. Some side effects may be managed with observation, blood product replacement, or growth stimulation drugs. Also, supportive care and other symptom-specific treatments (e.g., antibiotics for bacterial infections, antinausea drugs, or diarrhoea medications) can be prescribed. It is important to communicate with your doctor regarding any symptoms you are experiencing so that they may treat your side effects appropriately.