Carfilzomib

Carfilzomib is an anticancer medicine belonging to the proteasome inhibitor class and is used primarily to treat adults with relapsed or refractory multiple myeloma. It is a second-generation, epoxyketone-based proteasome inhibitor that irreversibly inhibits the chymotrypsin-like activity of the 20S proteasome. Proteasomes normally break down proteins that are no longer needed or have been damaged. Blocking this process causes accumulation of proteins and cellular stress, which can lead to apoptosis in susceptible myeloma cells. Carfilzomib is administered by intravenous infusion and is not available as an oral or subcutaneous formulation. Depending on the treatment regimen, it may be administered once weekly or twice weekly and can be used alone or in combination with medicines such as dexamethasone, lenalidomide, daratumumab, or isatuximab. Its clinical importance comes from its established role in relapsed or refractory multiple myeloma and the availability of several dosing schedules and combination regimens. Treatment requires careful clinical and laboratory monitoring because the medicine can affect blood counts, cardiovascular function, renal function, blood pressure, and other organ systems.

Carfilzomib was developed as a selective and irreversible proteasome inhibitor and was initially identified during research into epoxyketone-based proteasome inhibitors. Early clinical development focused on patients with relapsed or refractory multiple myeloma. The U.S. Food and Drug Administration (FDA) granted the first approval for carfilzomib on July 20, 2012, initially for patients with multiple myeloma who had received at least two prior therapies, including bortezomib and an immunomodulatory agent, and whose disease had progressed during or shortly after completion of the last therapy. Subsequent FDA approvals expanded its use to additional combination regimens and earlier lines of treatment. Current U.S. prescribing information includes use in combination with lenalidomide and dexamethasone, dexamethasone, daratumumab and dexamethasone, daratumumab with hyaluronidase-fihj and dexamethasone, or isatuximab and dexamethasone, as well as use as monotherapy in specified patients with relapsed or refractory multiple myeloma. In the European Union, marketing authorisation for Kyprolis was granted by the European Commission on November 19, 2015 following an assessment by the European Medicines Agency (EMA). Major clinical development programs included ASPIRE, ENDEAVOR, and ARROW, which evaluated different carfilzomib-based regimens in relapsed or refractory multiple myeloma.

Carfilzomib is used for adults with relapsed or refractory multiple myeloma. Under current U.S. labeling, it can be administered in combination with lenalidomide and dexamethasone, dexamethasone alone, daratumumab and dexamethasone, daratumumab with hyaluronidase-fihj and dexamethasone, or isatuximab and dexamethasone in patients who have received one to three prior lines of therapy, depending on the specific regimen. It is also approved as a single agent for adults with relapsed or refractory multiple myeloma who have received one or more prior lines of therapy. In the European Union, approved indications include combination treatment with dexamethasone, lenalidomide and dexamethasone, or daratumumab and dexamethasone after at least one prior therapy. The appropriate regimen depends on previous treatment, disease status, patient factors, and the applicable regulatory indication.

Carfilzomib is administered by intravenous infusion, and the dose and schedule depend on the treatment regimen. Approved U.S. regimens include once-weekly dosing that begins at 20 mg/m² and may increase to 70 mg/m² if tolerated, as well as twice-weekly schedules using different dose levels. A once-weekly 20/70 mg/m² schedule is used with certain combination regimens, while twice-weekly 20/56 mg/m² or 20/27 mg/m² schedules are used with other combinations or as monotherapy. Infusion duration also varies according to the regimen. Treatment is generally continued until disease progression or unacceptable toxicity. Dose interruption, reduction, or discontinuation may be required for clinically significant adverse reactions. Adequate hydration is generally recommended, particularly during the first treatment cycle, while fluid administration should be individualized in patients at risk of cardiac or renal complications. Blood counts, renal function, electrolytes, blood pressure, liver function, and clinically relevant cardiac and pulmonary findings should be monitored during treatment.

Common side effects of carfilzomib vary depending on whether it is administered alone or with other medicines. Frequently reported adverse reactions include anemia, fatigue, thrombocytopenia, nausea, fever, diarrhea, headache, cough, shortness of breath, peripheral edema, hypertension, upper respiratory tract infections, and insomnia. Reduced platelet counts and other blood-cell abnormalities may occur during treatment and can require laboratory monitoring. The frequency and severity of adverse effects can differ between approved regimens and between individual patients. Symptoms should be discussed with the treating healthcare professional because some complaints may indicate an adverse reaction requiring assessment or treatment modification.

Important serious risks associated with carfilzomib include cardiac toxicity, including heart failure and myocardial ischemia; acute renal failure; tumor lysis syndrome; pulmonary toxicity; pulmonary hypertension; severe shortness of breath; uncontrolled hypertension; venous thromboembolic events; infusion-related reactions; serious bleeding; thrombocytopenia; hepatic toxicity or hepatic failure; thrombotic microangiopathy; posterior reversible encephalopathy syndrome; and progressive multifocal leukoencephalopathy. Treatment may need to be interrupted, dose-reduced, or discontinued depending on the severity and nature of the toxicity. Carfilzomib can cause embryo-fetal toxicity, so appropriate pregnancy prevention and reproductive counselling are important. Patients with pre-existing cardiovascular, renal, pulmonary, hepatic, or other significant conditions require individualized assessment before and during treatment.

Before treatment, patients should be assessed for cardiovascular disease, renal impairment, pulmonary symptoms, hypertension, bleeding risk, hepatic impairment, and other clinically important conditions. Baseline and ongoing monitoring commonly includes complete blood counts, renal function, electrolytes, liver tests, and blood pressure. Hydration should be individualized because excessive fluid administration can increase the risk of cardiac complications in susceptible patients. Patients receiving hemodialysis should generally receive carfilzomib after the dialysis procedure. Dose adjustment is recommended for patients with mild or moderate hepatic impairment according to current prescribing information. Carfilzomib does not have the same degree of classic CYP-mediated drug-interaction potential associated with some small-molecule medicines, but concomitant medicines should still be reviewed for additive toxicities and other clinically relevant interactions. Vaccine decisions should be individualized during cancer treatment, and patients should discuss vaccination timing with their healthcare professional. Breastfeeding is not recommended during treatment according to current U.S. prescribing information.

Before initiating treatment, confirm the indication, previous myeloma therapies, selected combination regimen, baseline blood counts, renal function, electrolytes, liver function, blood pressure, fluid status, and relevant cardiovascular and pulmonary history. Ensure that the prescribed dose, body-surface-area calculation, dose-escalation schedule, infusion duration, and treatment-cycle schedule correspond to the selected regimen. Hydration should be adequate while avoiding unnecessary fluid overload. Dexamethasone premedication should be administered according to the relevant regimen and prescribing information to reduce the risk of infusion-related reactions. During treatment, monitor blood counts, renal function, potassium and other electrolytes, blood pressure, liver tests, and symptoms suggesting cardiac, pulmonary, thrombotic, bleeding, infusion-related, or neurologic complications. Pharmacists and infusion teams should also review concomitant medicines and apply appropriate dose interruptions or reductions when clinically significant toxicity occurs.