Carfilzomib is a proteasome inhibitor used for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. It is administered in combination with other agents such as lenalidomide and dexamethasone, dexamethasone alone, daratumumab with dexamethasone, daratumumab with hyaluronidase-fihj and dexamethasone, or isatuximab with dexamethasone. It may also be used as a single-agent therapy in patients who have received one or more prior treatments.

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, which is part of the 26S proteasome complex. It exhibits antiproliferative and proapoptotic effects in both solid and hematologic tumor cells. In animal studies, it has been shown to inhibit proteasome activity in blood and tissues and to delay tumor growth in models of multiple myeloma and other cancers.

Hydration: Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Carfilzomib administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles. Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure.

Premedications and Concomitant Medications: Premedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Carfilzomib during Cycle 1 to reduce the incidence and severity of infusion-related reactions. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles. Provide thromboprophylaxis for patients being treated with Carfilzomib in combination with other therapies. Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation.

Electrolyte Monitoring: Monitor serum potassium levels regularly during treatment with Carfilzomib.

Clinical Studies: Carfilzomib does not significantly affect the pharmacokinetics of sensitive CYP3A substrates such as midazolam when used together.

In Vitro Studies: Carfilzomib shows direct and time-dependent inhibition of CYP3A enzymes but does not induce CYP1A2 or CYP3A4 in vitro.

Effect of Transporters on Carfilzomib: Carfilzomib is a substrate of P-glycoprotein (P-gp) in vitro.

Effect of Carfilzomib on Transporters: Carfilzomib inhibits P-gp in vitro; however, due to intravenous administration and extensive metabolism, its pharmacokinetics are unlikely to be significantly affected by P-gp inhibitors or inducers.

In monotherapy, the most common adverse reactions (occurring in at least 20% of patients) include anemia, fatigue, thrombocytopenia, nausea, fever, shortness of breath, diarrhea, headache, cough, and peripheral edema. In combination therapy, commonly reported adverse effects include anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, fever, cough, shortness of breath, and insomnia.

Carfilzomib may cause harm to the fetus based on findings from animal studies and its mechanism of action. There is insufficient data on its use in pregnant women to fully assess the risk. Animal studies have shown embryo-fetal toxicity at doses lower than those used clinically. Therefore, pregnant women should be advised about the potential risk to the fetus. There is no information on the presence of Carfilzomib in human milk or its effects on the breastfed infant or milk production. Due to the risk of serious adverse reactions, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose.

• Cardiac Toxicity: Monitor for signs of heart failure or ischemia; withhold treatment and evaluate promptly if suspected.
• Acute Renal Failure: Check renal function regularly, including serum creatinine levels.
• Tumor Lysis Syndrome (TLS): Ensure adequate hydration before treatment; monitor uric acid and manage promptly.
• Pulmonary Toxicity: Includes ARDS, respiratory failure, and infiltrative lung disease; stop treatment and evaluate immediately if suspected.
• Pulmonary Hypertension: Monitor and discontinue therapy if required.
• Dyspnea: Assess immediately in cases of severe or life-threatening breathing difficulty.
• Hypertension (including crisis): Monitor blood pressure regularly; interrupt therapy if not controlled.
• Venous Thrombosis: Consider thromboprophylaxis where appropriate.
• Infusion-related Reactions: Premedicate with dexamethasone to reduce risk.
• Hemorrhage: Monitor for serious bleeding, including gastrointestinal, pulmonary, and intracranial.
• Thrombocytopenia: Monitor platelet count and adjust dose if necessary.
• Hepatic Toxicity: Check liver enzymes regularly; discontinue if toxicity is suspected.
• Thrombotic Microangiopathy: Monitor closely and discontinue if suspected.
• PRES (Posterior Reversible Encephalopathy Syndrome): Evaluate neurological symptoms and discontinue if suspected.
• PML (Progressive Multifocal Leukoencephalopathy): Monitor for new or worsening neurological signs and stop treatment if suspected.
• Combination Toxicity: Increased serious and fatal risks when used with melphalan and prednisone in certain patients.
• Embryo-fetal Toxicity: May cause fetal harm; advise effective contraception during treatment.

Tetrapeptide epoxyketone proteasome inhibitor

Unopened vials should be stored in a refrigerator at 2°C to 8°C and kept in the original packaging to protect from light.