From the Guidelines
Carfilzomib is a highly effective proteasome inhibitor used in the treatment of multiple myeloma, particularly in relapsed or refractory disease, and is typically administered in combination regimens such as KRd (carfilzomib, lenalidomide, dexamethasone) or Kd (carfilzomib, dexamethasone). The most recent and highest quality study, published in 2023 1, demonstrates the efficacy of carfilzomib in combination with dexamethasone, showing a significant improvement in median progression-free survival (PFS) and overall survival (OS) compared to bortezomib and dexamethasone.
Key Considerations for Carfilzomib Treatment
- Carfilzomib is administered intravenously, with a starting dose of 20 mg/m² on days 1 and 2 of cycle 1, then escalated to 27 mg/m² or 56 mg/m² for subsequent doses, depending on the specific regimen.
- Combination regimens, such as KRd or Kd, are commonly used, with treatment cycles typically running 28 days.
- Patients should receive appropriate hydration before each dose and prophylaxis against herpes zoster reactivation.
- Cardiac monitoring is essential, as carfilzomib can cause cardiovascular adverse effects, including hypertension and heart failure.
- Dose modifications may be necessary for patients with renal impairment or those experiencing toxicities.
Mechanism of Action and Advantages
- Carfilzomib works by irreversibly binding to the 20S proteasome, leading to accumulation of protein aggregates and inducing apoptosis in myeloma cells.
- It offers an advantage over first-generation proteasome inhibitors like bortezomib, particularly in patients with bortezomib resistance, due to its irreversible and highly potent proteasome inhibition activity 1.
- The mechanisms by which carfilzomib induces cardiovascular adverse events (CVAEs) are poorly understood, but speculations can be made on its effect on proteasome-mediated degradation of toxic products and modulation of nitric oxide levels 1.
Clinical Guidelines and Recommendations
- The NCCN guidelines recommend carfilzomib in combination with dexamethasone as a category 1, preferred option for patients with relapsed/refractory multiple myeloma 1.
- The European Myeloma Network and the Italian Society of Arterial Hypertension have published a consensus paper on the prevention, monitoring, and treatment of CVAEs in myeloma patients receiving carfilzomib 1.
- Carfilzomib is also recommended in combination with lenalidomide and dexamethasone (KRd) for patients with relapsed or refractory multiple myeloma 1.
From the FDA Drug Label
Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with: Lenalidomide and dexamethasone; or Dexamethasone; or Daratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone; or Isatuximab and dexamethasone Kyprolis is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
The role of Carfilzomib (Kyprolis) in the treatment of Multiple Myeloma is to treat adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy, in combination with other therapies or as a single agent. The main combinations include:
- Lenalidomide and dexamethasone
- Dexamethasone
- Daratumumab and dexamethasone
- Daratumumab and hyaluronidase-fihj and dexamethasone
- Isatuximab and dexamethasone 2
From the Research
Role of Carfilzomib in Multiple Myeloma Treatment
- Carfilzomib, also known as Kyprolis, is a selective proteasome inhibitor used in the treatment of relapsed and refractory multiple myeloma (MM) 3, 4, 5, 6, 7.
- It is approved as monotherapy and in combination with dexamethasone or lenalidomide-dexamethasone (Rd) for relapsed or refractory multiple myeloma 4.
- Carfilzomib has shown significant durable activity, good tolerability, and a favorable safety profile in clinical studies, supporting its extended use in MM treatment 3, 5, 6, 7.
Efficacy of Carfilzomib
- In clinical studies, single-agent carfilzomib demonstrated an overall response rate of 23.7% in patients with relapsed and refractory MM 3, 5, 6.
- The combination of carfilzomib with lenalidomide and dexamethasone (KRd) significantly improved progression-free survival (PFS) compared to lenalidomide and dexamethasone alone (median 26.3 vs 17.6 months) 4, 7.
- KRd also led to higher objective response and complete response or better rates compared to Rd, irrespective of previous treatment 4.
Safety Profile of Carfilzomib
- Common adverse events associated with carfilzomib include thrombocytopenia, anemia, fatigue, nausea, and diarrhea 3, 5, 6.
- Carfilzomib has a low incidence of grade 3 or higher peripheral neuropathy, making it a favorable option for patients with relapsed MM 5, 6.
- The tolerability profile of carfilzomib is acceptable, with a low discontinuation rate due to adverse events 7.