Carfilzomib — Drug Monograph
Brand names: Kyprolis
Drug class: Proteasome Inhibitor
Mechanism of Action
Second-generation, selective, epoxyketone proteasome inhibitor. Binds irreversibly and covalently to the chymotrypsin-like active site of the 20S proteasome subunit (β5 and β5i). Unlike bortezomib, carfilzomib does not inhibit serine proteases (HtrA2, cathepsin A, cathepsin G), which is thought to account for its lower rates of peripheral neuropathy. Irreversible proteasome inhibition causes accumulation of misfolded and polyubiquitinated proteins, triggering the unfolded protein response (UPR), endoplasmic reticulum stress, and apoptosis.
FDA Indications
- Multiple myeloma — relapsed/refractory (KRd: carfilzomib + lenalidomide + dexamethasone — ASPIRE trial)
- Multiple myeloma — relapsed/refractory (Kd: carfilzomib + dexamethasone — ENDEAVOR trial; superior PFS vs. bortezomib + dexamethasone)
- Multiple myeloma — relapsed/refractory (Kd monotherapy or with other combinations)
Common Side Effects
- Fatigue
- Anemia
- Nausea
- Thrombocytopenia
- Dyspnea
- Diarrhea
- Pyrexia
- Peripheral edema
- Hypertension
- Decreased appetite
Clinical Pearl
Carfilzomib's key advantage over bortezomib is dramatically lower peripheral neuropathy (PN) due to its selectivity for the proteasome (no serine protease off-target activity). This makes it the preferred proteasome inhibitor for patients with pre-existing neuropathy. The trade-off is greater cardiovascular toxicity — cardiology evaluation is recommended before initiating, and blood pressure must be checked before and after every dose. Herpes zoster (VZV) antiviral prophylaxis…
Related Therapies & Mechanisms
- Bortezomib (Velcade) — Proteasome Inhibitor · Myeloma
- Ixazomib (Ninlaro) — Proteasome Inhibitor · Myeloma
- Belantamab mafodotin (Blenrep) — Myeloma
- Ciltacabtagene autoleucel (Carvykti) — Myeloma