Introduction
Kyprolis (carfilzomib) is a second-generation proteasome inhibitor approved for the treatment of multiple myeloma. It represents a significant advancement in the management of relapsed or refractory multiple myeloma, offering a mechanism of action distinct from first-generation proteasome inhibitors. Kyprolis is typically administered in combination with other antimyeloma agents and has demonstrated substantial clinical efficacy in improving progression-free and overall survival in appropriate patient populations.
Mechanism of Action
Kyprolis is an epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. This binding inhibits the chymotrypsin-like activity of the proteasome, leading to accumulation of polyubiquitinated proteins, cell cycle arrest, and apoptosis. Unlike bortezomib, Kyprolis demonstrates greater selectivity for the chymotrypsin-like subunit and less inhibition of the trypsin-like and caspase-like activities, which may contribute to its differentiated safety profile and reduced neurotoxicity.
Indications
Kyprolis is FDA-approved for:
- Treatment of relapsed or refractory multiple myeloma in combination with:
- Dexamethasone (Kd regimen) - Lenalidomide and dexamethasone (KRd regimen) - Daratumumab and dexamethasone (DKd regimen) - Isatuximab and dexamethasone
- Monotherapy for relapsed or refractory multiple myeloma in patients who have received at least two prior therapies including bortezomib and an immunomodulatory agent
Dosage and Administration
Standard dosing:- Cycle 1-2: 20 mg/m² IV on days 1 and 2, then 56 mg/m² IV on days 8, 9, 15, and 16 of 28-day cycles
- Subsequent cycles: 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of 28-day cycles
- Administer as a 30-minute IV infusion
- Pre-medicate with dexamethasone 4 mg IV or PO 30 minutes to 4 hours before each dose during cycles 1-2
- Ensure adequate hydration: 250-500 mL IV fluids before and after each dose in cycle 1
- Renal impairment: No initial dose adjustment required for CrCl ≥15 mL/min
- Hepatic impairment: Reduce dose in severe hepatic impairment (Child-Pugh Class C)
- Elderly: Monitor closely due to increased risk of adverse events
Pharmacokinetics
Absorption: Administered intravenously, achieving complete bioavailability Distribution: Steady-state volume of distribution approximately 28 L Metabolism: Primarily via peptidase cleavage and epoxide hydrolysis Elimination: Half-life <1 hour; primarily eliminated via extra-hepatic metabolism Excretion: Feces (72%) and urine (22%)Contraindications
- Hypersensitivity to carfilzomib or any component of the formulation
- Left ventricular ejection fraction below 40%
- Myocardial infarction within 6 months prior to initiation
- New York Heart Association Class III or IV heart failure
- Uncontrolled hypertension
Warnings and Precautions
Cardiac toxicity: May cause cardiac arrest, congestive heart failure, myocardial ischemia, and hypertension. Monitor cardiac function regularly. Pulmonary toxicity: Acute respiratory distress syndrome, acute respiratory failure, and dyspnea may occur. Hepatotoxicity: Drug-induced liver injury, hepatitis, and hepatic failure have been reported. Thrombocytopenia: Monitor platelet counts frequently during therapy. Tumor lysis syndrome: May occur, particularly in patients with high tumor burden. Infusion reactions: Pre-medication with dexamethasone is recommended. Posterior reversible encephalopathy syndrome (PRES): Rare but serious neurologic syndrome.Drug Interactions
Strong CYP3A4 inhibitors: Avoid concomitant use (e.g., ketoconazole, ritonavir) Strong CYP3A4 inducers: May decrease carfilzomib concentrations (e.g., rifampin, carbamazepine) QT-prolonging drugs: May have additive effects on QT interval Nephrotoxic agents: Increased risk of renal impairmentAdverse Effects
Very common (≥20%):- Fatigue (56%)
- Anemia (47%)
- Nausea (45%)
- Thrombocytopenia (41%)
- Dyspnea (35%)
- Diarrhea (33%)
- Pyrexia (30%)
- Insomnia (26%)
- Peripheral edema (25%)
- Cough (23%)
- Peripheral neuropathy (21%)
- Cardiac failure (7%)
- Acute renal failure (5%)
- Pulmonary hypertension (4%)
- Severe infusion reactions (2%)
Monitoring Parameters
Prior to initiation:- Complete blood count with differential
- Comprehensive metabolic panel
- Cardiac evaluation including ECG and echocardiogram
- Assessment of hydration status
- Weekly CBC during first two cycles, then prior to each dose
- Serum electrolytes, creatinine, liver function tests prior to each cycle
- Regular assessment of cardiac function
- Monitoring for signs of infusion reactions
- Regular neurological assessment
- Blood pressure monitoring before and after infusion
Patient Education
- Report any signs of infection, bleeding, or bruising immediately
- Maintain adequate hydration between treatments
- Monitor for signs of heart problems (shortness of breath, swelling, chest pain)
- Report neurological symptoms (tingling, numbness, weakness)
- Avoid pregnancy during treatment and use effective contraception
- Inform all healthcare providers about Kyprolis therapy
- Be aware of potential infusion reactions and report any symptoms during or after infusion
- Maintain regular follow-up appointments and laboratory monitoring
References
1. FDA Prescribing Information: Kyprolis (carfilzomib) 2. Moreau P, et al. Oral carfilzomib and dexamethasone for patients with relapsed multiple myeloma. Blood. 2020;136(13):1514-1524 3. Siegel DS, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(8):728-734 4. Stewart AK, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152 5. National Comprehensive Cancer Network. Multiple Myeloma Guidelines Version 3.2023 6. Wang M, et al. Phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Blood. 2013;122(18):3121-3128