Carfilzomib

Summary

Carfilzomib is an FDA-approved second-generation proteasome inhibitor derived from a tetrapeptide epoxyketone scaffold. It is indicated for the treatment of relapsed or refractory multiple myeloma, administered intravenously. It offers improved selectivity and irreversible inhibition compared to first-generation agents like bortezomib.

Mechanism of Action

Irreversibly inhibits the chymotrypsin-like activity of the 20S proteasome by covalently binding to the active site threonine residue, leading to accumulation of polyubiquitinated proteins, induction of apoptosis, and inhibition of tumor cell proliferation.

Routes of Administration

Goals & Uses

• Proteasome pathway suppressionMechanistic/ResearchHigh
• Reduction of tumor burden in multiple myelomaOncologyHigh
• Treatment of newly diagnosed multiple myeloma (off-label/investigational)OncologyModerate
• Treatment of relapsed/refractory multiple myelomaOncologyHigh

Contraindications

• Hypersensitivity to carfilzomibAllergyHigh
• Uncontrolled cardiac diseaseCardiovascularHigh
• Severe hepatic impairmentOrganModerateLiver function concerns

Adverse Effects

• HypertensionCardiovascularCommonHigh blood pressure
• ThrombocytopeniaHematologicCommonLow platelet count
• AnemiaHematologicCommonLow red blood cell count or hemoglobin
• FatigueGeneralCommonLow energy or tiredness
• Infusion-related reactionsHypersensitivityUncommon
• Cardiac failure / cardiomyopathyCardiovascularUncommon

Drug Interactions

• Anticoagulants (e.g., warfarin)Moderate
• Antihypertensive agentsModerate
• Strong CYP3A4 inhibitors (e.g., ketoconazole)Low

Population Constraints

• PregnancyReproductive SafetyAbsolute
• Renal impairmentOrgan ImpairmentRelative
• LactationReproductiveAbsolute
• Elderly patients (≥75 years)AgeRelative

Regulatory Status

• European UnionApprovedApproved: Relapsed or refractory multiple myeloma in adults who have received at least one prior therapyApproved by EMA in 2015; marketed as Kyprolis.
• United StatesApprovedApproved: Relapsed or refractory multiple myeloma (in combination with lenalidomide and dexamethasone), Relapsed or refractory multiple myeloma (in combination with daratumumab and dexamethasone), Relapsed or refractory multiple myeloma (monotherapy or with dexamethasone) in patients who have received 1–3 prior lines of therapyInitially approved via accelerated approval in 2012 by FDA; full approval granted for combination regimens.
• United KingdomApprovedApproved: Relapsed or refractory multiple myeloma in adultsApproved by MHRA post-Brexit; NICE has issued technology appraisals for specific combination regimens.

Approved by FDA in 2012 under accelerated approval; full approval granted subsequently. Approved by EMA in 2015. Indicated for relapsed/refractory multiple myeloma in combination regimens (e.g., with lenalidomide/dexamethasone or daratumumab/dexamethasone).

Evidence & Sources

No sources recorded yet.