Carfilzomib

• Multiple Myeloma:
  Carfilzomib is approved for the treatment of relapsed or refractory multiple myeloma in patients who have received one or more prior therapies. It is used as:
• Monotherapy for patients with relapsed and refractory disease.
• Combination therapy with lenalidomide and dexamethasone or with dexamethasone alone in relapsed multiple myeloma.
• Off-label/Investigational Uses:
• Other hematologic malignancies such as mantle cell lymphoma and amyloidosis are under investigation.

• Route: Intravenous (IV) infusion.
• Standard Adult Dose for Multiple Myeloma:
• Cycle 1:
• Day 1 & 2: 20 mg/m² IV over 10 minutes.
• Days 8, 9, 15, 16: 27 mg/m² IV over 10 minutes.
• Subsequent Cycles (2–12):
• Days 1, 2, 8, 9, 15, 16: 27 mg/m² IV over 10 minutes every 28-day cycle.
• Dose Modifications:
• May increase to 56 mg/m² in select regimens based on tolerability and physician discretion.
• Dose adjustments required for adverse events or toxicity (e.g., thrombocytopenia, neuropathy).
• Special Populations:
• Elderly: No dose adjustment solely based on age; monitor closely for toxicity.
• Renal Impairment: No adjustment needed in mild to moderate impairment; limited data in severe renal failure—use cautiously.
• Hepatic Impairment: Use with caution; no formal dose adjustment recommendations.
• Administration Notes:
• Administer over approximately 10 minutes.
• Pre-medicate with dexamethasone to reduce infusion reactions and tumor lysis syndrome risk.
• Adequate hydration recommended prior to and after infusion.

Carfilzomib is a selective, irreversible proteasome inhibitor targeting the chymotrypsin-like activity of the 20S proteasome. By binding covalently to the proteasome’s active sites, it disrupts the ubiquitin-proteasome pathway critical for intracellular protein degradation. This leads to accumulation of misfolded proteins, inducing cellular stress and apoptosis preferentially in malignant plasma cells. The irreversible inhibition results in sustained proteasome blockade, promoting cell cycle arrest and apoptotic death in multiple myeloma cells.

• Absorption: Not applicable (administered IV).
• Distribution: Volume of distribution approximately 22–30 L; extensively distributed in tissues.
• Metabolism: Primarily metabolized via extrahepatic mechanisms; minimal CYP450 involvement.
• Elimination:
• Half-life: ~1 hour (rapid systemic clearance).
• Excreted mainly via biliary/fecal routes; minor renal elimination.
• Onset of Action: Immediate proteasome inhibition after infusion; proteasome activity recovers slowly due to irreversible binding.

• Pregnancy:
• Category D (positive evidence of human fetal risk). Use only if benefits outweigh risks.
• Animal studies demonstrate teratogenicity and embryo-fetal toxicity.
• Lactation:
• Unknown if excreted in human milk; potential for serious adverse reactions in nursing infants.
• Breastfeeding should be discontinued during treatment and for at least two weeks after the last dose.

• Primary Class: Antineoplastic agent
• Subclass: Proteasome inhibitor

• Known hypersensitivity to Carfilzomib or any excipients.
• Concurrent use with strong CYP3A inducers is generally avoided due to lack of data.
• Severe uncontrolled cardiovascular disease (relative contraindication).

• Cardiovascular Toxicity: Monitor for heart failure, hypertension, ischemia.
• Pulmonary Toxicity: Risk of dyspnea, pulmonary hypertension, or interstitial lung disease.
• Infusion Reactions: Pre-medicate and monitor during infusion.
• Tumor Lysis Syndrome: Risk present, especially in patients with high tumor burden.
• Hepatotoxicity: Monitor liver function tests.
• Thrombocytopenia & Anemia: Frequent CBC monitoring recommended.
• Renal Toxicity: Monitor renal function; hydration important.
• Peripheral Neuropathy: Monitor and dose adjust if severe.
• Pregnancy & Lactation: Use caution; teratogenic risk present.

• Common:
• Fatigue, anemia, thrombocytopenia, nausea, dyspnea, diarrhea, fever, headache.
• Hematologic: Thrombocytopenia, anemia, neutropenia.
• Cardiovascular: Hypertension, heart failure, ischemic events.
• Pulmonary: Dyspnea, cough.
• Infusion reactions: Chills, fever, rash.
• Rare: Severe hypersensitivity, tumor lysis syndrome, hepatic failure.

• Minimal CYP450 metabolism reduces interaction risk.
• Avoid concurrent use with strong CYP3A inducers (e.g., rifampin) as efficacy may be reduced.
• Care with nephrotoxic or cardiotoxic agents due to overlapping toxicity risks.

• FDA approvals have expanded indications for combination therapy in multiple myeloma.
• EMA guidelines emphasize cardiovascular monitoring due to emerging safety data.
• Recent clinical trials have evaluated higher dosing and alternative schedules.
• Ongoing investigations into novel combinations and earlier lines of therapy.

• Store 2°C to 8°C (refrigerated).
• Protect from light; keep vial in carton until use.
• Do not freeze.
• Use immediately after reconstitution or per manufacturer instructions.
• Discard unused portion as per aseptic technique recommendations.