Bortezomib

Approved Indications:

• Multiple Myeloma:
• For previously untreated patients, in combination with melphalan and prednisone.
• As monotherapy or in combination with dexamethasone for relapsed or refractory multiple myeloma.
• Mantle Cell Lymphoma (MCL):
• For patients with relapsed or progressive disease after at least one prior therapy.

Off-label / Clinically Accepted Uses:

• Systemic AL Amyloidosis: Used as part of chemotherapy regimens in patients with light chain (AL) amyloidosis.
• Waldenström Macroglobulinemia: In select relapsed or refractory cases.
• Non-Hodgkin’s Lymphomas: In investigational or refractory scenarios.

Administration Route: Intravenous (IV) or subcutaneous (SC) injection.

Adults – Multiple Myeloma:

• Initial dose: 1.3 mg/m² twice weekly on Days 1, 4, 8, and 11 of a 21-day cycle.
• Subsequent cycles: Dosing schedules vary based on combination therapy and patient response.

Mantle Cell Lymphoma:

• Recommended dose: 1.3 mg/m² administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (21-day cycle).

Pediatrics:

• Not FDA-approved; investigational dosing may apply in clinical trials under strict oncological supervision.

Elderly:

• No specific dose adjustment required based solely on age. Monitor closely for peripheral neuropathy and other toxicities.

Renal or Hepatic Impairment:

• Renal: No initial dose adjustment necessary.
• Hepatic:
• Mild impairment: No adjustment.
• Moderate to severe impairment (bilirubin >1.5x ULN): Start with reduced dose of 0.7 mg/m² in the first cycle; consider escalation if tolerated.

Bortezomib is a reversible inhibitor of the 26S proteasome, a large protease complex responsible for degrading ubiquitinated proteins within cells. By inhibiting this proteolytic pathway, Bortezomib disrupts multiple intracellular signaling cascades, leading to accumulation of pro-apoptotic factors and inhibition of NF-κB activation. The result is enhanced tumor cell apoptosis, especially in malignant plasma cells and lymphocytes which are more sensitive to proteasome inhibition due to their high turnover and metabolic activity.

• Absorption: Rapid following IV administration; subcutaneous route leads to slower peak concentration but similar exposure (AUC).
• Bioavailability: High with IV; SC bioavailability is comparable (~70–100%).
• Distribution: Widely distributed; plasma protein binding ~83%.
• Metabolism: Primarily hepatic via CYP450 enzymes (CYP3A4, 2C19, 1A2).
• Elimination Half-life: Approximately 40–190 hours; prolonged with repeated dosing.
• Excretion: Mainly via hepatic metabolism; excreted in bile.

• Pregnancy Risk: Not assigned (previously Category D).
• Bortezomib may cause fetal harm based on animal data; contraindicated in pregnancy.
• Lactation: Unknown if excreted in human milk; due to potential for serious adverse reactions in infants, breastfeeding is not recommended during therapy and for 2 months after the last dose.
• Recommendation: Use effective contraception during treatment and for at least 7 months after the final dose (females) and 4 months (males).

• Primary Class: Antineoplastic Agent
• Subclass: Proteasome Inhibitor
• Generation: First-generation reversible 26S proteasome inhibitor

• Known hypersensitivity to Bortezomib, boron, or mannitol
• Intrathecal administration (fatal cases reported)
• Severe hepatic impairment (relative contraindication without dose adjustment)

• Peripheral Neuropathy: May be severe; monitor closely; consider dose reduction or discontinuation.
• Hematologic Toxicity: Thrombocytopenia and neutropenia are common; frequent CBC monitoring required.
• Cardiac Effects: Risk of heart failure, arrhythmias, and hypotension; caution in patients with existing heart disease.
• Pulmonary Toxicity: Rare interstitial lung disease or acute respiratory distress.
• Herpes Zoster Reactivation: Prophylactic antiviral therapy recommended.
• Tumor Lysis Syndrome: Risk in patients with high tumor burden.
• Hepatic Toxicity: Hepatic failure, including fatal cases, reported.
• Posterior Reversible Encephalopathy Syndrome (PRES): Monitor for seizures, confusion, or visual disturbances.

Common:

• Neurological: Peripheral neuropathy, paresthesia
• Gastrointestinal: Nausea, vomiting, diarrhea, constipation
• Hematologic: Thrombocytopenia, neutropenia, anemia
• General: Fatigue, fever, anorexia

Serious:

• Heart failure, arrhythmias
• Pulmonary complications (dyspnea, pneumonitis)
• Hepatic failure
• PRES
• Hypotension and syncope
• Herpes zoster reactivation

Rare:

• Stevens-Johnson syndrome
• Tumor lysis syndrome
• Pancreatitis

• Strong CYP3A4 Inhibitors (e.g., ketoconazole): May increase Bortezomib exposure and toxicity.
• CYP3A4 Inducers (e.g., rifampin, carbamazepine): May reduce efficacy.
• Antihypertensives: Additive hypotension possible.
• Vaccines: Avoid live vaccines during treatment due to immunosuppression.
• NSAIDs and Anticoagulants: Increased bleeding risk, especially with thrombocytopenia.

• EMA & FDA: Recommend SC over IV route due to reduced neuropathy risk without compromising efficacy.
• NCCN Guidelines (Latest): Continue to recommend Bortezomib as part of frontline and relapsed myeloma regimens (e.g., VRd - bortezomib, lenalidomide, dexamethasone).
• Updated Dosing Adjustments: More refined guidance for patients with hepatic impairment.

• Unreconstituted Vials:
• Store at 2°C to 8°C (Refrigerate; Do Not Freeze)
• Protect from light; store in original carton.
• Reconstituted Solution:
• IV Preparation: Stable for up to 8 hours at 25°C.
• SC Preparation: Use within 8 hours; do not refrigerate.
• Do not shake; gently swirl for mixing.