What is bortezomib?

What is Bortezomib?

Bortezomib is a first-in-class, reversible proteasome inhibitor that functions as an antineoplastic agent by selectively blocking the 26S proteasome's chymotrypsin-like activity, leading to disruption of cellular homeostasis and cancer cell death. 1

Chemical Structure and Formulation

• Bortezomib is a modified dipeptidyl boronic acid with the chemical name [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid 1
• The molecular formula is C19H25BN4O4 with a molecular weight of 384.24 1
• Available as a sterile lyophilized powder containing 3.5 mg bortezomib per vial with citric acid (10 mg) and tromethamine (8.4 mg) as inactive ingredients 1
• The drug exists in its cyclic anhydride form as a trimeric boroxine and is provided as a citric acid boronic ester 1

Mechanism of Action

• Bortezomib reversibly inhibits the chymotrypsin-like activity of the 26S proteasome, a large protein complex responsible for degrading ubiquitinated proteins 1
• The ubiquitin-proteasome pathway regulates intracellular protein concentrations and maintains cellular homeostasis 1
• Inhibition of the 26S proteasome prevents targeted proteolysis, affecting multiple signaling cascades including the nuclear factor-κB pathway 1, 2
• This disruption leads to cell-cycle arrest, apoptosis, and inhibition of angiogenesis and proliferation 2, 3
• Bortezomib targets both intrinsic and extrinsic apoptotic signaling pathways, whereas corticosteroids like dexamethasone target only the intrinsic pathway, providing rationale for combination therapy 4

FDA-Approved Indications

Multiple Myeloma

• Approved in 2003 for relapsed/refractory multiple myeloma and in 2008 for previously untreated multiple myeloma 2
• Bortezomib-based regimens (with dexamethasone, doxorubicin, or thalidomide) are category 1 options for primary therapy in transplant candidates 4
• Particularly valuable in patients with renal failure and adverse cytogenetic features including t(4;14) 4, 5

Mantle Cell Lymphoma

• Approved in 2006 for relapsed/refractory mantle cell lymphoma and in 2014 for previously untreated mantle cell lymphoma 2, 6

Waldenström's Macroglobulinemia

• Recommended as primary therapy for patients with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia, cold agglutinemia, amyloidosis, and renal impairment 4
• Preferred in young patients where avoidance of alkylator or nucleoside analog therapy is desired 4

Routes of Administration and Pharmacokinetics

• Available for both intravenous and subcutaneous administration 1, 3
• Subcutaneous route is strongly preferred as it significantly reduces peripheral neuropathy rates while maintaining equivalent systemic exposure and pharmacodynamic effects 5, 3
• Following IV administration of 1.3 mg/m² doses, mean maximum plasma concentrations (Cmax) are 112 ng/mL 1
• Distribution volume ranges from 498 to 1884 L/m² with 83% plasma protein binding 1
• Elimination half-life ranges from 40 to 193 hours with multiple dosing 1
• Primarily metabolized by hepatic CYP3A4, CYP2C19, and CYP1A2 enzymes 1

Key Toxicities and Management

Peripheral Neuropathy

• The dose-limiting toxicity occurring in 35-47% of patients, with Grade 3/4 severity in 8-13% 5
• Predominantly sensory, though motor neuropathy occurs in 10% of cases 5
• Weekly dosing reduces Grade 3/4 neuropathy to 6-7% compared to twice-weekly schedules while maintaining efficacy 4, 5
• Approximately 70% of patients experience partial or complete reversibility with early recognition, dose reduction, or discontinuation 5

Hematologic Toxicities

• Neutropenia presents as Grade 3/4 in up to 58% of patients in certain regimens 5
• Severe thrombocytopenia occurs in approximately 5% or less in the frontline setting 5
• These effects are generally manageable and predictable with appropriate monitoring 5

Infectious Complications

• Prophylactic acyclovir is mandatory to reduce the incidence of herpes zoster reactivation 4, 5

Gastrointestinal Effects

• Diarrhea occurs in 52% of patients, with Grade 3 severity in 26% in some combination regimens 5

Special Populations

Renal Impairment

• No starting dose adjustment required for any degree of renal impairment 1
• For patients requiring dialysis, bortezomib should be administered after the dialysis procedure 1

Hepatic Impairment

• No dose adjustment needed for mild hepatic impairment (total bilirubin ≤1× ULN and AST > ULN) 1
• Reduce starting dose in patients with moderate (bilirubin 1.5-3× ULN) or severe (bilirubin >3× ULN) hepatic impairment due to increased drug exposure 1

Diabetic Patients

• Hypoglycemia and hyperglycemia reported in diabetic patients receiving oral hypoglycemics 1
• Close monitoring of blood glucose levels and adjustment of antidiabetic medication doses required 1

Clinical Advantages

• Low risk of deep vein thrombosis compared to immunomodulatory agents, eliminating the need for routine anticoagulation prophylaxis 4, 5
• Adverse events are predictable and manageable with patient monitoring and appropriate supportive care 4, 5
• Effective across poor prognostic subgroups including ISS stage III disease and high-risk cytogenetic abnormalities 4