How is bortezomib (a reversible proteasome inhibitor) dosed, administered, monitored, and what are its side effects, contraindications, and alternative proteasome inhibitors for treating multiple myeloma and mantle‑cell lymphoma?

Bortezomib: Clinical Management Guide

Mechanism and Indications

Bortezomib is a reversible proteasome inhibitor approved for multiple myeloma and mantle cell lymphoma that works by inhibiting the 26S proteasome's chymotrypsin-like activity, disrupting cancer cell survival pathways. 1

• FDA-approved in 2003 for multiple myeloma treatment 1
• Approved for mantle cell lymphoma in 2006 2, 3
• Does not require dose adjustment in renal impairment, making it ideal for patients with renal failure 1, 4, 5

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Dosing and Administration

Standard Dosing

• 1.3 mg/m² per dose administered twice weekly on days 1,4,8, and 11 of a 21-day cycle 2, 6
• Six cycles is the typical treatment duration 6

Route of Administration

Subcutaneous administration is strongly preferred over intravenous delivery. 1, 4

• Subcutaneous route reduces peripheral neuropathy from 53% to 38% for all grades 1
• Grade 3/4 neuropathy decreases from 16% to 6% with subcutaneous administration 1, 4
• Efficacy remains equivalent between routes 1, 4

Schedule Optimization

Weekly dosing is preferred over twice-weekly schedules to minimize toxicity while maintaining efficacy. 1, 4

• Weekly bortezomib combined with rituximab showed 88% overall response rate with no grade ≥3 peripheral neuropathy 1
• Grade 3/4 neuropathy reduced to 6-7% with weekly dosing 4

Dose Modifications

• Patients with cardiac involvement should start at 0.7-1.0 mg/m² and uptitrate as tolerated 4
• For Grade 1-2 cutaneous reactions, reduce dose to 1.0 mg/m² 7
• No dose adjustment required for renal impairment 1, 5, 2

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Mandatory Prophylaxis

Herpes Virus Prophylaxis

All patients receiving bortezomib must take acyclovir or valacyclovir throughout the entire treatment course to prevent herpes virus reactivation. 1, 4, 7

• This is a universal recommendation from NCCN and ASCO 4
• Continue prophylaxis for the duration of proteasome inhibitor therapy 4

Pneumocystis Prophylaxis

• Consider PJP prophylaxis when bortezomib is combined with rituximab-containing regimens 4

Thromboprophylaxis

Bortezomib does not require routine anticoagulation prophylaxis, unlike immunomodulatory drugs (thalidomide, lenalidomide). 1, 4

• This represents a significant advantage over IMiD-based regimens 1, 4
• When combined with thalidomide or lenalidomide, thromboprophylaxis becomes necessary due to the IMiD component 1

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Monitoring Requirements

Peripheral Neuropathy Surveillance

Peripheral neuropathy is the key dose-limiting toxicity requiring systematic monitoring at every visit. 1, 4, 7

• Overall incidence: 35-47% of patients 4
• Grade 3/4 severity: 8-13% of patients 4
• Use NCI CTC criteria combined with neuropathy-specific questionnaires (Total Neuropathy Score) 1
• Monitor for distal symmetric symptoms: paresthesia, numbness, burning sensation, weakness 1
• Bortezomib-induced neuropathy is mostly reversible, with 60% complete resolution within median 5.7 months 1

Patients with pre-existing neuropathy should avoid bortezomib or receive attenuated dosing. 1, 4

Cardiac Monitoring

• Proteasome inhibitors carry increased risk of cardiotoxicity and congestive heart failure 1, 4
• Monitor for signs of cardiac dysfunction, particularly in patients with baseline cardiac disease 1, 4

Hematologic Monitoring

• Neutropenia: Grade 3/4 in up to 58% with certain regimens 4
• Thrombocytopenia: Severe in approximately 5% or less in frontline settings 4
• Monitor complete blood counts regularly 1

Renal Function

• Monitor serum creatinine and electrolytes 5
• No dose adjustment needed for renal impairment 5, 2

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Side Effects and Management

Peripheral Neuropathy (Most Important)

Peripheral neuropathy is the primary dose-limiting toxicity. 1, 4, 7

• Incidence with twice-weekly IV dosing: 30-39% grade 2,30% grade 3 1
• Incidence with weekly subcutaneous dosing: 54% grade 1-2,0-5% grade ≥3 1
• Symptoms start distally and may progress proximally 1
• Mostly reversible unlike thalidomide-induced neuropathy 1

Management approach:

• Prompt dose reduction when neuropathy develops 1
• Switch to weekly administration or 4-week cycles instead of 3-week cycles 1
• For painful neuropathy: gabapentin, pregabalin, oxcarbazepine, or duloxetine 1
• Acetyl-L-carnitine and alpha lipoic acid may have benefit 1

Hematologic Toxicities

• Neutropenia: 2% Grade 4 events 7
• Lymphopenia in combination regimens 7
• Thrombocytopenia: approximately 5% severe cases 4

Gastrointestinal Effects

• Nausea and vomiting: Grade 3/4 in 8-11% 1
• Diarrhea: Grade ≥3 reported 1
• Constipation 1

Cardiovascular Effects

• Hypotension: Grade 3 reported 1
• Rare cardiomyopathy 1
• Dizziness and syncope 1

Dermatologic Reactions

• Skin and subcutaneous tissue disorders: 8% Grade 3 or higher with twice-weekly dosing 7
• Switching to subcutaneous administration reduces skin reactions 7
• Dose reduction to 1.0 mg/m² for Grade 1-2 cutaneous reactions 7

Other Toxicities

• Fatigue 1
• Fever 1
• Respiratory infections 1
• Myopathy 1

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Contraindications and Precautions

Absolute Contraindications

• Hypersensitivity to bortezomib, boron, or mannitol 2

Relative Contraindications/High-Risk Situations

• Pre-existing grade 2 or higher peripheral neuropathy (consider alternative agents or attenuated dosing) 1, 4
• Severe cardiac disease (start at lower doses 0.7-1.0 mg/m²) 4

Drug Interactions

• Metabolized by CYP3A4, 2C19, and 1A2 2
• Use caution with strong CYP3A4 inhibitors or inducers 2

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Combination Regimens

Multiple Myeloma - Transplant Eligible

Bortezomib/lenalidomide/dexamethasone (VRd) is the preferred primary therapy. 1

• Overall response rate: 100% with 74% VGPR or better 1
• PFS: 41-43 months 1
• Grade 3 neuropathy: 24% with IV administration 1

Multiple Myeloma - Transplant Ineligible

Melphalan/prednisone/bortezomib (MPB) is a category 1 recommendation. 1

• 3-year overall survival: 68.5% vs 54% with MP alone 1
• Effective regardless of age, renal function, or adverse cytogenetics 1
• Median time to neuropathy improvement: 1.9 months; 60% complete resolution within 5.7 months 1

Mantle Cell Lymphoma

Bortezomib/rituximab/dexamethasone shows high activity in relapsed/refractory disease. 6

• Overall response rate: 81.3% with 43.8% complete response 6
• Median PFS: 12.1 months 6
• Median OS: 38.6 months 6

Waldenström Macroglobulinemia

• Weekly bortezomib/rituximab: 81-88% overall response rate 1
• Lower neuropathy rates with weekly dosing 1

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Alternative Proteasome Inhibitors

Carfilzomib

Carfilzomib is an irreversible proteasome inhibitor with significantly lower neuropathy risk than bortezomib. 1

• FDA-approved in 2012 for relapsed/refractory multiple myeloma 1
• Overall peripheral neuropathy incidence: 13.9%; Grade 3: 1.3%; no Grade 4 1
• Preferred for patients with pre-existing neuropathy 1
• Main toxicities: fatigue, anemia, thrombocytopenia, hypertension 1
• Rare thrombotic microangiopathy 1
• Carfilzomib/rituximab/dexamethasone in Waldenström's: 87% overall response rate 1

Ixazomib and Oprozomib

• Oral proteasome inhibitors under investigation 1
• May offer convenient alternatives to parenteral administration 1

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Special Populations

Renal Impairment/Cast Nephropathy

Bortezomib-based regimens should be initiated immediately in cast nephropathy as they do not require dose adjustment and can be safely used in dialysis patients. 5

• No dose adjustment needed for any degree of renal impairment 1, 5, 2
• Bortezomib overcomes the negative prognostic impact of renal insufficiency 1
• Target >50% reduction in free light chains by end of cycle 1 5

Elderly Patients

• Melphalan/prednisone/bortezomib preferred in elderly or comorbid patients with renal impairment 1
• Efficacy maintained regardless of advanced age 1

High-Risk Cytogenetics

• Bortezomib-based regimens effective regardless of adverse cytogenetics including t(4;14), t(14;16), del(17p) 1
• Proteasome inhibitors considered critical for high-risk myeloma 1

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Clinical Pearls

Key Advantages

• No routine anticoagulation needed (unlike IMiDs) 1, 4
• Safe in renal failure without dose adjustment 1, 4, 5
• Effective in high-risk cytogenetics 1
• Mostly reversible neuropathy (unlike thalidomide) 1

Critical Pitfalls to Avoid

• Failing to prescribe herpes prophylaxis (universal requirement) 1, 4, 7
• Using IV route when subcutaneous is available (significantly higher neuropathy) 1, 4
• Continuing twice-weekly dosing when weekly dosing reduces toxicity 1, 4
• Using bortezomib in patients with pre-existing grade 2+ neuropathy without dose attenuation 1, 4
• Delaying dose reduction when neuropathy develops 1

Optimization Strategy

The optimal bortezomib regimen uses subcutaneous administration on a weekly schedule with mandatory herpes prophylaxis. 1, 4

This approach maximizes efficacy while minimizing the key dose-limiting toxicity of peripheral neuropathy 1, 4.