What are the side effects of Bortezomib (Velcade)?

Bortezomib Side Effects: Comprehensive Overview

Bortezomib causes a broad spectrum of adverse effects, with peripheral neuropathy and thrombocytopenia being the most clinically significant dose-limiting toxicities, alongside frequent gastrointestinal disturbances, fatigue, and hematologic complications. 1

Most Common Adverse Effects (>20% incidence)

The FDA label for bortezomib documents the following most frequently reported side effects in clinical trials 1:

• Nausea (52%) - most common overall adverse effect 1
• Diarrhea (52%) - equally prevalent gastrointestinal toxicity 1
• Fatigue (39%) - significant impact on quality of life 1
• Peripheral neuropathies (35%) - key dose-limiting toxicity 1, 2
• Thrombocytopenia (33%) - major hematologic concern 1, 2
• Constipation (30%) 1
• Vomiting (29%) 1
• Anorexia (21%) 1

Dose-Limiting Toxicities

Peripheral Neuropathy

• Peripheral neuropathy is the primary dose-limiting toxicity and the most common reason for treatment discontinuation (8% of patients) 1, 3
• Manifests predominantly as sensory neuropathy with paresthesias occurring in 42% of patients (12% Grade 3 or higher) 1
• The NCCN guidelines emphasize this as the key dose-limiting toxicity requiring careful monitoring 3
• Subcutaneous administration reduces neuropathy risk compared to intravenous dosing 4, 2

Thrombocytopenia

• Occurs in 33% of patients overall, with 4% experiencing Grade 4 thrombocytopenia 1
• Represents the second major dose-limiting toxicity alongside peripheral neuropathy 2
• Requires close monitoring of platelet counts throughout treatment 1

Gastrointestinal Toxicities

Gastrointestinal side effects are extremely common with bortezomib, occurring in up to 84% of patients 5:

• Diarrhea (52%) - can be severe enough to cause dehydration requiring hospitalization 1
• Nausea (52%) 1
• Vomiting (29%) 1
• Constipation (30%) 1
• Rare but serious: pseudomembranous colitis has been reported, potentially related to changes in colonic microflora 6

The mechanisms of proteasome inhibitor-induced gastrointestinal toxicity remain largely unexplored, though these effects are consistently reported across all proteasome inhibitors 5.

Hematologic Toxicities

Beyond thrombocytopenia, bortezomib causes multiple hematologic adverse effects 1:

• Neutropenia - 2% Grade 4 events 1
• Anemia - common across multiple studies 1
• Lymphopenia - reported in combination regimens 7

Infectious Complications

• Herpes zoster (11%) - Grade 3 or higher in 3% of patients 1
• Prophylaxis with acyclovir/valacyclovir is recommended to prevent herpes virus reactivation 4
• Pneumonia reported as a serious adverse event requiring hospitalization 1

Cardiovascular Toxicities

Cardiac side effects are underrecognized but potentially serious, particularly in elderly patients and those with preexisting cardiac conditions 8:

• Congestive heart failure has been reported, including fatal cases 1, 8
• Cardiogenic shock and cardiac arrest documented as bortezomib-related deaths 1
• Risk increases after cumulative doses exceeding 20 mg/m² 8
• Left ventricular ejection fraction can drop significantly (case report: 45-50% to 25%) but may normalize with treatment cessation 8

Critical caveat: Elderly patients and those with prior cardiac disease require intensive cardiovascular monitoring, especially after reaching cumulative doses of 20 mg/m² 8.

Dermatologic Reactions

• Rash (11%) - generally mild (Grade 3 in only 2%) 1
• Skin and subcutaneous tissue disorders (8% Grade 3 or higher on twice-weekly dosing) 7
• Switching to subcutaneous administration reduces skin reactions 4
• Dose reduction to 1.0 mg/m² recommended for Grade 1-2 cutaneous reactions 4

Constitutional Symptoms

• Fatigue (25%) - Grade 3 or higher in 6% 1
• Asthenia (16%) - Grade 3 or higher in 5% 1
• Pyrexia/Fever (16%) 1
• Insomnia (10%) 1

Metabolic and Nutritional Disorders

• Anorexia (19%) - Grade 3 or higher in 2% 1
• Dehydration requiring hospitalization reported as serious adverse event 1

Serious Adverse Reactions

Twenty-four percent of bortezomib-treated patients experienced serious adverse reactions requiring hospitalization or meeting other serious criteria 1:

• Most common serious events: diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each) 1
• Four deaths were considered bortezomib-related: cardiogenic shock, respiratory insufficiency, congestive heart failure, and cardiac arrest 1

Treatment Discontinuation Rates

• 25% of patients discontinued bortezomib due to adverse effects 1
• Peripheral neuropathy was the leading cause of discontinuation (8%) 1
• This is higher than the 18% discontinuation rate seen with dexamethasone comparator 1

Important Clinical Considerations

Route of Administration Impact

Subcutaneous bortezomib administration significantly reduces overall toxicity, particularly peripheral neuropathy and skin reactions, compared to intravenous dosing 4, 2.

Dosing Schedule Modifications

Weekly dosing instead of twice-weekly reduces toxicity burden while maintaining efficacy 4, 9. A study of weekly bortezomib with methylprednisolone showed only 2 patients with Grade 3 neuropathy and excellent tolerability 9.

Concomitant Medication Effects

Dexamethasone, frequently used with bortezomib, may contribute to additional side effects including taste disturbances, acneiform eruptions, and skin fragility 3, 4.

Combination Regimen Considerations

When bortezomib is combined with other agents, overlapping toxicities can be challenging 2. For example, in combination with carfilzomib and dexamethasone, rates of hypertension (15%), anemia (16%), and dyspnea (6%) were notable 7.