💊 Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma and certain lymphomas (e.g. mantle cell lymphoma). It was the first-in-class drug to exploit the concept of proteasome inhibition, a key innovation in oncology pharmacology. It is typically given by subcutaneous or intravenous injection.

⚙️ Mechanism of Action

Bortezomib reversibly inhibits the 26S proteasome, an enzyme complex responsible for degradation of ubiquitinated proteins. In cancer cells—particularly plasma cells—this leads to accumulation of misfolded proteins, triggering endoplasmic reticulum stress and apoptosis. It also disrupts NF-κB signalling, reducing tumour growth and survival signalling.

📋 Indications (UK Context)

First-line and relapse therapy in multiple myeloma (alone or with dexamethasone/thalidomide/lenalidomide).
Mantle cell lymphoma in patients unsuitable for intensive chemotherapy.
Sometimes used off-label for amyloidosis (AL type) under specialist supervision.

💉 Administration

Given by subcutaneous injection (preferred due to less neuropathy) or IV route.
Commonly dosed twice weekly for 2 weeks, followed by a rest week (21-day cycle).
Dose adjustment is required in hepatic impairment or toxicity.

⚠️ Adverse Effects

Peripheral neuropathy (dose-limiting; sensory >> motor).
Myelosuppression — especially thrombocytopenia.
Gastrointestinal upset: nausea, diarrhoea, constipation.
Reactivation of herpes zoster — prophylactic aciclovir is recommended.
Fatigue, hypotension, transaminitis.

🧠 Key Clinical Points

Always give antiviral prophylaxis (aciclovir 200–400 mg BD).
Neuropathy often improves if drug is withheld early — monitor symptoms closely.
Used in combination regimens such as VTD (bortezomib-thalidomide-dexamethasone).
Contraindicated in severe hepatic impairment or active infection.

🔬 Pathophysiological Rationale

Myeloma cells have high immunoglobulin synthesis and depend on proteasome-mediated degradation to survive. Blocking this pathway causes a toxic build-up of misfolded proteins, selectively killing malignant plasma cells while sparing most normal tissues. This illustrates a targeted therapy exploiting tumour cell biology rather than general cytotoxicity.

📚 References & Notes

BNF: Bortezomib
NICE TA129, TA228: use in myeloma and mantle cell lymphoma.
Rajkumar SV, *N Engl J Med* 2020;3

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Bortezomib