Definition
- Proteasome inhibitors block the ubiquitin–proteasome pathway, which is responsible for degrading misfolded or regulatory proteins.
- This leads to accumulation of proteins, cell cycle arrest, and apoptosis, particularly in malignant plasma cells.
Key Drugs
| Drug | Route | Indications | Mechanism / Notes | Major Toxicities |
|---|---|---|---|---|
| Bortezomib | IV / SC | Multiple myeloma, mantle cell lymphoma | Reversible 26S proteasome inhibitor; inhibits NF-κB | Peripheral neuropathy, thrombocytopenia, GI upset, fatigue, VZV reactivation |
| Carfilzomib | IV | Relapsed/refractory multiple myeloma | Irreversible 20S proteasome inhibitor; more selective than bortezomib | Cardiac toxicity, hypertension, dyspnea, fatigue, thrombocytopenia |
| Ixazomib | Oral | Relapsed/refractory multiple myeloma (combo with lenalidomide/dexamethasone) | Reversible 20S proteasome inhibitor | GI toxicity, thrombocytopenia, peripheral neuropathy (less than bortezomib) |
Mechanism of Action
- Inhibits proteasomal degradation of proteins.
- Accumulated misfolded proteins → ER stress → apoptosis.
- Inhibits NF-κB signaling → reduces tumor cell proliferation and survival.
- Particularly effective in plasma cell malignancies (myeloma) due to high protein turnover.
Clinical Uses
- Multiple myeloma – frontline or relapsed/refractory settings.
- Mantle cell lymphoma – bortezomib or carfilzomib in relapsed/refractory disease.
- Investigational: some solid tumors, Waldenström macroglobulinemia, AL amyloidosis.
Toxicities
- Peripheral neuropathy – dose- and schedule-dependent (especially bortezomib).
- Myelosuppression – thrombocytopenia, anemia, neutropenia.
- Cardiovascular – carfilzomib can cause heart failure, hypertension, arrhythmias.
- GI – nausea, diarrhea, constipation.
- Infections – VZV reactivation (prophylaxis recommended).
- Fatigue, rash, edema.
Monitoring
- CBC – before each cycle.
- Neurologic assessment – baseline and during therapy.
- Cardiac monitoring – for carfilzomib or patients with heart disease.
- Liver function tests – baseline and periodically.
- Infection prophylaxis – antiviral for VZV when on bortezomib or combination therapy.
Summary
Proteasome inhibitors disrupt protein degradation, causing apoptosis in malignant cells, especially plasma cells. Bortezomib, carfilzomib, and ixazomib differ in selectivity, route, and toxicity profile. Key clinical considerations include peripheral neuropathy, myelosuppression, cardiovascular risk (carfilzomib), and infection prophylaxis.