13
Proteasome Inhibitors
What are the chemotherapy agents in the proteasome inhibitor class?
• Bortezomib (Velcade®), carfilzomib (Kyprolis®)
What malignancies are each proteasome inhibitor FDA approved for?
FDA-Approved Uses of Proteasome Inhibitors
Bortezomib |
Carfilzomib |
Multiple myeloma, mantle cell lymphoma |
Multiple myeloma, relapsed/refractory |
Abbreviation: FDA, U.S. Food and Drug Administration.
How do the proteasome inhibitors work?
• In normal cells, the proteasome works to degrade intracellular proteins and maintain homeostasis
• Proteasome inhibitors bind and inhibit the chymotrypsin-like activity of the proteasome, preventing degradation of intracellular proteins
– Bortezomib binds reversibly to the proteasome
– Carfilzomib binds irreversibly, is more potent than bortezomib, more selective for the chymotrypsin-like activity of the proteasome, and is active in bortezomib-resistant cells
• Accumulation of proteins normally marked for degradation leads to cell death through the unfolded protein response and the endoplasmic reticulum stress pathway
• Accumulation of proteins critical for regulating cell cycle progression (eg, p27, cyclin B) leads to cell cycle arrest
• Proteasome inhibitors also inhibit nuclear factor kappa B (NF-KB) activity of cancer cells through preventing degradation of the inhibitor of NF-KB (IKB); NF-KB activation is heavily involved in cell proliferation, angiogenesis, and suppression of apoptosis
What are the common mechanisms of resistance to proteasome inhibitor therapy?
• Alternative degradation of ubiquitinated proteins through the aggresome pathway, dependent on histone deacetylase 6 (HDAC6) (HDAC inhibitors can synergize with proteasome inhibitors through inhibition of this resistance pathway—see Chapter 11)
• Mutations in the β-subunits of the proteasome that alter proteasome inhibitor binding
• Upregulation of proteasomal subunits
What are the common dosing ranges for each proteasome inhibitor?
• Bortezomib: 1.3 mg/m2 intravenously (IV)/subcutaneously (subQ) days 1, 4, 8, and 11 of a 21-day cycle; 1.5 mg/m2 IV weekly, days 1, 8, 15, and 22 of a 28-day cycle
• Carfilzomib: 20 mg/m2 IV days 1, 2, 8, 9, 15, and 16 (cycle 1; 28-day cycle), then 27 mg/m2 IV days 1, 2, 8, 9, 15, and 16 of subsequent 28-day cycles
Are the proteasome inhibitors metabolized/eliminated renally or hepatically?
• The proteasome inhibitors are metabolized hepatically and require dose adjustment for hepatic dysfunction
Are there drug interactions with any of the proteasome inhibitors?
• Drugs that modulate the CYP3A4 pathway may increase/decrease bortezomib concentrations
What are the most common adverse effects of the proteasome inhibitors?
• Peripheral neuropathy
– Typically a reversible sensory neuropathy
– More common with bortezomib than carfilzomib
– SubQ administration and weekly administration of bortezomib have both been shown (individually) to reduce peripheral neuropathy without impacting efficacy
• Myelosuppression (primarily thrombocytopenia)
• Herpes zoster and herpes simplex reactivation (prophylaxis with acyclovir is recommended)
• Nausea, vomiting, and diarrhea (typically mild)
• Fevers, fatigue, and weakness
• Congestive heart failure, dyspnea, peripheral edema, and renal failure (more common with carfilzomib)
What are the premedications required?
Premedications Required for Proteasome Inhibitors
Drug |
Premedication |
Bortezomib |
None |
Carfilzomib |
250–500 mL normal saline (or other intravenous [IV] fluid) predose; can also give another 250–500 mL postdose if needed |
What is the emetogenicity level of the proteasome inhibitors?
• Both agents are categorized as low (10%–30% frequency)
Are the proteasome inhibitors vesicants or irritants?
• Bortezomib and carfilzomib are neither vesicants nor irritants