Carfilzomib

Carfilzomib is an epoxyketone-based, irreversible proteasome inhibitor structurally related to bortezomib but with greater selectivity for the chymotrypsin-like activity of the 20S proteasome core. By inhibiting the ubiquitin-proteasome pathway, it prevents degradation of pro-apoptotic regulatory proteins (e.g., p53, Bax, I\u03baB) and causes accumulation of misfolded proteins, triggering the unfolded protein response and ultimately apoptosis in malignant plasma cells, which are particularly sensitive due to their high protein synthesis burden (monoclonal immunoglobulin production).\n\nClinical use: Primarily indicated for relapsed or refractory multiple myeloma, often combined with dexamethasone \u00b1 lenalidomide or other agents, especially in patients who have progressed on bortezomib.\n\nMechanistic distinction from bortezomib: Carfilzomib binds irreversibly (requiring new proteasome synthesis for recovery of activity), whereas bortezomib is reversible. Carfilzomib also has less off-target activity against serine proteases, which is thought to reduce the incidence of peripheral neuropathy compared to bortezomib.\n\nKey adverse effects (high-yield for boards):\n- Cardiotoxicity: heart failure, hypertension, arrhythmias \u2014 a signature toxicity more prominent than with bortezomib; requires cardiac monitoring.\n- Tumor lysis syndrome (due to rapid tumor cell death in myeloma).\n- Thrombocytopenia, anemia, fatigue.\n- Pulmonary hypertension and dyspnea.\n- Infusion reactions.\n- Less peripheral neuropathy than bortezomib (an important distinguishing fact for USMLE).\n\nMnemonic/Association: Think \u201cCarfilzomib = Cardiotoxicity\u201d to differentiate from bortezomib\u2019s hallmark peripheral neuropathy.\n\nMechanism relevance to Step 1: Tests understanding of the ubiquitin-proteasome pathway, plasma cell biology, and chemotherapy drug class adverse effect profiles.