Carfilzomib

In plain language

Carfilzomib is a cancer drug for multiple myeloma, sold as Kyprolis. It is a small ring of four amino acids with a special warhead that jams the proteasome, the cell's protein shredder.

Cancer cells depend heavily on the proteasome to dispose of damaged proteins, so blocking it kills them. It is used after earlier drugs fail, usually in combination with dexamethasone or lenalidomide, and its design came from a natural molecule made by soil bacteria.

For students

Carfilzomib is a tetrapeptide epoxyketone (about 719 Da) derived from epoxomicin, a Streptomyces proteasome inhibitor. The epoxyketone warhead reacts covalently and essentially irreversibly with the N-terminal threonine of the 20S proteasome's chymotrypsin-like active site (beta5 subunit), with the morpholine cap improving solubility and pharmacokinetics.

Developed by Onyx Pharmaceuticals (with chemistry rooted in Craig Crews' work on epoxomicin), it was approved in 2012 for relapsed/refractory multiple myeloma after two prior lines. The ASPIRE trial (n=792, carfilzomib plus lenalidomide-dexamethasone versus placebo plus the same) improved progression-free survival (26.3 versus 17.6 months), and ENDEAVOR (n=929) showed superiority over bortezomib. Its distinctive risks are cardiac (heart failure, rare cardiac arrest) and pulmonary (dyspnea), requiring hydration and monitoring, and it is dosed as a 10-minute or 30-minute infusion on two days weekly for three weeks of a 28-day cycle.

For researchers and instructors

Biochemistry. The epoxyketone reacts with both the hydroxyl and amino groups of the N-terminal threonine to form a fused morpholine ring, an irreversible dual-covalent linkage distinct from bortezomib's boronate; this underlies minimal cross-resistance.

Pharmacology. Substrate of CYP3A metabolism and P-glycoprotein; cardiac and pulmonary toxicities require baseline and on-treatment assessment; thrombocytopenia is dose-related; infusion reactions prevented by dexamethasone premedication.

Human evidence. ASPIRE (Lancet 2015), ENDEAVOR (NEJM 2015) and ARROW (weekly dosing, n=429) ground its indications; the FOCUS trial in later-line patients was the regulatory hinge for initial accelerated approval.

Teaching point. Teaches irreversible covalent inhibitors in a peptide format, and the arc from natural product to mechanism-of-action-based cancer therapy.