Proteasome inhibitor (bortezomib, carfilzomib, ixazomib)
Drugs that block the cell's protein-recycling machine. Myeloma cells make huge amounts of antibody protein and choke on the backlog when the proteasome is blocked; normal cells cope far better.
Bortezomib (2003) was the first, given subcutaneously to limit neuropathy; carfilzomib is irreversible and more potent but has cardiovascular toxicity; ixazomib is oral. They pair with immunomodulatory drugs and dexamethasone in VRd/KRd induction, in relapsed combinations with daratumumab or isatuximab, and bortezomib is also used in mantle cell lymphoma and AL amyloidosis. Resistance and the shift to CD38 antibodies, CAR-T and bispecifics have reduced their role at relapse, but they remain in nearly every first-line regimen.
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