Proteasomal inhibition revolutionized myeloma
therapies in this decade of novel agents. The only US Food and Drug Administration approved
proteasome inhibitor so far,
bortezomib effectively targets the constitutive
proteasome subunit β5 of the
26S proteasome.
Bortezomib induces high and quality response rates that are durable. However, myeloma cells acquire resistance to
bortezomib through various mechanisms. Further, grade 3/4
peripheral neuropathy is seen in up to a quarter of patients treated with
bortezomib. While the recent change in the mode of administration via the subcutaneous route is associated with a lower incidence of grade 3/4
peripheral neuropathy, it remains a major concern. The second generation
proteasome inhibitors are promising, with increased preclinical efficacy and a better administration schedule. The current review spotlights the second generation
proteasome inhibitors with special focus on the safety and efficacy of
carfilzomib, an epoxyketone with lesser
peripheral neuropathy, which exhibits irreversible
proteasome inhibition. In this article, we review the pharmacology and preclinical and clinical efficacy and safety of
carfilzomib alone and in combination with other chemotherapeutic agents in the various lymphoid
neoplasms and
multiple myeloma as well as ongoing clinical trials.