	The recent approval of the second-generation proteasome inhibitor carfilzomib by the FDA comes nine years after the initial approval of bortezomib, the first-in-class drug of its type. Not only does carfilzomib demonstrate activity in a relapsed and refractory setting, it has a superior toxicity profile as well. Multiple new proteasome inhibitors currently in clinical or preclinical development bode well for potential future therapies for multiple myeloma, both in frontline and relapsed or refractory settings.

 The recent significant improvements in overall survival and remission duration in multiple myeloma (MM) are largely due to the advent of novel therapeutic agents, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

 Proteasomes serve an important cellular function in enabling clearance of abnormal or mutant proteins.2 Tumor cells are more heavily dependent on this clearance mechanism and are sensitive to proteasome inhibition, leading to an antiproliferative and proapoptotic effect mediated via induction of endoplasmic reticulum stress, activation of caspases, and reactive oxygen species.

	For many years, bortezomib (Velcade), an intravenous/subcutaneous dipeptide boronate PI, was the only available agent in its class. Bortezomib is a reversible inhibitor of the chymotrypsin-like catalytic activity of the β5 subunit of the 20S mammalian proteasome. It was initially approved by the FDA in 2003 for refractory MM, and subsequently expanded for use in combination therapy in the first-line setting.

 Bortezomib therapy in MM is limited by development of peripheral neuropathy and eventual drug resistance

 mediated via overexpression of the β5 subunit, mutation of active drug binding sites, or downstream upregulation of survival pathways.

	This mandates development of novel agents that retain activity in a multi-agent refractory setting and are easy to administer (orally vs intravenous) and tolerate. This review will address the current clinical development and results with second-generation PIs including carfilzomib, oprozomib (ONX 0912), ixazomib (MLN9708), marizomib (NPI-0052), and delanzomib (CEP-18770) (

). They have a distinct mechanism of action as well as pharmacokinetic profile compared with bortezomib. Of these, carfilzomib has been recently approved by the FDA, and it and the others are being investigated in clinical trials (

			Table 1.Second-Generation Proteasome Inhibitors

	Carfilzomib (Kyprolis, PR-171), is an intravenous, irreversible tetrapeptide epoxyketone second-generation PI. The irreversible binding and higher affinity for proteasome translates into superior biological activity and cytotoxicity in bortezomibresistant cell lines in vitro and in vivo.15,16 It was approved by the FDA on July 20, 2012, for treatment of patients with MM who have received at least two prior therapies, including bortezomib and a IMiD, and have demonstrated disease progression within 60 days of completion of last therapy.

 The FDA approval was based on a phase II study of 266 patients that demonstrated a response rate of 23.7%, median response duration of 7.8 months, and median overall survival of 15.6 months.

	The current carfilzomib administration schedule consists of intravenous (IV) dosing of 20 mg/m

 for cycle 1 concurrently with IV fluids for hydration and dexamethasone, and subsequent dose escalation to 27 mg/m

 if cycle 1 was well tolerated.18 It is anticipated that the administration will be further simplified, especially in a frontline setting, as well as dose escalation to 36 or 45 mg/m

, with higher doses currently being studied.

	The side effects with single-agent carfilzomib were generally mild, with largely nonhematologic side effects, as well as a clear superiority over bortezomib in terms of peripheral neuropathy. In fact, patients with preexisting neuropathy did not have worsening symptoms with carfilzomib. As with development of bortezomib, carfilzomib is also being tested in combination chemotherapy and in frontline settings (

). Clinical trials evaluating first-line use of carfilzomib may be especially relevant for patients who have significant preexisting peripheral neuropathy, and are therefore not good candidates for bortezomib.

			Table 2. Selected Clinical Trials with Second-Generation Proteasome Inhibitors

						Relapsed MM after at least 1 prior therapy

						Relapsed MM patients who have received 1 to 3 prior therapies

						Relapsed and refractory MM patients who have received 3 or more prior therapies

						MLN9708 + R + d/D vs placebo + R + d/D

Articles

Multiple new proteasome inhibitors currently in clinical or preclinical development bode well for potential future therapies for multiple myeloma, both in frontline and relapsed or refractory settings.

Vinay Gupta, MD

Articles

Novel Proteasome Inhibitors for Multiple Myeloma