Novel Proteasome Inhibitors for Multiple Myeloma

Vinay Gupta, MD

Department of Hematology, Mayo Clinic Rochester,

Rochester, MN

Wilson I. Gonsalves, MD

Department of Hematology, Mayo Clinic Rochester,

Rochester, MN

Corresponding Author:

Shaji K. Kumar, MD

Department of Hematology, Mayo Clinic Rochester,

Rochester, MN;

kumar.shaji@mayo.edu

Abstract

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).¹Proteasomes serve an important cellular function in enabling clearance of abnormal or mutant proteins.²Tumor 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.²

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.³Bortezomib therapy in MM is limited by development of peripheral neuropathy and eventual drug resistance⁴mediated 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) (Table 1). 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 2^5-14).

TABLE 1. Second-Generation Proteasome Inhibitors

Drug

Company

Binding

Route

Status

Carfilzomib(Kyprolis)

Onyx Pharmaceuticals

Irreversible

IV

FDA-approved for multiple myeloma

Oprozomib(ONX 0912)

Onyx Pharmaceuticals

Irreversible

Oral

Phase I

Ixazomib citrate(MLN9708)

Millennium Pharmaceuticals

Reversible

IV, Oral

Phase I/II

Marizomib(NPI-0052)

Nereus Pharmaceuticals

Irreversible

Oral

Phase I

Delanzomib(CEP-18770)

Cephalon Inc.

Reversible

Oral

Phase I

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 bortezomib-resistant cell lines in vitro and in vivo.^15,16It 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.¹⁷The FDA approval wasbased 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.¹⁸

The current carfilzomib administration schedule consists of intravenous (IV) dosing of 20 mg/m2 for cycle 1 concurrently with IV fluids for hydration and dexamethasone, and subsequent dose escalation to 27 mg/m²if cycle 1 was well tolerated.¹⁸It is anticipated that the administration will be further simplified, especially in a frontline setting, as well as dose escalation to 36 or 45 mg/m², 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 (Table 2). Clinical trials evaluating firstline 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

Drug

Clinical Trial

Phase

Study Design

Study Population

Carfilzomib(PR-171)

CYCLONE⁵

I/II

Cy + C + T + D

Newly diagnosed MM

ENDEAVOR⁶

III

C + d vs Bor + d

Relapsed MM after at least 1 prior therapy

ASPIRE⁷

III

R + d + C vs R + d

Relapsed MM patients who have received 1 to 3 prior therapies

FOCUS⁸

III

Single-agent C vs placebo

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

Ixazomib(MLN9708)

NCT01217957⁹

I/II

MLN9708 + R + d

Newly diagnosed MM

NCT01564537¹⁰

III

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

Relapsed and/or refractory MM

Delanzomib(CEP-18770)

NCT01348919¹¹

I/II

CEP-18770 + R + d

Relapsed or refractory MM

Oprozomib(ONX 0912)

NCT01416428¹²

Ib/II

Single-agent ONX 0912

Relapsed or refractory MM

NCT01832727¹³

Ib/II

ONX 0912 + d

Relapsed or refractory MM

Marozomib(NPI-0052)

NCT00461045¹⁴

I

Single-agent NPI-0052

Relapsed or refractory MM

Bor = bortezomib; C = carfilzomib; Cy = cyclophosphamide; d = dexamethasone low-dose; D = dexamethasone high-dose; MM = multiple myeloma; R = lenalidomide; T = thalidomide.

Ixazomib citrate (MLN9708) is a reversible, oral/ intravenous boronate peptide PI,¹⁹currently being tested in clinical trials. Although it is a boronic acid-containing molecule like bortezomib, it is pharmacokinetically distinct with faster dissociation from the 20S proteasome,leading to superior tissue penetration and biological activity.²⁰In plasma, it hydrolyzes quickly into its biologically active form MLN2238, which activates proapoptotic enzymes, including caspase-3, caspase-8, and caspase-9; induces endoplasmic reticulum stress; and inhibits nuclear factor-kB (NF-kB) and tumor-associated angiogenic activity.¹⁹Preclinical studies showed synergistic activity with lenalidomide and dexamethasone and formed the basis of recent clinical trials with MLN9708.²⁰

Two phase I trials with expansion cohorts have been conducted with single-agent MLN9708.21,22 The first trial involved administration of MLN9708 on a twice-weekly basis (days 1, 4, 8, 11) of a 21-day cycle.²¹In the second trial, MLN9708 was administered once weekly for 3 out of 4 weeks.²²The drug was well tolerated, with gastrointestinal and hematologic adverse events being the most common. Skin rash has been seen, especially in combination with lenalidomide. Clinical efficacy was clearly demonstrated in both trials, especially at the higher doses, with some patients achieving a very good partial response (VGPR) to therapy.

Subsequently, the phase I/II study consisting of 65 patients treated with weekly MLN9708 in combination with lenalidomide and dexamethasone revealed a VGPR rate of 44% or more, a complete response (CR) rate of 26%, and an overall response rate (ORR) of 88%.²³Treatment was well tolerated with largely nonhematologic side effects without significant neurotoxicity. MLN9708 is being explored in combination with other agents in phase II/III trials.^9,10The synergistic activity of MLN9708 and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDAC), provides the rationale for future clinical trials incorporating these two agents.¹⁹

Clinical Pearls

• Carfilzomib is active in refractory MM and has a superior sideeffect profile, especially with considerably less neurotoxicity— even in patients with grade 1/2 neuropathy.
• There is a promising drug pipeline for novel PIs being tested in relapsed, refractory, and frontline settings.
• The development of active oral PIs, with obvious benefit in terms of ease of administration, is eagerly awaited.

Oprozomib (ONX 0912) is an oral, irreversible, tripeptide epoxyketone that exerts its activity via inhibition of chymotrypsin- like activity of the proteasome.²⁴Biochemically, it is the oral analogue of carfilzomib, and demonstrates similar antiangiogenic and proapoptotic activity in vitro and in vivo.²⁴A synergistic effect with bortezomib and with a combination of lenalidomide and dexamethasone was also seen in preclinical studies, and hypothesized to be secondary to differential effects on proapoptotic signaling pathways.²⁴The primary advantage with oprozomib is the ease of administration via the oral route. The strong preclinical data for equipotent efficacy to carfilzomib has laid the groundwork for clinical trials. Oprozomib is being evaluated as a single agent and in combination with lowdose dexamethasone in relapsed and refractory MM.^12,13

Conclusion

Other PIs of interest include marizomib and delanzomib. Marizomib (NPI-0052) is an oral, irreversible ββ-lactone derivative that binds selectively to the active proteasomal sites.²⁵In vivo studies with marizomib demonstrate reduced tumor growth without significant toxicity in myeloma xenograft models.²⁶A phase I trial in refractory and relapsed MM is under way.¹⁴Delanzomib (CEP-18770) is an oral/intravenous, reversible boronate peptide agent.²⁷Piva et al²⁸demonstrated equivalent antiproliferative activity of delanzomib and bortezomib in MM cell lines and xenograft models. The effects of delanzomib were mediated via down-regulation of NFkB, sustained inhibition of the proteasome, and potent antiangiogenic activity.²⁸A higher tumoral concentration of delanzomib was achieved in preclinical studies when compared with bortezomib. A phase I trial consisting of 38 patients encouragingly revealed a lack of neurotoxicity that is commonly associated with bortezomib.²⁷It is being evaluated in phase I/II studies at this time.¹¹Other promising agents in preclinical development include immunoproteasome inhibitors such as PR-92429 and ISPI-101.³⁰The second-generation PIs offer advantages over bortezomib either via ease of administration (oral agents such as oprozomib, ixazomib, marizomib, and delanzomib) or via abrogating bortezomib-resistant disease with stronger or irreversible binding to the proteasome (carfilzomib, oprozomib, and marizomib). The advantage of the nonpeptide PI (marizomib) is its inherent resistance to degradation by endogenous plasma and cellular peptidases resulting in increased bioavailability. Whether this will translate to increased efficacy remains unproven at this time.

Second-generation PIs have demonstrated single-agent efficacy in patients with refractory disease and provide therapeutic options for continued care. The newer agents have potentially less toxicity to the progenitor stem cells and normal cells than existing therapies.

Future research includes incorporation of these agents into multiagent chemotherapy and upfront use as part of induction therapy. In this regard, carfilzomib is already being tested in first-line settings. The incorporation of novel PIs as part of upfront multiagent therapy is under way. Whether these agents will be effective in high-risk patients remains unknown. There is laboratory evidence that the epoxyketone-based PIs have additional antiresorptive and bone-anabolic effects,³¹which should be explored in future clinical trials.

Author Disclosures

Drs. Gupta, Gonsalves, and Kumar have no conflicts of interest to report.

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