ONCOLOGY. Vol. 25 2

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The Future of Proteasome Inhibitors in Relapsed/Refractory Multiple Myeloma

By Robert Z. Orlowski, MD, PhD¹ | November 7, 2011

¹The University of Texas MD Anderson Cancer Center, Houston, Texas

Patients with relapsed multiple myeloma

Agents that show activity in relapsed and refractory myeloma are typically rapidly moved into earlier disease settings, including relapsed myeloma, and then eventually newly diagnosed disease. Next-generation PIs are certainly following that path both as single agents[33,35,36,40] and in rationally designed combination regimens based on strong preclinical data showing their ability to cooperate with other antimyeloma agents.[37-39,41-43] Data are particularly well developed for carfilzomib, which as detailed earlier in this supplement, was able to induce a 53% ORR in a bortezomib(Drug information on bortezomib)-naive population of patients with relapsed myeloma who had a median of two prior lines of therapy, and who received 20 mg/m² of carfilzomib during cycle 1, and 27 mg/m² thereafter.[88] Carfilzomib was also able to be easily combined with lenalidomide and dexamethasone(Drug information on dexamethasone), as demonstrated in a phase Ib/II trial of this regimen for relapsed and/or refractory disease.[89] This study showed that full-dose carfilzomib was tolerated well, along with the standard lenalidomide and low-dose dexamethasone regimen.[90] Moreover, it achieved rapid responses and a 78% ORR,[89] leading to the initiation of a phase III trial comparing the three-drug regimen to lenalidomide and low-dose dexamethasone in patients with one to three prior lines of therapy.[91]

TABLE

Ongoing Studies Incorporating Next-Generation Proteasome Inhibitors for Relapsed and/or Refractory Multiple Myelomaa

Bortezomib is now used in combination with a wide array of both conventional and novel agents against multiple myeloma, and it is likely that the same will become true for carfilzomib and other second-generation PIs. Indeed, a number of such trials are currently underway (Table). The regimens being studied include combinations with other standards of care like lenalidomide and dexamethasone, as well as combinations with novel drugs like the histone deacetylase inhibitor panobinostat and the kinesin spindle protein inhibitor ARRY-520. Still others are in the planning stages.

An especially interesting combination approach suggested by the different chemistries and targets of the various PIs is the possibility that two such agents could be combined to good effect. One such combination could include bortezomib, which can inhibit both the chymotrypsin(Drug information on chymotrypsin)-like activity and the post–glutamyl peptide hydrolyzing, or caspase-like activity,[92,93] together with marizomib, which inhibits the chymotrypsin-like and trypsin-like activities (and also the caspase-like activity, although to a lesser extent than this is inhibited by bortezomib).[41] Such a regimen has already been validated using both in vitro[41] and in vivo[42] models. Similarly, preclinical studies have shown that inhibitors that predominantly target proteasome catalytic sites other than β5, such as the β1 caspase-like[44] and β2 trypsin-like[45] activities, can sensitize to bortezomib.

It may also be possible to use bortezomib, which targets both the constitutive proteasome and the immunoproteasome, in combination with an immunoproteasome-specific inhibitor, although some data suggest that targeting both β5 and β5i is needed to optimally induce cell death.[48] It is also possible that additive effects could be achieved by combining bortezomib or carfilzomib with some of the agents that target the α proteasome subunits, such as clinically relevant analogs of 5AHQ[53] and chloroquine(Drug information on chloroquine).[54] Validation of some of these approaches would still be needed, but one could envision randomized studies comparing, for example, bortezomib and dexamethasone to bortezomib with marizomib and dexamethasone—targeting either patients with previous bortezomib exposure, or PI-naive patients. Were the synergy that has been demonstrated preclinically to translate well to the clinic, it is possible that lower doses of each agent could be used, which would result in enhanced or at least similar antimyeloma activity with decreased treatment-emergent toxicities, such as peripheral neuropathy.

Myeloma patients who are intolerant of bortezomib

Early studies of single-agent bortezomib in relapsed and/or refractory myeloma[3-6] identified four major categories of toxicities. These included constitutional symptoms such as fatigue and nausea, cytopenias such as neutropenia and thrombocytopenia, gastrointestinal effects such as diarrhea and constipation, and peripheral neuropathy. After more than a decade of experience with bortezomib,[94] these remain the major notable toxicities, and of these, neuropathy, which was seen in 21% to 64% of patients treated in the phase III studies,[95-97] has most influenced dosing. A number of approaches can be used to limit the incidence and severity of bortezomib-induced peripheral neuropathy. Among these are the application of a dose-reduction algorithm,[98] the use of bortezomib in the context of combination regimens,[8] dosing of bortezomib once weekly,[99-103] and, most recently, administration of bortezomib as a subcutaneous injection.[104] Despite these options, grade 2–4 peripheral neuropathy remains a significant complication of bortezomib in both the newly diagnosed and the relapsed and/or refractory settings. For example, in a randomized study of bortezomib given either subcutaneously or intravenously with oral dexamethasone, the overall rate of neuropathy of any grade was 38% vs 53%, respectively, while the incidence of grade 3 or worse neuropathy was 6% vs 16%, respectively.[104]

Fortunately, for patients in whom bortezomib-induced peripheral neuropathy has previously developed, next-generation PIs seem to be emerging as an especially rational option. Presentations of data from phase I studies of MLN9708[62] and marizomib[60,61] have reported a low rate of neuropathy, although one could argue that this may be due to the relatively limited exposure of patients to these agents in early-phase clinical trials. More experience has been gained from studies of carfilzomib, both in terms of the number of patients treated and the duration of treatment. Phase I trials of single-agent carfilzomib showed relatively low levels of grade 3 and 4 peripheral neuropathy in all patients[58,59]; this has also been the case in the two completed phase II trials.[63,105,106] Indeed, a pooled safety analysis of all four studies revealed that only 20 patients (3.9%) experienced any grade of neuropathy, with just two (0.4%) having grade 3 symptoms.[107] Moreover, the presence of baseline peripheral neuropathy did not seem to have an impact on either the depth or durability of responses to carfilzomib, or on the tolerability of this agent.[108] One hypothesis that has been proposed to explain the different effects of bortezomib and carfilzomib is that both these drugs induce the mitochondrial high-temperature-requirement protein A2 (HtrA2)/Omi.[109] However, this serine protease, which has been implicated in neuronal cell survival, is inhibited by bortezomib but not by carfilzomib, possibly resulting in greater proapoptotic signaling in neurons of bortezomib-treated patients.

Trials targeting patients who previously could not tolerate bortezomib due to neuropathy-related adverse events will be needed in order for novel PIs to gain approval for this indication. These trials could include patients who were intolerant of bortezomib because of its other toxicities, including dermatologic effects such as epidermal necrolysis[110] and vasculitis,[111] pulmonary effects such as interstitial pneumonitis[112,113] and capillary leak syndrome,[114] hepatitis,[115] and cardiac toxicities,[116] among others. The low incidence of these effects would probably dictate that most patients eligible for such a study would indeed have neuropathy. Randomized studies in such patients comparing the novel inhibitor to bortezomib as a control may be difficult to perform for ethical reasons. However, it may be possible in the future to pursue such studies in bortezomib-naive patients selected specifically for their risk of neuropathy. A recent trial of bortezomib with melphalan(Drug information on melphalan) and prednisone(Drug information on prednisone) as initial induction therapy found that the presence of neuropathy at baseline was the best predictor of the development of treatment-emergent symptoms.[117]

If corroborated by other findings, this would suggest that patients with preexisting neuropathy could benefit more from regimens based on a next-generation PI such as carfilzomib. Moreover, molecular studies suggest that the use of gene-expression profiling and single-nucleotide polymorphism analyses of patients at baseline may be able to identify those who are at increased risk for bortezomib-induced peripheral neuropathy.[118,119] Such patients would also be candidates for studies testing nerve-sparing PIs such as carfilzomib.

Conclusions

During the first decade of experience with bortezomib, proteasome inhibition has been firmly established as part of the standard of care for patients with newly diagnosed and relapsed and/or refractory multiple myeloma. The next generation of PIs, including carfilzomib, CEP-18770, marizomib, MLN9708, and ONX 0912, which have novel pharmacologic, pharmacokinetic, and pharmacodynamic properties, have now entered the clinical arena; others will probably do so soon. Among the attractive molecular properties of some of these agents are their ability to inhibit the proteasome more specifically, their ability to bind more proteasome protease activities, their ability to target the immunoproteasome, and their ability to induce proteasome inhibition by binding to α subunits, which may induce allosteric changes in the proteasome itself. From a clinical perspective, these agents are attractive due to the possibility of oral dosing, the likelihood that they can overcome drug resistance (including to bortezomib), the ability to combine them easily with other antimyeloma agents, and the possibility of improving the safety profile with a lower incidence of peripheral neuropathy. Regulatory approvals in the relapsed and/or refractory setting will likely first be achieved for these agents as stand-alone approaches in patients whose myeloma has progressed during their most recent line of therapy. These agents will then be good candidates for use (either singly or in combination with standard or novel drugs, including other PIs) in patients with fewer lines of therapy who have relapsed after a previous treatment.

FIGURE

A Possible Future Therapeutic Decision Tree for Bortezomib-Refractory Patients

Randomized studies comparing bortezomib to next-generation agents will be needed to determine which drugs will be preferred in PI-naive patients; these studies may be able to identify subgroups who would benefit more from one agent or another. For patients who have previously received bortezomib, optimal use and sequencing of other PIs will be aided by an understanding of the mechanisms of de novo and acquired drug resistance in patient plasma cells, as well as the potential contributions to resistance from the marrow microenvironment and the macroenvironment (Figure). During the next decade, the validation of next-generation agents and their use in rationally designed combination regimens and sequences seem destined to further revolutionize the care of myeloma patients and bring us closer to a cure for this disease.

Acknowledgments: The author would like to thank Brian E. Szente, PhD, of Fishawack Communications for his editorial assistance with this manuscript. Editorial support was funded by Onyx Pharmaceuticals.

Financial Disclosure: Robert Z. Orlowski has served as a member of an advisory board for Onyx Pharmaceuticals, Inc.

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SUPPLEMENT

The Future of Treatment for Patients With Relapsed/ Refractory Multiple Myeloma

The goal of this supplement is to present a comprehensive overview of the major current and emerging treatment options for patients with relapsed and/or refractory multiple myeloma.

The Future of Treatment for Patients With Relapsed/Refractory Multiple Myeloma
ONCOLOGY, November 7, 2011

Multiple Myeloma: A Clinical Overview
ONCOLOGY, November 7, 2011

Current Challenges in the Management of Patients with Relapsed/Refractory Multiple Myeloma
ONCOLOGY, November 7, 2011

Comparative Mechanisms of Action of Proteasome Inhibitors
ONCOLOGY, November 7, 2011

Current Advances in Novel Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma
ONCOLOGY, November 7, 2011

Current Advances in Non–Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma
ONCOLOGY, November 7, 2011

Treatment-Related Adverse Events in Patients With Relapsed/Refractory Multiple Myeloma
ONCOLOGY, November 7, 2011

The Future of Proteasome Inhibitors in Relapsed/Refractory Multiple Myeloma
ONCOLOGY, November 7, 2011

Topic Index

Cancer Types
Breast Breast (HER2+) Breast (Triple-Negative) CML Colorectal Gastrointestinal GIST Genitourinary Gynecologic Head & Neck	Hematology Kidney (Renal Cell) Leukemia Lung Lymphoma Melanoma Multiple Myeloma Ovarian Prostate Sarcoma
Supportive Care	More Topics
Bone Metastases End-of-Life Care Palliative Care	Ethics in Oncology Practice Management Practice & Policy

All Topics

The Future of Proteasome Inhibitors in Relapsed/Refractory Multiple Myeloma

Patients with relapsed multiple myeloma

Myeloma patients who are intolerant of bortezomib

Conclusions

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REFERENCES