ONCOLOGY. Vol. 25 2

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Current Advances in Non–Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma

By Abhishek Singla, MBBS¹, Shaji Kumar, MD¹ | November 7, 2011

¹Division of Hematology, Mayo Clinic, Rochester, Minnesota

Heat Shock Protein 90 Inhibitors

Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and that leads to stabilization of various client proteins involved in cell-cycle control and apoptotic signaling.[81] HSP90 overexpression may contribute to tumor cell survival by stabilizing aberrant signaling proteins, leading to increased proliferation and resistance to apoptosis. HSP90 inhibitors decrease MM proliferation, suppress the long-term replicative potential of MM cells, and may also sensitize MM cells to other anticancer agents.[82] Several HSP90 inhibitors have been evaluated in early-stage clinical trials.

Tanespimycin was one of the first HSP90 inhibitors to be tested in myeloma. In a phase I dose-escalation study, tanespimycin, 150 mg/m² to 525 mg/m², was given on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles to a group of heavily pretreated patients with R/R myeloma. Common adverse events included diarrhea, back pain, fatigue, nausea, anemia, and thrombocytopenia. One patient achieved MR, with a PFS of 3 months. Fifteen patients (52%) had stable disease with a median PFS of 2.1 months. Overall, tanespimycin monotherapy was well tolerated but had limited evidence of activity.[83]

Based on their mechanism of action (as with HDAC inhibitors), there is sufficient rationale to combine HSP90 inhibitors with bortezomib(Drug information on bortezomib). In a multicenter phase I/II trial, tanespimycin (100 mg/m² to 340 mg/m²) was combined with bortezomib (0.7 mg/m² to 1.3 mg/m²) given on days 1, 4, 8, and 11 of each 21-day cycle.[84] The highest tested dose of tanespimycin (340 mg/m²) and bortezomib (1.3 mg/m²) was selected for the phase II portion of the study. Seventy-two patients with relapsed or relapsed and refractory MM were enrolled; 63 patients (89%) completed the study. The combination was well tolerated, and among 67 efficacy-evaluable patients there were two CRs (3%) and eight PRs (12%), for an overall response rate of 27%, including eight minimal responses (12%).

Inhibitors of the PI3k/AKT Pathway, Including mTOR Inhibitors

This pathway, which consists of a series of kinases, including PI3k/AKT, mammalian target of rapamycin (mTOR), and p70S6K, as well as several intervening signaling molecules, plays an important role in the regulation of cell growth, proliferation, and survival.[85-87] Once activated, PI3k converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3) at the inner surface of the plasma membrane. As a consequence of the interaction with PIP3, pyruvate dehydrogenase kinase (PDK)1 is recruited to the plasma membrane and activated. AKT is also recruited to the plasma membrane, where PDK1 catalyzes phosphorylation of AKT on Thr308, one of the two phosphorylations required for maximal AKT activation. After activation, AKT phosphorylates and alters the biologic activity of a variety of substrates.[88-90] One of the downstream molecules is the mTOR kinase that facilitates cell-cycle progression from G1 into S-phase by phosphorylating two important cell constituents, p70S6K and 4E-BP1,[91,92] resulting in activation of transcription factors S6 and eIF4E. This leads to increased transcriptional activity of genes encoding for cyclin D1; the transcription factors C-myc, hypoxia inducible factor (HIF)-1α, and signal transducer and activator of transcription (STAT)3; ornithine decarboxylase; the growth factors VEGF and fibroblast growth factor (FGF); and ribosomal proteins themselves.[85,90,93-96]

The PI3k/AKT pathway is critical for proliferation and survival of the myeloma cell and mediates some of the antiapoptotic and proliferative effects of IL-6[97], IGF-1[97,98], SDF-1α[99], and hepatocyte growth factor (HGF).[100] Increased phosphorylation of AKT is seen in myeloma cells compared with normal marrow cells and appears to correlate with advanced disease, especially plasma cell leukemia.[101] The pathway partly mediates the proliferative and antiapoptotic effects of IL-6 in myeloma cell lines.[102] IL-6 triggers activation of PI3k and its association with SHP2, deactivates caspase-9, and protects against dexamethasone(Drug information on dexamethasone)-induced apoptosis. IL-6 triggers PI3k/AKT signaling, resulting in inactivation of forkhead transcriptional factor (FKHR), with related G1/S phase transition, whereas PI3k inhibitors, such as LY294002, block this signaling, resulting in upregulation of p27(KIP1) and G1 growth arrest.[102] IGF-1 stimulation of the myeloma cells leads to activation of this pathway with sustained activation of NFκB and AKT; phosphorylation of FKHRL-1; up-regulation of the antiapoptotic proteins FLIP, survivin, cIAP-2, A1/Bfl-1, and X-linked inhibitor of apoptosis (XIAP).[103] Activation of this pathway also mediates the migration of plasma cells induced by IGF-1.[104]

Perifosine is the best-studied AKT inhibitor in the setting of myeloma.[105] Initial trials focused on it as a single agent. Sixty-four patients with relapsed myeloma and a median of four lines of prior therapy were enrolled in a phase II trial of perifosine alone or with dexamethasone.[106] Among 48 patients evaluable for response, the best response to monotherapy after two cycles was MR in one patient (2%) and stable disease in 22 patients (46%). The addition of dexamethasone in 37 patients with disease progression led to a PR in 13% of the patients. The most common adverse events included nausea, vomiting, diarrhea, fatigue, increased serum creatinine level, and anemia. Subsequent trials examined the combination of perifosine with bortezomib or lenalidomide.[107,108]

The mTOR kinase, downstream in the PI3k/AKT pathway, is a serine/threonine kinase that receives multiple upstream signals regarding the nutrient and energy status of the cell.[85,96] On activation, mTOR facilitates cell-cycle progression from G1 into S-phase by phosphorylating two important cell constituents, p70S6K and 4E-BP1.[109,110] mTOR exists in mutually exclusive complexes with either Raptor (regulatory-associated protein of TOR) or Rictor (rapamycin-insensitive companion of TOR).[85,96,111] Note that the Raptor–mTOR complex is rapamycin-sensitive and is responsible for phosphorylation of p70S6K and 4E-BP1, whereas the Rictor–mTOR complex is rapamycin-insensitive and is one of the enzymes that can catalyze the activating phosphorylation of AKT at Ser473.[111] mTOR inhibitors include the macrolide rapamycin and its analogs temsirolimus (Torisel) and everolimus.[112] Preclinical studies confirm the antimyeloma activity of rapamycin and its analogs.[113,114] Both temsirolimus and everolimus have been studied in phase II trials in patients with relapsed disease and have shown very little clinically relevant antimyeloma activity. Better understanding of the reciprocal activity of TOR complex (TORC)1 and TORC2 has shed light on potential mechanisms of action and has led to the development of dual inhibitors. In addition, combined targeting of the PI3k/AKT/mTOR pathways may provide a way to enhance activity, and several dual inhibitors are currently going through early-phase trials.[71]

Monoclonal Antibodies

Monoclonal antibody therapy has been quite successful in lymphoid malignancies, as seen in the results with rituximab (Rituxan) in lymphoma and with alemtuzumab(Drug information on alemtuzumab) (Campath) in chronic lymphocytic leukemia. However, the search for monoclonal antibody–based therapy in myeloma has been beset by the heterogeneous expression of surface proteins in myeloma. More recently, early trials with the humanized monoclonal antibody elotuzumab (HuLuc63) have shown encouraging results. It induces antibody-dependent cell cytotoxicity–mediated apoptosis in vitro, and it significantly reduced tumor growth in preclinical myeloma models.[115] It has also shown significant activity in combination with bortezomib and lenalidomide in in vitro studies, which formed the basis for clinical evaluation of these combinations.[116] In a phase I study in patients who had received one to three prior therapies for myeloma, escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg) were administered intravenously on days 1 and 11 in combination with bortezomib, 1.3 mg/m², administered intravenously on days 1, 4, 8, and 11 of a 21-day cycle.[117] Dexamethasone, 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of subsequent cycles, was added for patients with disease progression. No disease-limiting toxicities (DLTs) were observed during cycle 1, and the MTD was not reached. The most frequent grade 3/4 adverse events were lymphopenia, fatigue, thrombocytopenia, neutropenia, hyperglycemia, PN, pneumonia, and anemia. A PR or better was observed in 13 of 27 evaluable patients (48%), including CR in 7% and PR in 41%. The results of the initial trials looking at the combination with lenalidomide were even more promising.[118] Escalating dose cohorts of elotuzumab (5, 10, and 20 mg/kg) were administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and then days 1 and 15 of each subsequent cycle, along with oral lenalidomide, 25 mg/d, on days 1 to 21, and oral dexamethasone, 40 mg weekly. No DLTs were observed at up to 20 mg/kg during the escalation phase and hence no MTD was established. The most frequent grade 3/4 toxicities were neutropenia and thrombocytopenia, and two patients experienced serious infusion-related reactions. A PR or better was seen in 82% (23 of 28) of treated patients and 96% (21 of 22) of lenalidomide-naive patients.

The inflammatory cytokine IL-6 is a survival factor for malignant plasma cells and is secreted by myeloma cells. Preclinical data suggest that CNTO328 (siltuximab), a novel human-mouse chimeric monoclonal antibody targeting IL-6, has an inhibitory effect on tumor burden and potentiates bortezomib-mediated apoptosis. Initial studies support the feasibility of combining the antibody with bortezomib in patients with relapsed myeloma.[119]

Conclusion

There are a number of classes of therapeutic agents in late-stage clinical trials for the treatment of myeloma. Among the IMiDs, both lenalidomide and pomalidomide represent significant additions to the armamentarium. While lenalidomide has been extensively studied in the setting of relapsed disease, current treatment patterns increasingly use it as part of initial therapy, especially in the United States. While studies suggest that retreatment with lenalidomide can have efficacy in selected groups of patients, pomalidomide is likely to fill that need once the drug is approved. Clearly, nonoverlapping mechanisms of action are in place given the activity of pomalidomide among patients whose disease is refractory to lenalidomide. The results of these trials need to be considered in the context of several promising drugs that are currently undergoing clinical trials. One potentially promising class of compounds are the HDAC inhibitors, including vorinostat and panobinostat. While their activity as single agents is limited, their sensitizing capacity and efficacy in combination are being vigorously investigated. HSP90 inhibitors such as tanespimycin fall into a similar category, with limited single-agent activity but signs of potential in combination settings. Monoclonal antibodies such as elotuzumab also offer significant promise both as monotherapies and in multidrug combinations. Encouraging preliminary data have also been seen with PI3K/AKT inhibitors and compounds targeting the mTOR pathway. It is likely that in the near future the treatment armamentarium for MM will undergo a significant expansion as a number of these additional target pathways become validated, offering additional hope for extending survival in patients with MM.

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

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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