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Proteasome inhibitor bortezomib for the treatment of multiple myeloma

Abstract

Bortezomib (formerly PS-341) has been the first proteasome inhibitor to enter clinical trials in cancer patients. Based on results of preclinical studies showing that this novel agent directly inhibits the proliferation of myeloma cells, induces their apoptosis and abrogates paracrine tumor growth through alteration of myeloma–stromal cell interactions and nuclear factor-κB-dependent cytokine secretion, several large phase II and III studies of bortezomib were initiated in patients with advanced relapsed and/or refractory multiple myeloma (MM). Favorable results of these studies led to accelerated approval for use of bortezomib in MM patients who have progressed after at least their second therapy and, more recently, to expanded approval for second-line use in patients on whom one prior therapy has failed. In the meantime, combination studies of bortezomib with various agents, including dexamethasone, DNA-damaging drugs, thalidomide and lenalidomide, have been designed and are currently ongoing in patients with both relapsed/refractory and newly diagnosed disease. Bortezomib offers great promise to overcome resistance to conventional chemotherapy and may be the ‘backbone’ for the development of more effective treatment strategies to improve patient outcome in MM.

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References

  1. Ciechanover A, Orian A, Schwartz AL . Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 2000; 22: 442–451.

    Article  CAS  PubMed  Google Scholar 

  2. Zwickl P, Voges D, Baumeister W . The proteasome: a macromolecular assembly designed for controlled proteolysis. Philos Trans R Soc Lond B Biol Sci 1999; 354: 1501–1511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kisselev AF, Goldberg AL . Proteasome inhibitors: from research tools to drug candidates. Chem Biol 2001; 8: 739–758.

    Article  CAS  PubMed  Google Scholar 

  4. Voorhees PM, Dees EC, O'Neil B, Orlowski RZ . The proteasome as a target for cancer therapy. Clin Cancer Res 2003; 9: 6316–6325.

    CAS  PubMed  Google Scholar 

  5. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T . The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 1994; 78: 773–785.

    Article  CAS  PubMed  Google Scholar 

  6. Almond JB, Cohen GM . The proteasome: a novel target for cancer chemotherapy. Leukemia 2002; 16: 433–443.

    Article  CAS  PubMed  Google Scholar 

  7. Spataro V, Norbury C, Harris AL . The ubiquitin-proteasome pathway in cancer. Br J Cancer 1998; 77: 448–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li B, Dou QP . Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proc Natl Acad Sci USA 2000; 97: 3850–3855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61: 3071–3076.

    CAS  PubMed  Google Scholar 

  10. Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 2003; 9: 1136–1144.

    CAS  PubMed  Google Scholar 

  11. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003; 101: 2377–2380.

    Article  CAS  PubMed  Google Scholar 

  12. Russo SM, Tepper JE, Baldwin Jr AS, Liu R, Adams J, Elliott P et al. Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. Int J Radiat Oncol Biol Phys 2001; 50: 183–193.

    Article  CAS  PubMed  Google Scholar 

  13. Delic J, Masdehors P, Omura S, Cosset JM, Dumont J, Binet JL et al. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer 1998; 77: 1103–1107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Masdehors P, Omura S, Merle-Beral H, Mentz F, Cosset JM, Dumont J et al. Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br J Haematol 1999; 105: 752–757.

    Article  CAS  PubMed  Google Scholar 

  15. Orlowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Dang CV . Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. Cancer Res 1998; 58: 4342–4348.

    CAS  PubMed  Google Scholar 

  16. Richardson PG, Hideshima T, Anderson KC . Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control 2003; 10: 361–369.

    Article  PubMed  Google Scholar 

  17. Adams J, Behnke M, Chen S, Cruickshank AA, Dick LR, Grenier L et al. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett 1998; 8: 333–338.

    Article  CAS  PubMed  Google Scholar 

  18. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 2615–2622.

    CAS  PubMed  Google Scholar 

  19. Hideshima T, Chauhan D, Richardson P, Anderson KC . Identification and validation of novel therapeutic targets for multiple myeloma. J Clin Oncol 2005; 23: 6345–6350.

    Article  CAS  PubMed  Google Scholar 

  20. Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 1996; 87: 1104–1112.

    CAS  PubMed  Google Scholar 

  21. Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE et al. SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem 2000; 275: 27845–27850.

    CAS  PubMed  Google Scholar 

  22. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor–stromal cell interactions in multiple myeloma. Blood 2000; 95: 2630–2636.

    CAS  PubMed  Google Scholar 

  23. Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001; 15: 1950–1961.

    Article  CAS  PubMed  Google Scholar 

  24. Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J . Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell Immunol 1995; 162: 248–255.

    Article  CAS  PubMed  Google Scholar 

  25. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639–16647.

    Article  CAS  PubMed  Google Scholar 

  26. LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 2002; 62: 4996–5000.

    CAS  PubMed  Google Scholar 

  27. Anderson KC . Targeted therapy for multiple myeloma. Semin Hematol 2001; 38: 286–294.

    Article  CAS  PubMed  Google Scholar 

  28. Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC . The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 2001; 20: 4519–4527.

    Article  CAS  PubMed  Google Scholar 

  29. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 2002; 99: 14374–14379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003; 101: 1530–1534.

    Article  CAS  PubMed  Google Scholar 

  31. Berenson JR, Ma HM, Vescio R . The role of nuclear factor-kappaB in the biology and treatment of multiple myeloma. Semin Oncol 2001; 28: 626–633.

    Article  CAS  PubMed  Google Scholar 

  32. Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS . Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 1999; 93: 3044–3052.

    CAS  PubMed  Google Scholar 

  33. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ . Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 2003; 171: 88–95.

    Article  CAS  PubMed  Google Scholar 

  34. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002; 20: 4420–4427.

    Article  CAS  PubMed  Google Scholar 

  35. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–2617.

    Article  CAS  PubMed  Google Scholar 

  36. Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004; 127: 165–172.

    Article  CAS  PubMed  Google Scholar 

  37. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498.

    Article  CAS  PubMed  Google Scholar 

  38. Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102: 1115–1123.

    Article  PubMed  Google Scholar 

  39. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood 2005; 106: 2977–2981.

    Article  CAS  PubMed  Google Scholar 

  40. Berenson JR, Jagannath S, Barlogie B, Siegel DT, Alexanian R, Richardson PG et al. Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer 2005; 104: 2141–2148.

    Article  CAS  PubMed  Google Scholar 

  41. Jagannath S, Barlogie B, Berenson JR, Singhal S, Alexanian R, Srkalovic G et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function. Cancer 2005; 103: 1195–1200.

    Article  CAS  PubMed  Google Scholar 

  42. Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 2005; 106: 3777–3784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Berenson JR, Yang HH, Sadler K, Jarutirasarn SG, Vescio RA, Mapes R et al. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol 2006; 6: 937–944.

    Article  Google Scholar 

  44. Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005; 105: 3058–3065.

    Article  CAS  PubMed  Google Scholar 

  45. Small GW, Somasundaram S, Moore DT, Shi YY, Orlowski RZ . Repression of mitogen-activated protein kinase (MAPK) phosphatase-1 by anthracyclines contributes to their antiapoptotic activation of p44/42-MAPK. J Pharmacol Exp Ther 2003; 307: 861–869.

    Article  CAS  PubMed  Google Scholar 

  46. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99: 4525–4530.

    Article  CAS  PubMed  Google Scholar 

  47. Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 2005; 129: 755–762.

    Article  CAS  PubMed  Google Scholar 

  48. Jagannath S, Durie BG, Wolf J, Camacho E, Irwin D, Lutzky J et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 2005; 129: 776–783.

    Article  CAS  PubMed  Google Scholar 

  49. Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106: 35–39.

    Article  CAS  PubMed  Google Scholar 

  50. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR . Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 431–436.

    Article  CAS  PubMed  Google Scholar 

  51. Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106: 4050–4053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Cavo, M. Proteasome inhibitor bortezomib for the treatment of multiple myeloma. Leukemia 20, 1341–1352 (2006). https://doi.org/10.1038/sj.leu.2404278

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