International Journal of Clinical Oncology

, Volume 12, Issue 5, pp 318–326 | Cite as

Proteasome inhibitor, bortezomib, for myeloma and lymphoma

REVIEW ARTICLE

Abstract

Bortezomib, a boronic acid, is a potent and selective proteasome inhibitor. The 20S proteasome is an enzyme complex present in cells, and it degrades many cell-cycle control factors, signal transduction factors, transcription factors, and oncogene and anti-oncogene products, thus controlling cell proliferation, differentiation, and apoptosis. Bortezomib is a novel molecular targeting agent which was designed to exhibit an antitumor effect by selectively inhibiting the 20S proteasome. Multiple myeloma is one of the incurable B-cell malignancies that continues to relapse with current treatment modalities, and the duration to progression becomes shorter in patients who repeatedly receive chemotherapy. There are no available treatment options in which durable efficacy can be expected after relapse; therefore, an effective therapy with a novel mechanism of action has been desired. In this review article, the results of clinical trials of bortezomib for multiple myeloma, including a Japanese phase I/II and pharmacokinetic/pharmacodynamic study, and those for non-Hodgkin lymphoma, especially for mantle cell lymphoma, are summarized. In the Japanese phase I/II study of bortezomib for relapsed multiple myeloma, this agent showed remarkable efficacy, with acceptable toxicities and unique pharmacokinetic/pharmacodynamic profiles, warranting further investigations, including more relevant administration schedules.

Key words

Proteasome inhibitor Bortezomib Multiple myeloma Lymphoma 

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References

  1. 1.
    Kisselev, AF, Goldberg, AL 2001Proteasome inhibitors: from research tools to drug candidatesChem Biol8739758PubMedCrossRefGoogle Scholar
  2. 2.
    Maki, CG, Huibregtse, JM, Howley, PM 1996In vivo ubiquitination and proteasome-mediated degradation of p53Cancer Res5626492654PubMedGoogle Scholar
  3. 3.
    Clurman, BE, Sheaff, RJ, Thress, K,  et al. 1996Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylationGenes Dev1019791990PubMedCrossRefGoogle Scholar
  4. 4.
    Tatebe, H, Yanagida, M 2000Cut8, essential for anaphase, controls localization of 26S proteasome, facilitating destruction of cyclin and Cut2Curr Biol1013291338PubMedCrossRefGoogle Scholar
  5. 5.
    Cayrol, C, Ducommun, B 1998Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21Oncogene1724372444PubMedCrossRefGoogle Scholar
  6. 6.
    Pagano, M, Tam, SW, Theodoras, AM,  et al. 1995Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27Science269682685PubMedCrossRefGoogle Scholar
  7. 7.
    Adams, J, Palombella, VJ, Sausville, EA,  et al. 1999Proteasome inhibitors: a novel class of potent and effective antitumor agentsCancer Res5926152622PubMedGoogle Scholar
  8. 8.
    Adams, J, Palombella, VJ, Elliott, PJ 2000Proteasome inhibition: a new strategy in cancer treatmentInvest New Drugs18109121PubMedCrossRefGoogle Scholar
  9. 9.
    Hideshima, T, Chauhan, D, Schlossman, R,  et al. 2001The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applicationsOncogene2045194527PubMedCrossRefGoogle Scholar
  10. 10.
    Hideshima, T, Richardson, P, Chauhan, D,  et al. 2001The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cellsCancer Res6130713076PubMedGoogle Scholar
  11. 11.
    Mitsiades, N, Mitsiades, CS, Poulaki, V,  et al. 2002Molecular sequelae of proteasome inhibition in human multiple myeloma cellsProc Natl Acad Sci USA9914 37414 379CrossRefGoogle Scholar
  12. 12.
    Hideshima, T, Mitsiades, C, Akiyama, M,  et al. 2003Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341Blood10115301534PubMedCrossRefGoogle Scholar
  13. 13.
    Oken, MM 1994Standard treatment of multiple myelomaMayo Clin Proc69781786PubMedGoogle Scholar
  14. 14.
    Oken, MM 1998Management of myeloma: current and future approachesCancer Control5218225PubMedGoogle Scholar
  15. 15.
    Myeloma Trialists Collaborative Group1998Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6633 patients from 27 randomized trialsJ Clin Oncol1638323842Google Scholar
  16. 16.
    Takenaka, T, Itoh, K, Suzuki, T,  et al. 2004Phase III study of ranimustine, cyclophosphamide, vincristine, melphalan, and prednisolone (MCNU-COP/MP) versus modified COP/MP in multiple myeloma: a Japan Clinical Oncology Group study, JCOG 9301Int J Hematol79165173PubMedGoogle Scholar
  17. 17.
    Barlogie, B, Smith, L, Alexanian, R 1984Effective treatment of advanced multiple myeloma refractory to alkylating agentsN Engl J Med31013531356PubMedCrossRefGoogle Scholar
  18. 18.
    Attal, M, Harousseau, JL, Facon, T,  et al. 2003Single versus double autologous stem-cell transplantation for multiple myelomaN Engl J Med34924952502PubMedCrossRefGoogle Scholar
  19. 19.
    Attal, M, Harousseau, J, Stoppa, J,  et al. 1996A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myelomaN Engl J Med3359197PubMedCrossRefGoogle Scholar
  20. 20.
    Child, JA, Morgan, GJ, Davies, FE,  et al. 2003High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myelomaN Engl J Med34818751883PubMedCrossRefGoogle Scholar
  21. 21.
    Barlogie, B, Kyle, RA, Anderson, KC,  et al. 2006Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321J Clin Oncol24929936PubMedCrossRefGoogle Scholar
  22. 22.
    Buzaid, AC, Durie, BG 1988Management of refractory myeloma: a reviewJ Clin Oncol6889905PubMedGoogle Scholar
  23. 23.
    Paccagnella, A, Chiarion-Sileni, V, Soesan, M,  et al. 1991Second and third responses to the same induction regimen in relapsing patients with multiple myelomaCancer68975980PubMedCrossRefGoogle Scholar
  24. 24.
    Stewart KA, O'Connor OA, Alsina M, et al. (2007) Phase I evaluation of carfilzomib (PR-171) in hematological malignancies: responses in multiple myeloma and Waldenstrom's macroglobulinemia at well-tolerated doses. Proc Am Soc Clin Oncol 25: no. 8003Google Scholar
  25. 25.
    Orlowski, RZ, Stinchcombe, TE, Mitchell, BS,  et al. 2002Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignanciesJ Clin Oncol2044204427PubMedCrossRefGoogle Scholar
  26. 26.
    Aghajanian, C, Soignet, S, Dizon, DS,  et al. 2002A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignanciesClin Cancer Res825052511PubMedGoogle Scholar
  27. 27.
    Richardson, PG, Barlogie, B, Berenson, J,  et al. 2003A phase 2 study of bortezomib in relapsed, refractory myelomaN Engl J Med34826092617PubMedCrossRefGoogle Scholar
  28. 28.
    Jagannath, S, Barlogie, B, Berenson, J,  et al. 2004A phase 2 study of two doses of bortezomib in relapsed or refractory myelomaBr J Haematol127165172PubMedCrossRefGoogle Scholar
  29. 29.
    Blade, J, Samson, D, Reece, D,  et al. 1998Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantationBr J Haematol10211151123PubMedCrossRefGoogle Scholar
  30. 30.
    Richardson, PG, Barlogie, B, Berenson, J,  et al. 2005Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myelomaBlood10629772981PubMedCrossRefGoogle Scholar
  31. 31.
    Jagannath, S, Barlogie, B, Berenson, JR,  et al. 2005Bortezomib in recurrent and/or refractory multiple myeloma: initial clinical experience in patients with impaired renal functionCancer10311951200PubMedCrossRefGoogle Scholar
  32. 32.
    Lonial, S, Waller, EK, Richardson, PG,  et al. 2005Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myelomaBlood10637773784PubMedCrossRefGoogle Scholar
  33. 33.
    Richardson, P, Sonneveld, P, Schuster, MW,  et al. 2005Bortezomib or high-dose dexamethasone for relapsed multiple myelomaN Engl J Med35224872498PubMedCrossRefGoogle Scholar
  34. 34.
    Richardson PG, Sonneveld P, Schuster M, et al. (2005) Bortezomib continues demonstrate superior efficacy compared with high-dose dexamethasone in relapsed multiple myeloma: updated results of the APEX trial. Blood (ASH Annual Meeting Abstracts) 106: no. 2547Google Scholar
  35. 35.
    Kane, RC, Farrell, AT, Sridhara, R,  et al. 2006United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapyClin Cancer Res1229556290PubMedCrossRefGoogle Scholar
  36. 36.
    Richardson, PG, Sonneveld, P, Schuster, MW,  et al. 2007Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myelomaBr J Haematol137429435PubMedCrossRefGoogle Scholar
  37. 37.
    Greipp, PR, San Miguel, J, Durie, BG,  et al. 2005International staging system for multiple myelomaJ Clin Oncol2334123420PubMedCrossRefGoogle Scholar
  38. 38.
    Jagannath, S, Durie, BG, Wolf, J,  et al. 2005Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myelomaBr J Haematol129776783PubMedCrossRefGoogle Scholar
  39. 39.
    Harousseau JL, Nagler A, Sonneveld P, et al. (2007) Effect of the combination of pegylated liposomal doxorubicin and bortezomib on time to progression (TTP) and overall survival of patients with relapsed/refractory multiple myeloma compared with bortezomib alone. Proc Am Soc Clin Oncol 25: no. 8002Google Scholar
  40. 40.
    Orlowski, RZ, Voorhees, PM, Garcia, RA,  et al. 2005Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignanciesBlood10530583065PubMedCrossRefGoogle Scholar
  41. 41.
    Tobinai K, Watanabe T, Ogawa Y, et al. (2006) Pharmacokinetic (PK) and pharmacodynamic (PD) profiles of bortezomib (B) in patients (pts) with relapsed multiple myeloma (MM): a phase I/II study in Japan. Blood (ASH Annual Meeting Abstracts) 108: no. 5106Google Scholar
  42. 42.
    Miyakoshi, S, Kami, M, Yuji, K,  et al. 2006Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myelomaBlood10734923494PubMedCrossRefGoogle Scholar
  43. 43.
    Gotoh, A, Ohyashiki, K, Oshimi, K,  et al. 2006Lung injury associated with bortezomib therapy in relapsed/refractory multiple myeloma in Japan: a questionnaire-based report from the “Lung Injury by Bortezomib” joint committee of the Japanese Society of Hematology and the Japanese Society of Clinical HematologyInt J Hematol84406412PubMedCrossRefGoogle Scholar
  44. 44.
    Goy, A, Younes, A, McLaughlin, P,  et al. 2005Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphomaJ Clin Oncol23667675PubMedCrossRefGoogle Scholar
  45. 45.
    O'Connor, OA, Wright, J, Moskowitz, C,  et al. 2005Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphomaJ Clin Oncol23676684PubMedCrossRefGoogle Scholar
  46. 46.
    Strauss, SJ, Maharaj, L, Hoare, S,  et al. 2006Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activityJ Clin Oncol2421052012PubMedCrossRefGoogle Scholar
  47. 47.
    Belch, A, Kouroukis, CT, Crump, M,  et al. 2007A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150Ann Oncol18116121PubMedCrossRefGoogle Scholar
  48. 48.
    Fisher, RI, Bernstein, SH, Kahl, BS,  et al. 2006Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphomaJ Clin Oncol2448674874PubMedCrossRefGoogle Scholar
  49. 49.
    Cheson, BD, Horning, SJ, Coiffier, B,  et al. 1999Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working GroupJ Clin Oncol1712441253PubMedGoogle Scholar
  50. 50.
    de Vos S, Dakhil S, McLaughlin P, et al. (2005) Bortezomib plus rituximab in patients with indolent non-Hodgkin's lymphoma (NHL): a phase 2 study. Blood (ASH Annual Meeting Abstracts) 106: no. 17Google Scholar
  51. 51.
    Coiffier, B, Lepage, E, Briere, J,  et al. 2002CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphomaN Engl J Med346235242PubMedCrossRefGoogle Scholar
  52. 52.
    Feugier, P, Van Hoof, A, Sebban, C,  et al. 2005Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'AdulteJ Clin Oncol2341174126PubMedCrossRefGoogle Scholar
  53. 53.
    Habermann, TM, Weller, EA, Morrison, VA,  et al. 2006Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphomaJ Clin Oncol2431213127PubMedCrossRefGoogle Scholar
  54. 54.
    Pfreundschuh, M, Trumper, L, Osterborg, A,  et al. 2006CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) GroupLancet Oncol7379391PubMedCrossRefGoogle Scholar
  55. 55.
    Leonard JP, Furman RR, Cheung YK, et al. (2007) CHOP-R + bortezomib as initial therapy for diffuse large B-cell lymphoma (DLBCL). Proc Am Soc Clin Oncol 25: no. 8031Google Scholar
  56. 56.
    Mounier N, Ribrag V, Haioun C, et al. (2007) Efficacy and toxicity of two schedules of R-CHOP plus bortezomib in front-line B lymphoma patients: a randomized phase II trial from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Proc Am Soc Clin Oncol 25: no. 8010Google Scholar
  57. 57.
    Zinzani PL, Tani M, Musuraca G, et al. (2006) Phase II study of proteasome inhibitor bortezomib (Velcade®) in patients with relapsed/refractory T-cell lymphoma: preliminary results. Blood (ASH Annual Meeting Abstracts) 108: no. 2462Google Scholar
  58. 58.
    Tan, C, Waldmann, TA 2002Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemiaCancer Res6210831086PubMedGoogle Scholar
  59. 59.
    Satou, Y, Nosaka, K, Koya, Y,  et al. 2004Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitroLeukemia1813571363PubMedCrossRefGoogle Scholar
  60. 60.
    Rajkumar, VS, Richardson, PG, Hideshima, T,  et al. 2005Proteasome inhibition as a novel therapeutic target in human cancerJ Clin Oncol23630639PubMedCrossRefGoogle Scholar
  61. 61.
    Berenson, JR, Yang, HH, Sadler, K,  et al. 2006Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myelomaJ Clin Oncol24937944PubMedCrossRefGoogle Scholar
  62. 62.
    Kropff, M, Bisping, G, Schuck, E,  et al. 2007Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myelomaBr J Haematol138330337PubMedCrossRefGoogle Scholar
  63. 63.
    Suvannasankha, A, Smith, GG, Juliar, BE,  et al. 2006Weekly bortezomib/methylprednisolone is effective and well tolerated in relapsed multiple myelomaClin Lymphoma Myeloma7131134PubMedCrossRefGoogle Scholar

Copyright information

© The Japan Society of Clinical Oncology 2007

Authors and Affiliations

  1. 1.Hematology and Stem Cell Transplantation DivisionNational Cancer Center HospitalTokyoJapan

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