Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myeloma

Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study

Leukemia volume 22, pages 842–849 (2008)Cite this article

Abstract

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30–50, 51–80 and >80 ml min−1). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl ⩽50 ml min−1 (severe-to-moderate) and >50 ml min−1 (no/mild impairment). Response rates with bortezomib were similar (36–47%) and time to response rapid (0.7–1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl ⩽50 vs >50 ml min−1 (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl ⩽50 vs >50 ml min−1. These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Penfield JG . Multiple myeloma in end-stage renal disease. Semin Dial 2006; 19: 329–334.

    Article  PubMed  Google Scholar 

  2. Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J . Renal function in newly diagnosed multiple myeloma—a demographic study of 1353 patients. The nordic myeloma study group. Eur J Haematol 1994; 53: 207–212.

    Article  CAS  PubMed  Google Scholar 

  3. Knudsen LM, Hjorth M, Hippe E . Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic myeloma study group. Eur J Haematol 2000; 65: 175–181.

    Article  CAS  PubMed  Google Scholar 

  4. Augustson BM, Begum G, Dunn JA, Barth NJ, Davies F, Morgan G et al. Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United Kingdom medical research council trials between 1980 and 2002—medical research council adult leukaemia working party. J Clin Oncol 2005; 23: 9219–9226.

    Article  PubMed  Google Scholar 

  5. Alexanian R, Barlogie B, Dixon D . Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990; 150: 1693–1695.

    Article  CAS  PubMed  Google Scholar 

  6. Clark AD, Shetty A, Soutar R . Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Rev 1999; 13: 79–90.

    Article  CAS  PubMed  Google Scholar 

  7. Bladé J, Fernandez-Llama P, Bosch F, Montoliu J, Lens XM, Montoto S et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998; 158: 1889–1893.

    Article  PubMed  Google Scholar 

  8. Carlson K . Melphalan 200 mg/m2 with blood stem cell support as first-line myeloma therapy: impact of glomerular filtration rate on engraftment, transplantation-related toxicity and survival. Bone Marrow Transplant 2005; 35: 985–990.

    Article  CAS  PubMed  Google Scholar 

  9. Knudsen LM, Nielsen B, Gimsing P, Geisler C . Autologous stem cell transplantation in multiple myeloma: outcome in patients with renal failure. Eur J Haematol 2005; 75: 27–33.

    Article  PubMed  Google Scholar 

  10. Torra R, Blade J, Cases A, Lopez-Pedret J, Montserrat E, Rozman C et al. Patients with multiple myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series of 20 cases. Br J Haematol 1995; 91: 854–859.

    Article  CAS  PubMed  Google Scholar 

  11. Bladé J, Rosinol L . Renal, hematologic and infectious complications in multiple myeloma. Best Pract Res Clin Haematol 2005; 18: 635–652.

    Article  PubMed  Google Scholar 

  12. 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 impaired renal function. Cancer 2005; 103: 1195–1200.

    Article  CAS  PubMed  Google Scholar 

  13. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78: 21–33.

    Article  PubMed  Google Scholar 

  14. Sakhuja V, Jha V, Varma S, Joshi K, Gupta KL, Sud K et al. Renal involvement in multiple myeloma: a 10-year study. Ren Fail 2000; 22: 465–477.

    Article  CAS  PubMed  Google Scholar 

  15. Cavo M, Galieni P, Zuffa E, Baccarani M, Gobbi M, Tura S . Prognostic variables and clinical staging in multiple myeloma. Blood 1989; 74: 1774–1780.

    CAS  PubMed  Google Scholar 

  16. Zangari M, Barlogie B, Thertulien R, Jacobson J, Eddleman P, Fink L et al. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma 2003; 4: 32–35.

    Article  CAS  PubMed  Google Scholar 

  17. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.

    Article  PubMed  Google Scholar 

  18. Mileshkin L, Biagi JJ, Mitchell P, Underhill C, Grigg A, Bell R et al. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood 2003; 102: 69–77.

    Article  CAS  PubMed  Google Scholar 

  19. San Miguel JF, Lahuerta JJ, Garcia-Sanz R, Alegre A, Blade J, Martinez R et al. Are myeloma patients with renal failure candidates for autologous stem cell transplantation? Hematol J 2000; 1: 28–36.

    Article  CAS  PubMed  Google Scholar 

  20. Kyle RA, Rajkumar SV . Multiple myeloma. N Engl J Med 2004; 351: 1860–1873.

    Article  CAS  PubMed  Google Scholar 

  21. Kane RC, Farrell AT, Sridhara R, Pazdur R . United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 2006; 12: 2955–2960.

    Article  CAS  PubMed  Google Scholar 

  22. Millennium Pharmaceuticals Inc. VELCADE® (bortezomib) for Injection. Prescribing Information. Cambridge, MA, USA, 2007; Issued October 2007, Rev 7.

  23. Mulkerin D, Remick S, Ramanathan R, Hamilton A, Takimoto C, Davies P et al. A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function. J Clin Oncol 2006; 24: 87s.

    Google Scholar 

  24. Mohrbacher A, Levine AM . Reversal of advanced renal dysfunction on bortezomib treatment in multiple myeloma patients. J Clin Oncol 2005; 23: 612s.

    Article  Google Scholar 

  25. Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 2007; 109: 2604–2606.

    Article  CAS  PubMed  Google Scholar 

  26. Malani AK, Gupta V, Rangineni R . Bortezomib and dexamethasone in previously untreated multiple myeloma associated with renal failure and reversal of renal failure. Acta Haematol 2006; 116: 255–258.

    Article  CAS  PubMed  Google Scholar 

  27. Terpos E, Katodritou E, Tsiftsakis E, Verrou E, Christoulas D, Anagnostopoulos A et al. Cystatin-C: an early marker of renal impairment and an independent predictive factor for survival in multiple myeloma. Reduction post bortezomib therapy. Haematologica 2007; 92: PO–227.

  28. Ludwig H, Drach J, Graf H, Lang A, Meran JG . Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica 2007; 92: 1411–1414.

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110: 3557–3560.

    Article  CAS  PubMed  Google Scholar 

  31. 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 

  32. Cockcroft DW, Gault MH . Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development LLC. We thank Steve Hill and Rosemary Washbrook for their assistance in drafting the manuscript. Steve Hill is a medical writer and Rosemary Washbrook is a medical editor with Gardiner-Caldwell London. We also thank the APEX Management Team; Dalton W, Anderson K, Harousseau J and San-Miguel J and the APEX Investigators; Abubakr Y, Agura E, Alexanian R, Alsina M, Andre M, Attal M, Avigan D, Baccarani M, Bahlis N, Barbui T, Barton, K, Belch A, Bensinger W, Ben-Yehuda D, Berdeja J, Bjorkstrand B, Bladé J, Boccadoro M, Boue F, Bourhis J, Bron D, Catlett J, Cavenagh J, Cavet J, Chanan-Khan A, Coiffier B, Comenzo R, Craddock C, Dearden C, Delforge M, Densmore J, Doyen C, Durk H, Ehninger G, Einsele H, Engelhardt M, Facon T, Fay J, Fehrenbacher L, Feremans W, Fermand JP, Fernandez H, Giguere J, Glasmacher A, Glass J, Goldschmidt H, Gordon P, Gramatzki M, Gruber A, Gyan E, Hamm J, Hegewisch-Becker S, Huber C, Hulin C, Hussein M, Ifthikharuddin J, Irwin D, Jackson G, Jagannath S, Jagasia M, Jakubowiak A, Klein A, Kobbe G, Kovacs M, Krishnan A, Kropff M, Kuter D, Lacy M, Lenhoff S, Limentani S, Lokhorst H, Lonial S, Ludwig H, Mandelli F, Marie JP, Marsden GJ, Martin T, Mason J, Mavromatis B, Morris C, Morrison V, Nowrousian M, Orlowski R, Pecora A, Phelan J, Posada, J, Rahemtulla A, Rai K, Reece D, Richardson P, Rowe JM, Schilder R, Schmidt W, Schuster M, Sezer O, Shadduck R, Shustik C, Siegel D, Singhal S, Sonneveld P, Sotto JJ, Stadtmauer E, Tarantolo S, Van Droogenbroeck J, Van Oers MH, Vellenga E, Vesole D, Vij R, Zachee P and Zangari M.

Author information

Authors and Affiliations

  1. Department of Hematology, Hospital Universitario. CIC Universidad de Salamanca-CSIC, Salamanca, Spain

    J F San-Miguel

  2. Department of Medical Oncology/Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, USA

    P G Richardson & K C Anderson

  3. Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands

    P Sonneveld

  4. Center for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, NY, USA

    M W Schuster

  5. Bone and Marrow Transplantation Program, Alta Bates Cancer Center, Berkeley, CA, USA

    D Irwin

  6. Bone Marrow and Stem Cell Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    E A Stadtmauer

  7. Services des Maladies du Sang, Hospital Claude Huriez, Lille, France

    T Facon

  8. Department of Hematology, Hotel Dieu Hospital, Nantes, France

    J-L Harousseau

  9. Department of Hematology, Hadassah University Hospital, Jerusalem, Israel

    D Ben-Yehuda

  10. The Winship Cancer Institute, Emory University, Atlanta, GA, USA

    S Lonial

  11. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    H Goldschmidt

  12. Division of Hematology–Oncology, Princess Margaret Hospital, Toronto, Canada

    D Reece

  13. Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain

    J Bladé

  14. Division of Hematology, University of Torino, Torino, Italy

    M Boccadoro

  15. Department of Haematology, St Bartholomew's Hospital, London, UK

    J D Cavenagh

  16. Millennium Pharmaceuticals, Inc., Cambridge, MA, USA

    R Neuwirth, A L Boral & D-L Esseltine

Authors
  1. J F San-Miguel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P G Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Sonneveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M W Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Irwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E A Stadtmauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Facon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J-L Harousseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Ben-Yehuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Lonial
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Goldschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D Reece
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Bladé
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Boccadoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J D Cavenagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. R Neuwirth
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. A L Boral
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. D-L Esseltine
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. K C Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J F San-Miguel.

Additional information

Statement of originality

The authors confirm that this manuscript contains original material.

Rights and permissions

Reprints and permissions

About this article

Cite this article

San-Miguel, J., Richardson, P., Sonneveld, P. et al. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 22, 842–849 (2008). https://doi.org/10.1038/sj.leu.2405087

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2405087

Keywords

This article is cited by

Search

Advanced search

Quick links