, Volume 29, Issue 3, pp 207–214 | Cite as

Bortezomib: A Review in Mantle Cell Lymphoma in Previously Untreated Patients Unsuitable for Stem-Cell Transplantation

  • Paul L. McCormack
Adis Drug Evaluation


Bortezomib (Velcade®) is a proteasome inhibitor that is approved for the treatment of multiple myeloma and mantle cell lymphoma (MCL). This article reviews the efficacy and tolerability of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in the treatment of previously untreated MCL unsuitable for stem-cell transplantation, and overviews the pharmacology of bortezomib. In the large, randomized, assessor-blinded, multinational LYM-3002 trial, induction therapy with VR-CAP improved progression-free survival significantly more than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) after a median follow-up of 40 months in patients with newly diagnosed MCL ineligible or not considered for stem-cell transplantation. Complete response and certain other secondary endpoints were improved significantly more with VR-CAP than R-CHOP. Overall survival data were not mature at the time of assessment. The improved efficacy with VR-CAP was accompanied by an increased incidence of grade 3 or higher adverse events, particularly haematological adverse events.


Overall Survival Bortezomib Mantle Cell Lymphoma Bendamustine Ibrutinib 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Paul L. McCormack is a salaried employee of Adis/Springer.


  1. 1.
    McKay P, Leach M, Jackson R, et al. Guidelines for the investigation and management of mantle cell lymphoma. Br J Haematol. 2012;159(4):405–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Brett LK, Williams ME. Current and emerging therapies in mantle cell lymphoma. Curr Treat Options Oncol. 2013;14(2):198–211.PubMedCrossRefGoogle Scholar
  3. 3.
    Dreyling M. Mantle cell lymphoma: biology, clinical presentation, and therapeutic approaches. In: American Society of Clinical Oncology educational book. 2014. p. 191–8.Google Scholar
  4. 4.
    Dreyling M, Geisler C, Hermine O, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii83–92.Google Scholar
  5. 5.
    National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guildelines®): non-Hodgkin’s lymphomas, version 2.2015. 2015. Accessed 2 June 2015.
  6. 6.
    European Medicines Agency. Velcade (bortezomib): summary of product characteristics. 2015. Accessed 2 June 2015.
  7. 7.
    US FDA. Velcade (bortezomib): US prescribing information. 2014. Accessed 2 June 2015.
  8. 8.
    Till BG, Li H, Bernstein SH, et al. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for previously untreated mantle cell lymphoma: SWOG 0601 [abstract no. 149]. Blood. 2014;124(21).Google Scholar
  9. 9.
    Curran MP, McKeage K. Bortezomib: a review of its use in patients with multiple myeloma. Drugs. 2009;69(7):859–88.PubMedCrossRefGoogle Scholar
  10. 10.
    Hoy SM. Subcutaneous bortezomib: in multiple myeloma. Drugs. 2013;73(1):45–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Schwartz RN, Davidson T. Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncology (Williston Park, NY). 2004;18(14 Suppl 11):14–21.Google Scholar
  12. 12.
    Hamilton AL, Eder JP, Pavlick AC, et al. Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle. J Clin Oncol. 2005;23(25):6107–16.PubMedCrossRefGoogle Scholar
  13. 13.
    Reece DE, Sullivan D, Lonial S, et al. Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother Pharmacol. 2011;67(1):57–67.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Ogawa Y, Tobinai K, Ogura M, et al. Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma. Cancer Sci. 2008;99(1):140–4.PubMedGoogle Scholar
  15. 15.
    Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy. Cancer Cell Int. 2005;5(1):18.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Hutter G, Rieken M, Pastore A, et al. The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma. Ann Hematol. 2012;91(6):847–56.PubMedCrossRefGoogle Scholar
  17. 17.
    Baran-Marszak F, Boukhiar M, Harel S, et al. Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma. Haematologica. 2010;95(11):1865–72.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Pérez-Galán P, Roué G, Villamor N, et al. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006;107(1):257–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Weniger MA, Rizzatti EG, Pérez-Galán P, et al. Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. Clin Cancer Res. 2011;17(15):5101–12.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Desai S, Maurin M, Smith MA, et al. PRDM1 is required for mantle cell lymphoma response to bortezomib. Mol Cancer Res. 2010;8(6):907–18.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Wang M, Han XH, Zhang L, et al. Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leukemia. 2008;22(1):179–85.PubMedCrossRefGoogle Scholar
  22. 22.
    Pekol T, Daniels JS, Labutti J, et al. Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos. 2005;33(6):771–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Uttamsingh V, Lu C, Miwa G, et al. Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos. 2005;33(11):1723–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Levêque D, Monteiro Carvalho MC, Maloisel F. Clinical pharmacokinetics of bortezomib. In Vivo. 2007;21(2):273–8.PubMedGoogle Scholar
  25. 25.
    LoRusso PM, Venkatakrishnan K, Ramanathan RK, et al. Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432. Clin Cancer Res. 2012;18(10):2954–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Leal TB, Remick SC, Takimoto CH, et al. Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. Cancer Chemother Pharmacol. 2011;68(6):1439–47.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Venkatakrishnan K, Rader M, Ramanathan RK, et al. Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: a prospective, multicenter, open-label, randomized, two-way crossover drug-drug interaction study. Clin Ther. 2009;31:2444–58.PubMedCrossRefGoogle Scholar
  28. 28.
    Quinn DI, Nemunaitis J, Fuloria J, et al. Effect of the cytochrome P450 2C19 inhibitor omeprazole on the pharmacokinetics and safety profile of bortezomib in patients with advanced solid tumours, non-Hodgkin’s lymphoma or multiple myeloma. Clin Pharmacokinet. 2009;48(3):199–209.PubMedCrossRefGoogle Scholar
  29. 29.
    Hellmann A, Rule S, Walewski J, et al. Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin’s lymphoma. Clin Pharmacokinet. 2011;50(12):781–91.PubMedCrossRefGoogle Scholar
  30. 30.
    Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015;372(10):944–53.PubMedCrossRefGoogle Scholar
  31. 31.
    Drach J, Huang H, Samoilova OS, et al. Efficacy and safety of frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) vs R-CHOP in a subset of newly diagnosed mantle cell lymphoma patients medically eligible for transplantation in the randomized phase 3 LYM-3002 study (NCT00722137) [abstract no. 3064 plus poster]. Blood. 2014;124(21).Google Scholar
  32. 32.
    Robak T, Huang H, Jin J, et al. Bortezomib(Btz) dose intensity is the strongest predictor of overall survival in mantle cell lymphoma patients not considered for transplantation, receiving frontline Btz plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) therapy in the phase 3 LYM-3002 study [abstract no. 4412]. Blood. 2014;124(21).Google Scholar
  33. 33.
    European Medicines Agency. MabThera (rituximab): summary of product characteristics. 2015. Accessed 2 June 2015.
  34. 34.
    US FDA. Rituxan (rituximab): US prescribing information. 2014. Accessed 2 June 2015.
  35. 35.
    Furtado M, Johnson R, Kruger A, et al. Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma. Br J Haematol. 2015;168(1):55–62.PubMedCrossRefGoogle Scholar
  36. 36.
    van Keep M, Gairy K, Seshagiri D, et al. Cost effectiveness of bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone for the first-line treatment of mantle cell lymphoma patients not eligible for stem cell transplantation [abstract no. P420 plus poster]. In: 20th Congress of the European Hematology Association. 2015.Google Scholar
  37. 37.
    Houot R, Le Gouill S, Ojeda Uribe M, et al. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS. Ann Oncol. 2012;23(6):1555–61.PubMedCrossRefGoogle Scholar
  38. 38.
    Chang JE, Peterson C, Choi S, et al. VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study. Br J Haematol. 2011;155(2):190–7.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Chang JE, Li H, Smith MR, et al. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood. 2014;123(11):1665–73.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Gressin R, Callanan M, Daguindau N, et al. Frontline therapy with the RiBVD regimen elicits high clinical and molecular response rates and long PFS in elderly patients mantle cell lymphoma (MCL); final results of a prospective phase II trial by the LYSA group [abstract no. 148]. Blood. 2014;124(21).Google Scholar
  41. 41.
    Ruan J, Martin P, Furman RR, et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29(6):690–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

Personalised recommendations