Skip to main content

Reduced frequency treatment with bortezomib plus dexamethasone for elderly patients with relapsed and/or refractory multiple myeloma: a phase 2 study of the Japanese Myeloma Study Group (JMSG-0902)

Abstract

Bortezomib is one of the most widely used novel drugs for the treatment of multiple myeloma (MM). However, twice-weekly intravenous administration is associated with innegligible adverse events and treatment discontinuation. We therefore evaluated the long-term efficacy and feasibility of reduced frequency treatment with intravenous bortezomib in elderly patients with relapsed and/or refractory MM. A total of 47 bortezomib-naïve patients (median age 75 years) received bortezomib (1.3 mg/m2, intravenously) and dexamethasone (20 mg) on days 1, 8, and 15 of every 4-week cycle. Twenty-six patients completed the planned 8 cycles. Best responses were stringent complete response (sCR) in 5 patients, very good partial response (VGPR) in 3, PR in 15, stable disease (SD) in 18, and disease progression (PD) in 6, respectively. Median progression-free and overall survivals were 9.6 and 35.1 months, respectively. After progression, 11 patients were retreated with bortezomib-based regimens and another 24 patients with immunomodulatory drugs. Multivariate analysis revealed that ISS 3, t(4;14), and <4 therapy cycles were significantly poor prognostic factors and that subsequent therapy with bortezomib-based regimens was a favorable factor for extended OS. The common adverse events were diarrhea, constipation, and peripheral neuropathy with no grade 4 toxicity. In conclusion, reduced frequency treatment with intravenous bortezomib + dexamethasone is an effective option for elderly patients with MM.

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

Fig. 1

References

  1. 1.

    International Myeloma Working Group (2003) Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121(5):749–757

    Article  Google Scholar 

  2. 2.

    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV et al (2014) International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15(12):e538–e548

    Article  PubMed  Google Scholar 

  3. 3.

    Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Blade J, Mateos MV et al (2011) Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood 118(17):4519–4529

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T et al (2007) Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110(10):3557–3560

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H et al (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 30(24):2946–2955

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–917

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al (2013) Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol 31(4):448–455

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R et al (2010) Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116(23):4745–4753

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M et al (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12(5):431–440

    Article  PubMed  Google Scholar 

  11. 11.

    Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J et al (2008) Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer 113(4):765–771

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Girnius SK, Lee S, Kambhampati S, Rose MG, Mohiuddin A, Houranieh A et al (2015) A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation. Br J Haematol 169(1):36–43

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Kamimura T, Miyamoto T, Yokota N, Takashima S, Chong Y, Ito Y et al (2013) Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen. Eur J Haematol 90(2):157–161

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36(3):842–854

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J et al (2005) International staging system for multiple myeloma. J Clin Oncol 23(15):3412–3420

    Article  PubMed  Google Scholar 

  16. 16.

    Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20(9):1467–1473

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL et al (2009) Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol 144(6):895–903

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3):452–458

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Harousseau JL, Palumbo A, Richardson PG, Schlag R, Dimopoulos MA, Shpilberg O et al (2010) Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood 116(19):3743–3750

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Mateos MV, Richardson PG, Dimopoulos MA, Palumbo A, Anderson KC, Shi H et al (2015) Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study. Am J Hematol 90(4):314–319

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca A, Hardan I et al (2015) Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol 33(30):3459–3466

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Hrusovsky I, Emmerich B, von Rohr A, Voegeli J, Taverna C, Olie RA et al (2010) Bortezomib retreatment in relapsed multiple myeloma - results from a retrospective multicentre survey in Germany and Switzerland. Oncology 79(3–4):247–254

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Taverna C, Voegeli J, Trojan A, Olie RA, von Rohr A (2012) Effective response with bortezomib retreatment in relapsed multiple myeloma--a multicentre retrospective survey in Switzerland. Swiss Med Wkly 142:w13562

    PubMed  Google Scholar 

  24. 24.

    Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW et al (2013) A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol 160(5):649–659

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L et al (2015) Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol 33(26):2863–2869

    Article  PubMed  Google Scholar 

  26. 26.

    Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D et al (2010) Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 28(30):4630–4634

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al (2010) Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 376(9758):2075–2085

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Barbee MS, Harvey RD, Lonial S, Kaufman JL, Wilson NM, McKibbin T et al (2013) Subcutaneous versus intravenous bortezomib: efficiency practice variables and patient preferences. Ann Pharmacother 47(9):1136–1142

    Article  PubMed  Google Scholar 

  29. 29.

    Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C et al (2015) Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: interim analysis from the prospective GMMG-MM5 trial. Haematologica 100(7):964–969

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G et al (2015) Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica 100(5):e207–e210

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank the physicians and medical staffs who participated in this study. Study investigators were as follows: Shuji Ozaki, Etsuko Sekimoto, Hironobu Shibata, and Toshio Shigekiyo, Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima; Kazutaka Sunami, Shoji Asakura, Jun Konishi, Shiro Kubonishi, Tomoko Inomata, and Haruto Yamada, Department of Hematology, NHO Okayama Medical Center, Okayama; Morio Sawamura, Morio Matsumoto, Momoko Mawatari, Akio Saitou, and Akinori Yuzuriha, Department of Hematology, NHO Nishigunma Hospital; Shibukawa; Hiroki Yano, Takahiro Imaizumi, and Yu Asao, Department of Hematology, Kainan Hospital, Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi; Hiroshi Kosugi, Naoyuki Tange, Masaaki Yuge, and Takeshi Kanematsu, Department of Hematology, Ogaki Municipal Hospital, Ogaki; Tomonori Nakazato, Department of Hematology, Yokohama Municipal Citizen’s Hospital, Yokohama; Taro Masunari, Department of Hematology, Chugoku Central Hospital, Fukuyama; Hideki Tsujimura and Kyoya Kumagai, Division of Hematology-Oncology, Chiba Cancer Center, Chiba; Takeshi Harada and Masahiro Abe, Department of Hematology, Tokushima University Hospital, Tokushima; Toshiaki Hayashi and Tadao Ishida, First Department of Internal Medicine, Sapporo Medical University Hospital, Sapporo; Tadahiko Igarashi, Division of Hematology and Oncology, Gunma Prefectural Cancer Center, Ohta; Hideto Tamura, Department of Hematology, Nippon Medical School Hospital, Tokyo; Ichiro Hanamura, Masuya Watarai, and Miyuki Takahashi, Department of Hematology, Aichi Medical University Hospital, Nagakute; Akira Katsumi and Miki Kobayashi, Division of Transfusion Medicine and Cell Therapy, National Center for Geriatrics and Gerontology, Obu; Toshiro Kurokawa, Department of Hematology, Toyama Red Cross Hospital, Toyama; Chihiro Shimazaki and Akira Okuno, Department of Hematology, JCHO Kyoto Kuramaguchi Medical Center, Kyoto, Japan

We also thank Advanced Clinical Research Organization and Ryoji Nakamura for their excellent support. This work was supported in part by a grant from the International Myeloma Foundation (IMF) Japan.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Shuji Ozaki.

Ethics declarations

Conflict of interest

KS received research funding from Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharmaceutical Co. Ltd., and Celgene Co. Ltd.

Additional information

This trial was registered at the UMIN Clinical Trial Registry (UMIN 000003345)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ozaki, S., Hata, H., Abe, M. et al. Reduced frequency treatment with bortezomib plus dexamethasone for elderly patients with relapsed and/or refractory multiple myeloma: a phase 2 study of the Japanese Myeloma Study Group (JMSG-0902). Ann Hematol 95, 921–929 (2016). https://doi.org/10.1007/s00277-016-2661-7

Download citation

Keywords

  • Multiple myeloma
  • Bortezomib
  • Dexamethasone
  • Relapsed
  • Refractory