Advertisement

A randomized phase II, open-label and multicenter study of combination regimens of bortezomib at two doses by subcutaneous injection for newly diagnosed multiple myeloma patients

  • Feng Li
  • Fu-Sheng Yao
  • Xi-Jun Zhu
  • Wei-Ying Gu
  • Xiao-Hua Wang
  • Bing Chen
  • Dong-Ping Huang
  • Jia-Hua Ding
  • Tian-Qin Wu
  • Yan Zhu
  • Qian Zhao
  • Yu-Mei Tang
  • Ping Song
  • Xiao-Gang Zhou
  • Zhi-Ming An
  • Xing Guo
  • Xu-Li Wang
  • Long Zhong
  • Xiao-Bao Xie
  • Yong-Ping ZhaiEmail author
Original Article – Clinical Oncology
  • 51 Downloads

Abstract

Purpose

Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM.

Methods

Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1–3 intravenously.

Results

After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3–4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS.

Conclusions

The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients.

Trial registration ClinicalTrials.gov: NCT02086942.

Keywords

Multiple myeloma Bortezomib Subcutaneous injection Different doses Efficacy 

Notes

Acknowledgements

The authors would like to acknowledge colleagues at Jinling Hospitals for the detailed scientific discussion. This work was supported by grants from the National Natural Science Foundation of China for Young Scholars (Grant No. 81800126) and the Six Talent Peak Project in Jiangsu Province (Grant No. 2015-WSN-011).

Author contributions

FL designed and conducted the experiments and wrote the manuscript. FL, F-SY, X-JZ, W-YG, X-HW, BC, D-PH, J-HD, T-QW, YZ, QZ, Y-MT, PS, X-GZ, Z-MA, XG, X-LW, LZ and X-BX carried out the collection of samples and clinical data. FL conducted the analysis of the clinical data. Y-PZ contributed to the experimental design, the review and revision of the manuscript, and the final approval of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that no conflicts of interest exist.

Ethical statements

All patients provided written informed consent for the use of their samples and data, and the study was approved by the Ethics Committee of Jinling Hospital, Nanjing, China.

Supplementary material

432_2019_2967_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 16 kb)

References

  1. Bensinger WI, Jagannath S, Vescio R et al (2010) Phase 2 study of two sequential three-drug combinations containing bortezomib, cyclophosphamide and dexamethasone, followed by bortezomib, thalidomide and dexamethasone as frontline therapy for multiple myeloma. Br J Haematol 148:562–568CrossRefGoogle Scholar
  2. Blaney SM, Bernstein M, Neville K et al (2004) Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: a Children’s Oncology Group study (ADVL0015). J Clin Oncol 22:4804–4809CrossRefGoogle Scholar
  3. Cavo M, Tacchetti P, Patriarca F 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 376:2075–2085CrossRefGoogle Scholar
  4. Cavo M, Rajkumar SV, Palumbo A et al (2011) International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 117:6063–6073CrossRefGoogle Scholar
  5. Chakraborty R, Muchtar E, Kumar SK et al (2018) Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation. Leukemia 32:712–718CrossRefGoogle Scholar
  6. Chng WJ, Chung TH, Kumar S et al (2016) Gene signature combinations improve prognostic stratification of multiple myeloma patients. Leukemia 30:1071–1078CrossRefGoogle Scholar
  7. Harousseau JL, Attal M, Avet-Loiseau H et al (2010) Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 28:4621–4629CrossRefGoogle Scholar
  8. He J, Yang L, Han X et al (2014) The choice of regimens based on bortezomib for patients with newly diagnosed multiple myeloma. PLoS One 9:e99174CrossRefGoogle Scholar
  9. Jagannath S, Barlogie B, Berenson J et al (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165–172CrossRefGoogle Scholar
  10. Jimenez-Zepeda VH, Duggan P, Nerl P et al (2017) Bortezomib-containing regimens (BCR) for the treatment of non-transplant eligible multiple myeloma. Ann Hematol 96:431–439CrossRefGoogle Scholar
  11. Kumar S, Flinn I, Richardson PG et al (2012) Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 119:4375–4382CrossRefGoogle Scholar
  12. Larsen JT, Chee CE, Lust JA et al (2011) Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival. Blood 118:2702–2707CrossRefGoogle Scholar
  13. Lee SE, Kim JH, Jeon YW et al (2015) Impact of extramedullary plasmacytomas on outcomes according to treatment approach in newly diagnosed symptomatic multiple myeloma. Ann Hematol 94:445–452CrossRefGoogle Scholar
  14. Lightcap ES, McCormack TA, Pien CS et al (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46:673–683Google Scholar
  15. Mai EK, Bertsch U, Durig J et al (2015) Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia 29:1721–1729CrossRefGoogle Scholar
  16. Mateos MV, Oriol A, Martinez-Lopez J et al (2010) Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 11:934–941CrossRefGoogle Scholar
  17. Mitra AK, Harding T, Mukherjee UK et al (2017) A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma. Blood Cancer J 7:e581CrossRefGoogle Scholar
  18. Moreau P, Pylypenko H, Grosicki S et al (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12:431–440CrossRefGoogle Scholar
  19. Moreau P, Hulin C, Macro M et al (2016) VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood 127:2569–2574CrossRefGoogle Scholar
  20. Pour L, Sevcikova S, Greslikova H et al (2014) Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica 99:360–364CrossRefGoogle Scholar
  21. Reeder CB, Reece DE, Kukreti V et al (2009) Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 23:1337–1341CrossRefGoogle Scholar
  22. Reeder CB, Reece DE, Kukreti V et al (2010) Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood 115:3416–3417CrossRefGoogle Scholar
  23. Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617CrossRefGoogle Scholar
  24. Richardson PG, Briemberg H, Jagannath S et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113–3120CrossRefGoogle Scholar
  25. Richardson PG, Mitsiades C, Schlossman R et al (2007) New drugs for myeloma. Oncologist 12:664–689CrossRefGoogle Scholar
  26. Sivaraj D, Green MM, Li Z et al (2017) Outcomes of maintenance therapy with bortezomib after autologous stem cell transplantation for patients with multiple myeloma. Biol Blood Marrow Transplant 23:262–268CrossRefGoogle Scholar
  27. Tanake K, Toyota S, Akiyama M et al (2019) Efficacy and safety of a weekly cyclophosphamide–bortezomib–dexamethasone regimen as induction therapy prior to autologous stem cell transplantation in japanese patients with newly diagnosed multiple myeloma: a phase 2 multicenter trial. Acta Haematol 141:111–118CrossRefGoogle Scholar
  28. Tricot G, Jagannath S, Vesole D et al (1995) Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood 85:588–596Google Scholar
  29. Tuchman SA, Moore JO, DeCastro CD et al (2017) Phase II study of dose-attenuated bortezomib, cyclophosphamide and dexamethasone (“VCD-Lite”) in very old or otherwise toxicity-vulnerable adults with newly diagnosed multiple myeloma. J Geriatr Oncol 8:165–169CrossRefGoogle Scholar
  30. Zamagni E, Patriarca F, Nanni C et al (2011) Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood 118:5989–5995CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Feng Li
    • 1
  • Fu-Sheng Yao
    • 2
  • Xi-Jun Zhu
    • 3
  • Wei-Ying Gu
    • 4
  • Xiao-Hua Wang
    • 5
  • Bing Chen
    • 6
  • Dong-Ping Huang
    • 7
  • Jia-Hua Ding
    • 8
  • Tian-Qin Wu
    • 9
  • Yan Zhu
    • 10
  • Qian Zhao
    • 1
  • Yu-Mei Tang
    • 1
  • Ping Song
    • 1
  • Xiao-Gang Zhou
    • 1
  • Zhi-Ming An
    • 1
  • Xing Guo
    • 1
  • Xu-Li Wang
    • 1
  • Long Zhong
    • 2
  • Xiao-Bao Xie
    • 4
  • Yong-Ping Zhai
    • 1
    Email author
  1. 1.Department of Hematology, Jinling Hospital, School of MedicineNanjing UniversityNanjingPeople’s Republic of China
  2. 2.Department of HematologyAn Qing Municipal HospitalAnqingPeople’s Republic of China
  3. 3.Department of HematologyXuancheng People’s HospitalXuanchengPeople’s Republic of China
  4. 4.Department of HematologyThe First People’s Hospital of Changzhou, Third Affiliated to Suzhou UniversityChangzhouPeople’s Republic of China
  5. 5.Department of HematologyThe Second People’s Hospital of WuhuWuhuPeople’s Republic of China
  6. 6.Department of HematologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingPeople’s Republic of China
  7. 7.Department of HematologyThe First Affiliated Hospital of Wannan Medical CollegeWuhuPeople’s Republic of China
  8. 8.Department of Hematology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingPeople’s Republic of China
  9. 9.Department of HematologyThe 904th Hospital of Chinese People’s Liberation ArmySuzhouPeople’s Republic of China
  10. 10.Department of HematologyAffiliated Hospital of Jiangsu UniversityZhenjiangPeople’s Republic of China

Personalised recommendations