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

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study

Leukemia volume 24, pages 1350–1356 (2010)Cite this article

Subjects

Abstract

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m2 (on days 1 and 8) plus bortezomib 1.3 mg/m2 (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1–14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m2, on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m2) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m2). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% ⩾very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m2, which was the highest dose tested.

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

Similar content being viewed by others

References

  1. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: 2516–2520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brenner H, Gondos A, Pulte D . Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008; 111: 2521–2526.

    Article  CAS  PubMed  Google Scholar 

  3. Jagannath S, Durie BG, Wolf JL, Camacho ES, Irwin D, Lutzky J et al. Extended follow-up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma. Br J Haematol 2009; 146: 619–626.

    Article  CAS  PubMed  Google Scholar 

  4. Harousseau JL, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006; 91: 1498–1505.

    CAS  PubMed  Google Scholar 

  5. Harousseau JL, Mathiot C, Attal M, Marit G, Caillot D, Hulin C et al. Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM): updated data from IFM 2005/01 trial. J Clin Oncol 2008; 26: 455s . Abstract 8505; updated data presented at the ASH 2008 joint ASH/ASCO symposium.

    Article  Google Scholar 

  6. Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106: 4050–4053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, Kabat B et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc 2007; 82: 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  8. Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF, Whittenberger BF et al. Superiority of lenalidomide (Len) plus high-dose dexamethasone (HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma (NDMM): results of the randomized, double-blinded, placebo-controlled SWOG trial S0232. Blood 2007; 110: 32a. Abstract 77.

    Google Scholar 

  9. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010; 11: 29–37.

    Article  CAS  PubMed  Google Scholar 

  10. Richardson PG, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE et al. High response rates and encouraging time-to-event data with lenalidomide, bortezomib, and dexamethasone in newly diagnosed multiple myeloma: final results of a phase I/II study. Blood 2009; 114: 501a–502a. Abstract 1218.

    Article  Google Scholar 

  11. Wang M, Delasalle K, Giralt S, Alexanian R . Rapid control of previously untreated multiple myeloma with bortezomib-lenalidomide-dexamethasone (BLD). Blood 2007; 110: 1057a. Abstract 3611.

    Google Scholar 

  12. Knop S, Liebisch P, Wandt H, Kropff M, Jung W, Kroeger N et al. Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: results of an interim analysis of the German DSMM Xia trial. J Clin Oncol 2009; 27: 437s. Abstract 8516.

    Google Scholar 

  13. Kumar S, Hayman S, Buadi F, Lacy M, Stewart K, Allred J et al. Phase II trial of lenalidomide (Revlimid) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. Blood 2008; 112: 40a. Abstract 91.

    Article  Google Scholar 

  14. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 2009; 23: 1337–1341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lahuerta JJ, Mateos MV, Martinez-Lopez J, Rosinol L, Sureda A, de la RJ et al. Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol 2008; 26: 5775–5782.

    Article  PubMed  Google Scholar 

  16. van de Velde HJK, Liu X, Chen G, Cakana A, Deraedt W, Bayssas M . Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 2007; 92: 1399–1406.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. National Cancer Institute. Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events, Version 3.0 http://ctep.cancer.gov 2006, Available from http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.

  19. Knight R, DeLap RJ, Zeldis JB . Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006; 354: 2079–2080.

    Article  CAS  PubMed  Google Scholar 

  20. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–2617.

    Article  CAS  PubMed  Google Scholar 

  21. Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San MJ, Barlogie B et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22: 414–423.

    Article  CAS  PubMed  Google Scholar 

  22. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. A phase III study of double autotransplantation incorporating bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: superior clinical outcomes with VTD compared to TD. Blood 2009; 114: 148a–149a. Abstract 351.

    Article  Google Scholar 

  23. Richardson P, Xie W, Mitsiades C, Chanan-Khan AA, Lonial S, Hassoun H et al. Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 2009; 27: 3518–3525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL et al. 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 2009; 144: 895–903.

    Article  CAS  PubMed  Google Scholar 

  25. Mateos M-V, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O et al. Peripheral neuropathy with VMP resolves in the majority of patients and shows a rate plateau. Clin Lymphoma Myeloma 2009; 9: S30. Abstract 172.

    Article  Google Scholar 

  26. Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N et al. Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol 2008; 141: 512–516.

    Article  CAS  PubMed  Google Scholar 

  27. Bensinger WI, Jagannath S, Vescio R, Camacho E, Wolf J, Irwin D et al. 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 2009, E-pub ahead of print; doi:10.1111/j.1365-2141.2009.07981.x.

    Article  CAS  PubMed  Google Scholar 

  28. Anderson KC, Kyle RA, Rajkumar SV, Stewart AK, Weber D, Richardson P . Clinically relevant end points and new drug approvals for myeloma. Leukemia 2008; 22: 231–239.

    Article  CAS  PubMed  Google Scholar 

  29. Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 2008; 112: 4017–4023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the patients who participated in the study, all the investigators, nursing staff and research support staff involved in the studyand the research team at Millennium Pharmaceuticals. We would like to acknowledge the editorial assistance of Sarah Maloney and Jane Saunders of FireKite during the development of this publication, which was funded by Millennium Pharmaceuticals and supported by Johnson & Johnson Pharmaceutical Research & Development, LLC and Millennium Pharmaceuticals.

Author information

Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    S K Kumar & S V Rajkumar

  2. Sarah Cannon Research Institute, Nashville, TN, USA

    I Flinn

  3. Department of Medical Oncology/Hematology, Sinai Hospital of Baltimore, Baltimore, MD, USA

    S J Noga

  4. Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA

    P Hari

  5. Department of Haematology/Oncology, Rocky Mountain Cancer Centers, Denver, CO, USA

    R Rifkin

  6. Department of Hematology, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

    N Callander

  7. Department of Haematology/Oncology, The Christ Hospital, Cincinnati, OH, USA

    M Bhandari

  8. Division of Hematology and Oncology, University of California Medical Center, San Francisco, CA, USA

    J L Wolf

  9. Adult Bone Marrow Transplant, Clinic Duke University, Durham, NC, USA

    C Gasparetto

  10. Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA

    A Krishnan

  11. Memorial Cancer Institute, Pembroke Pines, FL, USA

    D Grosman

  12. Louisiana State University Health Sciences Center, Shreveport, LA, USA

    J Glass

  13. Cell Transplantation Program, Western Pennsylvania Hospital, Pittsburgh, PA, USA

    E A Sahovic

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

    H Shi & I J Webb

  15. Department of Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA

    P G Richardson

Authors
  1. S K Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Flinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S J Noga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Hari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Rifkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Callander
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Bhandari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J L Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Gasparetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Krishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Grosman
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. E A Sahovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. I J Webb
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. P G Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. S V Rajkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S K Kumar.

Ethics declarations

Competing interests

SKK has a consultancy/advisory relationship, and has received research funding from Millennium Pharmaceuticals, Celgene; IF has received honoraria and research funding from Millennium Pharmaceuticals; SJN has received honoraria from Millennium Pharmaceuticals; PH has a consultancy/advisory relationship with Millennium Pharmaceuticals and Celgene; has received honoraria from Celgene and research funding from Millennium Pharmaceuticals; RR has a consultancy/advisory relationship with Millennium Pharmaceuticals and has received honoraria from Millennium Pharmaceuticals, Celgene and Amgen; NC has received research funding from Millennium Pharmaceuticals; MB has received honoraria from Pfizer, Spectrum Pharmaceuticals, Millennium Pharmaceuticals and Cephalon; JLW has received honoraria from Millennium Pharmaceuticals, Celgene and Ortho Biotech; CG has a consultancy/advisory relationship, and has received honoraria and research funding from Millennium Pharmaceuticals and Celgene; AK has stock/ownership interest in Celgene, and has received honoraria from Millennium Pharmaceuticals and Celgene; DG has a consultancy/advisory relationship with and has received honoraria from Millennium Pharmaceuticals; EAS has a consultancy/advisory relationship with Millennium Pharmaceuticals and has received honoraria from Millennium Pharmaceuticals and Celgene; HS and IJW are employees of Millennium Pharmaceuticals; PGR has a consultancy/advisory role in Millennium Pharmaceuticals and Celgene and has received research funding from Millennium Pharmaceuticals; JG and SVR declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, S., Flinn, I., Noga, S. et al. Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study. Leukemia 24, 1350–1356 (2010). https://doi.org/10.1038/leu.2010.116

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.116

Keywords

This article is cited by

Search

Advanced search

Quick links