Investigational New Drugs

, Volume 29, Issue 1, pp 175–181 | Cite as

Initial cytoreductive treatment with thalidomide plus bolus vincristine/doxorubicin and reduced dexamethasone followed by autologous stem cell transplantation for multiple myeloma

  • Jae-Cheol Jo
  • Byung Woog Kang
  • Sun Jin Sym
  • Sung Sook Lee
  • Geundoo Jang
  • Shin Kim
  • Dae Ho Lee
  • Sang-We Kim
  • Jung Shin Lee
  • Cheolwon Suh


Background High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) after combined chemotherapy with infusional vincristine/doxorubicin plus dexamethasone is effective in multiple myeloma (MM). Outpatient treatment with bolus vincristine/doxorubicin infusion plus dexamethasone is convenient and has acceptable efficacy and toxicity for MM. Thalidomide has recently been shown to have significant antimyeloma activity. We assessed the efficacy and toxicity of the combination of bolus vincristine/doxorubicin and reduced dose dexamethasone with thalidomide (T-bVAd), administered on an outpatient basis, in untreated MM. Patients and methods Twenty-six patients prospectively received T-bVAd, consisting of intravenous (i.v.) vincristine 0.4 mg plus doxorubicin 9 mg/m2, administered as a single bolus on days 1 to 4, dexamethasone 20 mg per os daily for 4 days, and thalidomide 200 mg/day at bedtime. Response assessment was conducted after each 4-week treatment cycle. Patients who achieved response were allowed to proceed to high-dose chemotherapy with ASCT. Results On an intention-to-treat basis, 23 of the 26 patients (88%) responded to treatment, with 16 (61%) achieving complete response (CR), 2 (8%) very good partial response (VGPR) and 5 (19%) partial response. Only three patients (12%) were rated as non-responders. Grade 3 and 4 hematologic toxicities consisted of neutropenia (13%), febrile neutropenia (6%), and thrombocytopenia (4%), without significant nonhematologic events. Of the 23 patients who showed response, 7 proceeded to single ASCT and 9 to tandem ASCT. With median follow-up time of 15.3 months (range, 9–25 months), median event free survival (EFS) and overall survival (OS) have not been reached yet, and OS and EFS rates for patients who achieved complete response after T-bVAd regimen were significantly higher than patients not. Conclusions Induction therapy with T-bVAd, administered as an outpatient regimen, was efficient and relatively well tolerated in the treatment of MM.


Induction therapy Autologous stem cell transplantation Multiple myeloma Modified schedule 


  1. 1.
    Alexanian R, Barlogie B, Tucker S (1990) VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 33:86–89CrossRefPubMedGoogle Scholar
  2. 2.
    Samson D, Gaminara E, Newland A, Van de Pette J, Kearney J, McCarthy D, Joyner M, Aston L, Mitchell T, Hamon M et al (1989) Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet 2:882–885CrossRefPubMedGoogle Scholar
  3. 3.
    Anderson H, Scarffe JH, Ranson M, Young R, Wieringa GS, Morgenstern GR, Fitzsimmons L, Ryder D (1995) VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 71:326–330PubMedGoogle Scholar
  4. 4.
    Segeren CM, Sonneveld P, van der Holt B, Baars JW, Biesma DH, Cornellissen JJ, Croockewit AJ, Dekker AW, Fibbe WE, Lowenberg B et al (1999) Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 105:127–130CrossRefPubMedGoogle Scholar
  5. 5.
    Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A et al (2003) Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol 14:1039–1044CrossRefPubMedGoogle Scholar
  6. 6.
    Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM (2002) A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer 95:2160–2168CrossRefPubMedGoogle Scholar
  7. 7.
    Cavenagh JD, Oakervee H (2003) Thalidomide in multiple myeloma: current status and future prospects. Br J Haematol 120:18–26CrossRefPubMedGoogle Scholar
  8. 8.
    Hayashi T, Hideshima T, Anderson KC (2003) Novel therapies for multiple myeloma. Br J Haematol 120:10–17CrossRefPubMedGoogle Scholar
  9. 9.
    Rajkumar SV, Gertz MA, Lacy MQ, Dispenzieri A, Fonseca R, Geyer SM, Iturria N, Kumar S, Lust JA, Kyle RA et al (2003) Thalidomide as initial therapy for early-stage myeloma. Leukemia 17:775–779CrossRefPubMedGoogle Scholar
  10. 10.
    Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M et al (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565–1571CrossRefPubMedGoogle Scholar
  11. 11.
    Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, Badros A, Zangari M, Anaissie E, Epstein J et al (2001) Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 98:492–494CrossRefPubMedGoogle Scholar
  12. 12.
    Zervas K, Dimopoulos MA, Hatzicharissi E, Anagnostopoulos A, Papaioannou M, Mitsouli C, Panagiotidis P, Korantzis J, Tzilianos M, Maniatis A (2004) Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study. Ann Oncol 15:134–138CrossRefPubMedGoogle Scholar
  13. 13.
    Hussein MA, Baz R, Srkalovic G, Agrawal N, Suppiah R, Hsi E, Andresen S, Karam MA, Reed J, Faiman B et al (2006) Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin Proc 81:889–895CrossRefPubMedGoogle Scholar
  14. 14.
    Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA (2006) Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer 106:848–858CrossRefPubMedGoogle Scholar
  15. 15.
    Porter CA, Rifkin RM (2007) Clinical benefits and economic analysis of pegylated liposomal doxorubicin/vincristine/dexamethasone versus doxorubicin/vincristine/dexamethasone in patients with newly diagnosed multiple myeloma. Clin Lymphoma Myeloma 7(Suppl 4):S150–S155CrossRefPubMedGoogle Scholar
  16. 16.
    Criteria for the classification of monoclonal gammopathies, (2003) multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121:749–57.Google Scholar
  17. 17.
    Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473CrossRefPubMedGoogle Scholar
  18. 18.
    Attal M, Huguet F, Schlaifer D, Payen C, Laroche M, Fournie B, Mazieres B, Pris J, Laurent G (1992) Intensive combined therapy for previously untreated aggressive myeloma. Blood 79:1130–1136PubMedGoogle Scholar
  19. 19.
    Jackson DV Jr, Sethi VS, Spurr CL, White DR, Richards F 2nd, Stuart JJ, Muss HB, Cooper MR, Castle MC (1981) Pharmacokinetics of vincristine infusion. Cancer Treat Rep 65:1043–1048PubMedGoogle Scholar
  20. 20.
    Munshi N, Tricot G, Barlogie B (2001) Plasma cell neoplasms. In: DeVita VT Jr, Hellman S, Rosenberg SA (eds) Cancer. Principles and practice of oncology, Volume 2, 6th edn. Lippincott Williams & Wilkins, Philadelphia, pp 2465–2509Google Scholar
  21. 21.
    Zhou S, Kestell P, Tingle MD, Paxton JW (2002) Thalidomide in cancer treatment: a potential role in the elderly? Drugs Aging 19:85–100CrossRefPubMedGoogle Scholar
  22. 22.
    Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA et al (2002) Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20:4319–4323CrossRefPubMedGoogle Scholar
  23. 23.
    Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R (2003) Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16–19CrossRefPubMedGoogle Scholar
  24. 24.
    Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E et al (2007) VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol 18:1369–1375CrossRefPubMedGoogle Scholar
  25. 25.
    Minnema MC, Breitkreutz I, Auwerda JJ, van der Holt B, Cremer FW, van Marion AM, Westveer PH, Sonneveld P, Goldschmidt H, Lokhorst HM (2004) Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy. Leukemia 18:2044–2046CrossRefPubMedGoogle Scholar
  26. 26.
    Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M et al (2006) Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367:825–831CrossRefPubMedGoogle Scholar
  27. 27.
    Hicks LK, Haynes AE, Reece DE, Walker IR, Herst JA, Meyer RM, Imrie K (2008) A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. Cancer Treat Rev 34:442–452CrossRefPubMedGoogle Scholar
  28. 28.
    Do Yeun Kim, Seock-Ah Im, Chu-Myong Seong, Soon Nam Lee, Soo-Mee Bang, Jae Hoon Lee, Sung-Soo Yoon, Byoung Kook Kim, Seon Yang Park, Myung-Ju Ahn (2002) Salvage therapy with Thalidomide in patients with relapsed or refractory multiple myeloma. Korean Journal of Hematology 37:259–264Google Scholar
  29. 29.
    Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N, Esseltine DL, Drake M, Morris C, Cavenagh JD (2008) Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol 141:512–516CrossRefPubMedGoogle Scholar
  30. 30.
    Blade J, Rosinol L (2008) Advances in therapy of multiple myeloma. Curr Opin Oncol 20:697–704CrossRefPubMedGoogle Scholar
  31. 31.
    Attal M, Harousseau JL (2009) The role of high-dose therapy with autologous stem cell support in the era of novel agents. Semin Hematol 46:127–132CrossRefPubMedGoogle Scholar
  32. 32.
    Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R et al (2007) Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc 82:1179–1184CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jae-Cheol Jo
    • 1
  • Byung Woog Kang
    • 1
  • Sun Jin Sym
    • 2
  • Sung Sook Lee
    • 3
  • Geundoo Jang
    • 4
  • Shin Kim
    • 1
  • Dae Ho Lee
    • 1
  • Sang-We Kim
    • 1
  • Jung Shin Lee
    • 1
  • Cheolwon Suh
    • 1
    • 5
  1. 1.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  2. 2.Department of OncologyGachon University Gil HospitalIncheonKorea
  3. 3.Department of Oncology, Severance HospitalYonsei University College of MedicineSeoulKorea
  4. 4.Department of OncologyHallym University Chunchon Sacred Heart HospitalChunchonKorea
  5. 5.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea

Personalised recommendations