International Journal of Hematology

, Volume 79, Issue 2, pp 165–173 | Cite as

Phase III Study of Ranimustine, Cyclophosphamide, Vincristine, Melphalan, and Prednisolone (MCNU-COP/MP) versus Modified COP/MP in Multiple Myeloma: A Japan Clinical Oncology Group Study, JCOG 9301

  • Takeaki Takenaka
  • Kuniaki Itoh
  • Takayo Suzuki
  • Atae Utsunomiya
  • Shin Matsuda
  • Takaaki Chou
  • Toshiaki Sai
  • Masayuki Sano
  • Susumu Konda
  • Tatsuji Ohno
  • Chikara Mikuni
  • Kijoh Deura
  • Takashi Yamada
  • Fumi Mizorogi
  • Haruhisa Nagoshi
  • Masao Tomonaga
  • Tomomitsu Hotta
  • Kohichi Kawano
  • Keitaro Tsushita
  • Masami Hirano
  • Masanori ShimoyamaEmail author
  • Lymphoma Study Group of the Japan Clinical Oncology Group
Case Report


To investigate whether combination chemotherapy with vincristine, cyclophosphamide, prednisolone, and melphalan (COP/ MP) with the addition of ranimustine (MCNU) (MCNU-COP/MP) is superior to the slightly modified COP/MP (mCOP/MP) regimen in multiple myeloma (MM), a multicenter randomized study was performed. Two hundred ten patients with newly diagnosed, overt MM not treated with chemotherapy were enrolled from 32 institutions of the Lymphoma Study Group of the Japan Clinical Oncology Group and were randomized to receive either MCNU-COP/MP or mCOP/MP. The response rate (RR) to mCOP/MP was 43.7% (95% confidence interval [CI], 33.9%–53.8%] and to MCNU-COP/MP was 56.1 % (95% CI, 46.1 %–65.7%) (P = .097). The progression-free survival (PFS) was significantly longer for patients treated with MCNU-COP/MP than for patients treated with mCOP/MP (median, 23.0 months [95% CI, 18.9–25.8] versus 15.8 months [95% CI, 14.1–19.4]) (P = .014). However, no significant difference in overall survival rate (OS) was observed between the groups (median, 49.9 months [95% CI, 40.4-59.1] versus 44.0 months [95% CI, 32.8–59.8]) ( P = .75). Grades 3 and 4 hematological toxicities were more frequently observed with MCNU-COP/MP than with mCOP/MP, but the incidence of grades 3 and 4 nonhematological toxicities was low in both groups. In conclusion, MCNU-COP/MP in comparison with mCOP/MP improved RR and PFS in overt MM; however, this outcome did not contribute to prolonging OS, indicating that addition of MCNU to mCOP/MP has no benefit on survival.

Key words

Ranimustine MP Combination chemotherapy Randomized study Multiple myeloma 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Myeloma Trialists’ Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.J Clin Oncol. 1998;16:3832–3842.Google Scholar
  2. 2.
    Takenaka T, Shirakawa S, Mikuni C, et al. Alternating combination chemotherapy COP (cyclophosphamide, vincristine, prednisolone) and MP (melphalan, prednisolone) in multiple myeloma: a multi- center phase IT study (JCOG8906).Jpn J Clin Oncol. 1999;29:485–489.PubMedCrossRefGoogle Scholar
  3. 3.
    Tanaka I, Kobayashi T, Shirakawa S, et al. Phase II study of methyl 6-[3-(2-chloroethyl)-3-nitrosoureoid]-6-deoxy-α-D-glucopyranoside (MCNU) fin Japanese with English summary].Jpn J Cancer Chemother. l985;12:493–498.Google Scholar
  4. 4.
    Imamura Y, Takagi T, Yawata Y, et al. Combination chemotherapy with MCNU, vindesine, melphalan, and prednisolone (MCNU- VMP therapy) in induction therapy for multiple myeloma.Int J Hematol. 199;4;59:113–123.Google Scholar
  5. 5.
    Wada M, Mizoguchi H, Kuriya S, et al. Induction therapy consisting of alternating cycles of ranimustine, vincristine, melphalan, dexamethasone and interferon α (ROAD-IN) and a randomized comparison of interferon α maintenance in multiple myeloma: a co-operative study in Japan.Br J Haematol. 2000;l09:805–814.CrossRefGoogle Scholar
  6. 6.
    Durie BGM. Staging and kinetics of multiple myeloma.Semin Oncol. 1986;13:300–309.Google Scholar
  7. 7.
    Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol. 1982;5:649–655.PubMedCrossRefGoogle Scholar
  8. 8.
    Shimoyama M, Fukuda H, Saijo N, Yamaguchi N. Japan Clinical Oncology Group (JCOG).JpnJ Clin Oncol 1998;28:158–162.CrossRefGoogle Scholar
  9. 9.
    Salmon SE, Haut A, Bonnet JD, et al. Alternating combination chemotherapy and levamisole improve survival in multiple myeloma: a Southwest Oncology Group Study.J Clin Oncol. 1983; 1:453–461.PubMedGoogle Scholar
  10. 10.
    Tobinai K, Kohno A, Shimada Y, et al. Toxicity grading criteria of the Japan Clinical Oncology Group.Jpn J Clin Oncol. 1993;23:250–257.PubMedGoogle Scholar
  11. 11.
    Kaplan EL, Meier P. Non-parametric estimation from incomplete observations.J Am Stat Assoc. 1958;53:457–481.CrossRefGoogle Scholar
  12. 12.
    Cox DR. Regression models and life-tables.J R Stat Soc Series B. 1972;34:187–220.Google Scholar
  13. 13.
    Kim K, DeMets DI.. Confidence intervals following group sequential tests in clinical trials.Biometrics. 1987;43:857–864.PubMedCrossRefGoogle Scholar
  14. 14.
    Rcboussin DM, DeMets DL, Kim KM, Lan KKG. Programs for computing group sequential boundaries using the Lan-DeMets methods version 2 (1998). Available at: http://www.medsch.wisc. edu/landemets/.Google Scholar
  15. 15.
    SAS/ATAT Software: Changes and Enhancements for Release 6.12. Gary, NC: SAS Institute; 1997.Google Scholar
  16. 16.
    Gregory WM, Richards MA, Malpas JS. Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials.J Clin Oncol. 1992;10:334–342.PubMedGoogle Scholar
  17. 17.
    Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.N Engl J Med. 1996;335:91–97.PubMedCrossRefGoogle Scholar
  18. 18.
    Siegel DS, Desikan KR, Mehta J, et al. Age is not a prognostic variable with autotransplants for multiple myeloma.Blood. 1999; 93:51–54.PubMedGoogle Scholar
  19. 19.
    Sirohi B, Powles R,Treleaven J, et al. High-dose chemotherapy and autologous transplantation in myeloma patients aged 65 years and over: a case-control comparison with younger patients.Blood. 1999;94:578a.Google Scholar
  20. 20.
    Myeloma Trialists’ Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview on 24 randomized trials and 4012 patients.Br J Haematol. 2001;113:1020–1034.CrossRefGoogle Scholar
  21. 21.
    Salmon SE, Crowley JJ, Balcerzak SP, Roach RW, Taylor SA. Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study.J Clin Oncol. 1998;16:890–896.PubMedGoogle Scholar
  22. 22.
    Alexanian R, Weber D, Dimopoulos M, Delasalle K, Smith TL. Randomized trial of α-intcrfcron or dexamethasone as maintenance treatment for multiple myeloma.Am J Hematol. 2000;65:204–209.PubMedCrossRefGoogle Scholar
  23. 23.
    Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalido- mide in refractory multiple myeloma.N Engl J Med. 1999;341:1561–1571.CrossRefGoogle Scholar
  24. 24.
    Juliusson G, Celsing F, Turesson I, Lenhoff S, Adriansson M, Malm C. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma.Br J Haematol. 2000;109:89–96.PubMedCrossRefGoogle Scholar
  25. 25.
    Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R.Thalid- omide alone or with dexamethasone for previously untreated multiple myeloma.J Clin Oncol 2003;21:16–19.PubMedCrossRefGoogle Scholar
  26. 26.
    Hussein MA, Elson P, Tose EA, Karam M, Srkaloci G. Doxil (D),vin- cristine (V), decadron (d) and thalidomide (T) (DVd-T) for relapsed/ refractory multiple myeloma [abstract].Blood. 2002(suppl l);100:403a .Google Scholar
  27. 27.
    Richardson PG, Schlossman RL, Weller E, et al. Imraunoraodula- tory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.Blood. 2002;100:3063–3067.PubMedCrossRefGoogle Scholar
  28. 28.
    Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hema- tologic malignancies.J Clin Oncol. 2002:20:4420–4427.PubMedCrossRefGoogle Scholar
  29. 29.
    Richardson P, Barlogie B, Berenson J, et al. A phase II multicenter study of the proteasome inhibitor bortezomib (Velcade, formerly PS-341) in multiple myeloma patients with relapsed/refractory disease [abstract].Blood. 2002(suppl l);100:104a.Google Scholar
  30. 30.
    Zangari M, Barlogie B, Prather J, et al. Marked activity also in del 13 multiple myeloma of PS 341 and subsequent thalidomide in a setting of resistance to post-autotransplant salvage therapies [abstract].Blood. 2002 (suppl l);100:105a.Google Scholar
  31. 31.
    Pinto OC, Hu E, Bernstein-Singer M, Pinter-Brown L, Govidarajan B. Acute hepatic injury after the withdrawal of immunosuppressive chemotherapy in patients with hepatitis B.Cancer. 1990;65:878–884.PubMedCrossRefGoogle Scholar
  32. 32.
    Ohtsu T, Sai T, Oka M, Sugai Y, Tobinai K. Activation of hepatitis B virus infection by chemotherapy containing glucocorticoid in hepa- titis B virus carriers with hematological malignancies.Jpn J Clin Oncol. 199121:360–365.PubMedGoogle Scholar
  33. 33.
    Yoshiba M, Sckiyama K, Iwabuchi S, et al. Recurrent fulminant hepatic failure in an HB carrier after intensive chemotherapy.Dig Dis Sci. 1993:38:1751–1755.PubMedCrossRefGoogle Scholar
  34. 34.
    Fan FS, Tzeng CH, Hsiao KI, Hu ST, Liu WT, Chen PM. Withdrawal of immunosuppressive therapy in allogeneic bone marrow transplantation reactivates chronic viral hepatitis C.Bone Marrow Transplant. 1991;8:417–420.PubMedGoogle Scholar
  35. 35.
    Fong T-L, Valinluck B, Govindarajan S, Charboneau F, Adkins RH, Redeker AG. Short-term prcdnisone therapy affects aminotrans- ferase activity and hepatitis C virus RNA levels in chronic hepatitis C.Gastroenterology.1994;107:196–199.PubMedGoogle Scholar
  36. 36.
    Vento S, Cainelli F, Mirandola F, et al. Fulminant hepatitis on withdrawal of chemotherapy in carriers of hepatitis C virus.Lancet. 1996;347:92–93.PubMedCrossRefGoogle Scholar
  37. 37.
    Bergsagel DE, Bailey AJ, Langley GR, MacDonald RN, White DF, Miller AB. The chemotherapy of plasma-cell myeloma and the incidence of acute leukemia.N Engl J Med. 1979;301:743–748.PubMedCrossRefGoogle Scholar
  38. 38.
    Tucker MA, Coleman CN, Cox RS, Varghese A, Rosenberg SA. Risk of second cancers after treatment for Hodgkin’s disease.N Engl J Med. 1988;318:76–81.PubMedCrossRefGoogle Scholar
  39. 39.
    Boffetta P, Kaldor JM. Secondary malignancies following cancer chemotherapy.Acta Oncol. 1994;33:591–598.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2004

Authors and Affiliations

  • Takeaki Takenaka
    • 1
  • Kuniaki Itoh
    • 2
  • Takayo Suzuki
    • 3
  • Atae Utsunomiya
    • 4
  • Shin Matsuda
    • 5
  • Takaaki Chou
    • 6
  • Toshiaki Sai
    • 7
  • Masayuki Sano
    • 8
  • Susumu Konda
    • 9
  • Tatsuji Ohno
    • 10
  • Chikara Mikuni
    • 11
  • Kijoh Deura
    • 12
  • Takashi Yamada
    • 13
  • Fumi Mizorogi
    • 14
  • Haruhisa Nagoshi
    • 15
  • Masao Tomonaga
    • 16
  • Tomomitsu Hotta
    • 17
  • Kohichi Kawano
    • 18
  • Keitaro Tsushita
    • 19
  • Masami Hirano
    • 20
  • Masanori Shimoyama
    • 21
    Email author
  • Lymphoma Study Group of the Japan Clinical Oncology Group
  1. 1.Hematology DivisionNational Cancer Center HospitalTokyo
  2. 2.Division of Hematology/OncologyNational Cancer Center Hospital EastKashiwa
  3. 3.Division of Hematology/OncologyShiga Medical Center for AdultsShiga
  4. 4.Department of Internal MedicineImamura Bun- in HospitalKagoshima
  5. 5.Ohla Nishinouchi HospitalKoriyama
  6. 6.Departments of Internal MedicineNiigata Cancer Center Niigata HospitalNiigata
  7. 7.Iwaki- Kyoritsu General HospitalIwaki
  8. 8.Saga Medical SchoolSaga
  9. 9.Department of Hematology and ImmunologyKanazawa Medical UniversityKahoku
  10. 10.Departments of Internal MedicineOhtsu Red Cross HospitalOhtsu
  11. 11.Sapporo National HospitalSapporo
  12. 12.Saku Central HospitalSaku
  13. 13.Jikei University Aoto HospitalTokyo
  14. 14.Daisan HospitalJikei UniversityKomae
  15. 15.St, Marianna University HospitalKawasaki
  16. 16.Department of Hematology, Molecular Medicine Unit, Atomic Bomb Disease InstituteNagasaki UniversityNagasaki
  17. 17.Fourth Department of Internal MedicineTokai UniversityIsehara
  18. 18.Department of Internal MedicineKyorin UniversityMitaka
  19. 19.Departments of HematologyNagoya National HospitalNagoya
  20. 20.Fujita Health UniversityToyoake
  21. 21.Medical Oncology DivisionNational Cancer Center HospitalTokyoJapan

Personalised recommendations