Treatment of Bendamustine and Prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with Melphalan and Prednisone—a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO)

  • W. Pönisch
  • P. S. Mitrou
  • K. Merkle
  • M. Herold
  • M. Assmann
  • G. Wilhelm
  • K. Dachselt
  • P. Richter
  • V. Schirmer
  • A. Schulze
  • R. Šubert
  • B. Harksel
  • N. Grobe
  • E. Stelzer
  • M. Schulze
  • A. Bittrich
  • M. Freund
  • R. Pasold
  • Th. Friedrich
  • W. Helbig
  • D. Niederwieser
Original Paper

Abstract

Purpose: This randomized phase III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone (MP) treatment in previously untreated patients with multiple Myeloma (MM). Patients and Methods: To be included, patients had to have histologically and cytologically proven stage II with progressive diseases or stage III MM. They were randomly assigned to receive BP (n=68) or MP (n=63). The primary endpoint was the time to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and quality of life. Results: The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%; P=0.007), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P<0.02). TTF and remission duration were significantly longer in the BP group. Patients receiving BP had higher QoL scores and reported pain less frequently than patients receiving MP. Conclusion: BP is superior to MP with respect to complete remission rate, TTF, cycles needed to achieve maximum remission and quality of life and should be considered the new standard in first-line treatment of MM patients not eligible for transplantation.

Keywords

Bendamustine Prednisone Multiple myeloma Melphalan Prednisone 

Notes

Acknowledgements

The authors wish to thank Barbara Hobbie for manuscript preparation, and all physicians, nurses, and support personnel for their care of patients on this study.

References

  1. Alberts DS, Chang SY, Chen HS, Evans TL, Moon TE (1979) Oral melphalan kinetics. Clin Pharmacol Ther 26(6):737–745PubMedGoogle Scholar
  2. Alexanian R, Dimopoulos M (1994) The treatment of multiple myeloma. N Engl J Med 330(7):484–489PubMedCrossRefGoogle Scholar
  3. Alexanian R, Bonnet J, Gehan E, Haut A, Hewlett J, Lane M et al (1972) Combination chemotherapy for multiple myeloma. Cancer 30(2):382–389PubMedCrossRefGoogle Scholar
  4. Anger G, Hesse P, Baufeld H (1969) Treatment of multiple myeloma with a new cytostatic agent: gamma-l-methyl-5-bis-(beta-chlorethyl)-amino-benzimidazolyl-(2)-butyric acid hydrochloride. DMW 94(48):2495–2500Google Scholar
  5. Anger G, Fink R, Fleischer J, Hesse P, Krug K, Raderecht C et al (1975) Vergleichsuntersuchungen zwischen Cytostasan und Cyclophosphamid bei der chronischen Lymphadenose, dem Plasmozytom, der Lymphogranulomatose und dem Bronchialkarzinom. Dt Gesundh -Wesen 30(27):1280–1285Google Scholar
  6. Attal G, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. New Engl J Med 335(2):91–97PubMedCrossRefGoogle Scholar
  7. Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D et al (1999) Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93(1):55–65PubMedGoogle Scholar
  8. Bensinger WI, Buckner D, Gahrton G (1997) Allogeneic stem cell transplantation for multiple myeloma. Hematol Oncol Clin North Am 11(1):147–157PubMedCrossRefGoogle Scholar
  9. Bergsagel DE, Sprague CC, Austin C, Griffith KM (1962) Evaluation of new chemotherapeutic agents in the treatment of multiple myeloma. IV. L-Phenylalanine mustard (NSC-8806). Cancer Chemother Rep 21(87):99Google Scholar
  10. Bergsagel DE, Bailey AJ, Langley GR, MacDonald RN, White DF, Miller AB (1979) The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med 301(14):743–748PubMedCrossRefGoogle Scholar
  11. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematology 102(5):1115–1123CrossRefGoogle Scholar
  12. Blumenstengel K, Ruffert K, Frincke HJ, Kath R, Höffken K (1998) Bendamustine vs. Melphalan in the primary treatment of multiple myeloma (MM). A randomized prospective study. J Cancer Res Clin Oncol 124:68Google Scholar
  13. Bosanquet AG, Gilby ED (1982) Pharmacokinetics of oral and intravenous melphalan during routine treatment of multiple myeloma. Eur J Cancer Clin Oncol 18(4):355–362PubMedCrossRefGoogle Scholar
  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):842–854PubMedCrossRefGoogle Scholar
  15. Ehrsson H, Eksborg S, Osterborg A, Mellstedt H, Lindfors A (1989) Oral melphalan pharmacokinetics–relation to dose in patients with multiple myeloma. Med Oncol Tumor Pharmacother 6(2):151–154PubMedGoogle Scholar
  16. Fernberg JO, Johansson B, Lewensohn R, Mellstedt H (1990) Oral dosage of melphalan and response to treatment in multiple myeloma. Eur J Cancer 26(3):393–396PubMedCrossRefGoogle Scholar
  17. Gahrton G, Svensson H, Cavo M, Apperley J, Bacigalupo A, Bjorkstrand B et al (2001) Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983–1993 and 1994–1998 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 113(1):209–216PubMedCrossRefGoogle Scholar
  18. Greenlee RT, Hill-Harmon MB, Murray T, Thun M (2001) Cancer statistics 2001. CA Cancer J Clin 51(1):15–36PubMedCrossRefGoogle Scholar
  19. Gregory WM, Richards MA, Malpas JS (1992) Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 10(2):334–342PubMedGoogle Scholar
  20. Harousseau J-L, Attal M, Divine M, Marit G, Leblond V, Stoppa A-M et al (1995) Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French Registry on autologous transplantation in multiple myeloma. Blood 85(11):3077–3085PubMedGoogle Scholar
  21. Hoeffken K, Merkle K, Schoenfelder M, Anger G, Brandtner M, Ridwelski K et al (1998) Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study. J Cancer Res Clin Oncol 124(11):627–632CrossRefGoogle Scholar
  22. Kyle RA (1975) Multiple myeloma: review of 869 cases. Mayo Clin Proc 50:29–40PubMedGoogle Scholar
  23. Leoni LM, Bailey B, Reifert J, Niemeyer C, Bendall H, Dauffenbach L et al (2003) SDX-105 (Bendamustine), a clinically active antineoplastic agent posesses a unique mechanism of action. Blood 102(11):640aGoogle Scholar
  24. Myeloma Trialists’ Collaborative Group (1998) Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol 16(12):3832–3842Google Scholar
  25. Oken MM (1994) Standard treatment of multiple myeloma. Mayo Clin Proc 69(8):781–786PubMedGoogle Scholar
  26. Peest D, Coldewey R, Deicher H, Sailer M, Vykoupil C, Leo R et al (1993) Prognostic value of clinical, laboratory, and histological characteristics in multiple myeloma: improved definition of risk groups. Eur J Cancer 29A(7):978–983PubMedCrossRefGoogle Scholar
  27. Peest D, Deicher H, Coldewey R, Leo R, Bartl R, Bartels H et al (1995) A comparison of polychemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma. A prospective trial of the German Myeloma Treatment Group. Eur J Cancer 31A(2):146–151PubMedCrossRefGoogle Scholar
  28. Raaijmakers HGP, Izquierdo MAI, Lokhorst HM, de Leeuw C, Belien JAM, Bloem AC et al (1998) Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood 91(3):1029–1036PubMedGoogle Scholar
  29. Raje N, Anderson KC (2000) Multiple myeloma. Curr Treat Options Oncol 1(1):73–82PubMedCrossRefGoogle Scholar
  30. Richardson PC, Barlogie B, Berenson J, Sighal S, Jagannath S, Irwin D et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617PubMedCrossRefGoogle Scholar
  31. Strumberg D, Harstrick A, Doll K, Hoffmann B, Seeber S (1996) Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs 7(4):415–421PubMedCrossRefGoogle Scholar
  32. Vesole DH, Tricot G, Jagannath S, Desikan KR, Siegel D, Bracy D et al (1996) Autotransplants in multiple myeloma: what have we learned? Blood 88(3):838–847PubMedGoogle Scholar
  33. Weber DM (2002) Newly diagnosed multiple myeloma. Curr Treat Options Oncol 3(3):235–245PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • W. Pönisch
    • 1
  • P. S. Mitrou
    • 2
  • K. Merkle
    • 3
  • M. Herold
    • 4
  • M. Assmann
    • 5
  • G. Wilhelm
    • 6
  • K. Dachselt
    • 7
  • P. Richter
    • 8
  • V. Schirmer
    • 9
  • A. Schulze
    • 4
  • R. Šubert
    • 10
  • B. Harksel
    • 11
  • N. Grobe
    • 12
  • E. Stelzer
    • 13
  • M. Schulze
    • 14
  • A. Bittrich
    • 15
  • M. Freund
    • 16
  • R. Pasold
    • 17
  • Th. Friedrich
    • 18
  • W. Helbig
    • 1
  • D. Niederwieser
    • 1
  1. 1.Department of Hematology and OncologyUniversity of LeipzigLeipzigGermany
  2. 2.Department of Hematology and OncologyUniversity of FrankfurtFrankfurtGermany
  3. 3.Ribosepharm GmbHMunichGermany
  4. 4.Division of Hematology and OncologyHELIOS KlinikumErfurtGermany
  5. 5.Hospital RiesaRiesaGermany
  6. 6.Harz-Klinikum Wernigerode GmbHWernigerodeGermany
  7. 7.Division of Hematology and OncologySüdharz Hospital NordhausenNordhausenGermany
  8. 8.Community HospitalZella-MehlisGermany
  9. 9.Division of Hematology and OncologyVogtland-Klinikum PlauenPlauenGermany
  10. 10.Division of Hematology and OncologyHELIOS KlinikumSchwerinGermany
  11. 11.Division of Hematology and OncologyHospital Johann KentmannTorgauGermany
  12. 12.Division of Hematology and OncologyHospital Neu BrandenburgBrandenburgGermany
  13. 13.Division of Hematology and OncologyWaldklinikum GeraGeraGermany
  14. 14.Division of Hematology and OncologyHematology and Oncology ZittauZittauGermany
  15. 15.Hematology and OncologyErfurtGermany
  16. 16.Division of Hematology and OncologyUniversity RostockRostockGermany
  17. 17.Division of Hematology and OncologyErnst von Bergmann Hospital PostdamPostdamGermany
  18. 18.Institute of PatologyUniversity LeipzigLeipzigGermany

Personalised recommendations