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.

  • Review
  • Published:

Maintenance therapy in multiple myeloma

Abstract

Therapeutic advances in the treatment of multiple myeloma have significantly improved remission duration and overall survival (OS). These strategies have included the use of immunotherapy (interferon), novel agents (bortezomib, thalidomide, and lenalidomide), corticosteroids, and chemotherapy. While novel agents have had a major impact on response rates with initial therapy, most patients with multiple myeloma will eventually relapse. In the setting of minimal residual disease following standard dose or high-dose therapy, a number of different ‘maintenance’ strategies have emerged to prolong the duration of initial or subsequent remissions. The impact of these strategies on OS and event-free survival (EFS) is critically important, as the use of ineffective maintenance therapy adds the burden of additional cost, morbidity, and may reduce quality of life. Truly successful maintenance therapy will be effective in the setting of minimal residual disease, and will improve not only EFS, but also OS. This review summarizes the currently available data in the maintenance setting for multiple myeloma, and will discuss potential future trials to further address this important issue.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kyle RA, Rajkumar SV . Multiple myeloma. N Engl J Med 2004; 351: 1860–1873.

    Article  CAS  PubMed  Google Scholar 

  2. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–1883.

    Article  CAS  PubMed  Google Scholar 

  3. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91–97.

    Article  CAS  PubMed  Google Scholar 

  4. Barlogie B, Tricot GJ, van Rhee F, Angtuaco E, Walker R, Epstein J et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 2006; 135: 158–164.

    Article  PubMed  Google Scholar 

  5. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC . Advances in biology of multiple myeloma: clinical applications. Blood 2004; 104: 607–618.

    Article  CAS  PubMed  Google Scholar 

  6. Mellstedt H, Ahre A, Bjorkholm M, Holm G, Johansson B, Strander H . Interferon therapy in myelomatosis. Lancet 1979; 1: 245–247.

    Article  CAS  PubMed  Google Scholar 

  7. Mandelli F, Avvisati G, Amadori S, Boccadoro M, Gernone A, Lauta VM et al. Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 1990; 322: 1430–1434.

    Article  CAS  PubMed  Google Scholar 

  8. Salmon SE, Crowley JJ, Grogan TM, Finley P, Pugh RP, Barlogie B . Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study. J Clin Oncol 1994; 12: 2405–2414.

    Article  CAS  PubMed  Google Scholar 

  9. Peest D, Deicher H, Coldewey R, Leo R, Bartl R, Bartels H et al. 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 1995; 31A: 146–151.

    Article  CAS  PubMed  Google Scholar 

  10. Drayson MT, Chapman CE, Dunn JA, Olujohungbe AB, Maclennan IC . MRC trial of alpha2b–interferon maintenance therapy in first plateau phase of multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 1998; 101: 195–202.

    Article  CAS  PubMed  Google Scholar 

  11. Blade J, San Miguel JF, Escudero ML, Fontanillas M, Besalduch J, Gardella S et al. Maintenance treatment with interferon alpha-2b in multiple myeloma: a prospective randomized study from PETHEMA (Program for the Study and Treatment of Hematological Malignancies, Spanish Society of Hematology). Leukemia 1998; 12: 1144–1148.

    Article  CAS  PubMed  Google Scholar 

  12. Westin J, Rodjer S, Turesson I, Cortelezzi A, Hjorth M, Zador G . Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study. Cooperative Study Group. Br J Haematol 1995; 89: 561–568.

    Article  CAS  PubMed  Google Scholar 

  13. Pulsoni A, Avvisati G, Petrucci MT, Mandelli F, Giannarelli D, Lauta VM et al. The Italian experience on interferon as maintenance treatment in multiple myeloma: ten years after. Blood 1998; 92: 2184–2186.

    CAS  PubMed  Google Scholar 

  14. Schaar CG, Kluin-Nelemans HC, te Marvelde C, le Cessie S, Breed WP, Fibbe WE et al. Interferon-{alpha} as maintenance therapy in patients with multiple myeloma. Ann Oncol 2005; 16: 634–639.

    Article  CAS  PubMed  Google Scholar 

  15. Alexanian R, Weber D, Dimopoulos M, Delasalle K, Smith TL . Randomized trial of alpha-interferon or dexamethasone as maintenance treatment for multiple myeloma. Am J Hematol 2000; 65: 204–209.

    Article  CAS  PubMed  Google Scholar 

  16. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001; 113: 1020–1034.

  17. Fritz E, Ludwig H . Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol 2000; 11: 1427–1436.

    Article  CAS  PubMed  Google Scholar 

  18. Attal M, Huguet F, Schlaifer D, Payen C, Laroche M, Fournie B et al. Intensive combined therapy for previously untreated aggressive myeloma. Blood 1992; 79: 1130–1136.

    CAS  PubMed  Google Scholar 

  19. Cunningham D, Powles R, Malpas J, Raje N, Milan S, Viner C et al. A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol 1998; 102: 495–502.

    Article  CAS  PubMed  Google Scholar 

  20. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006; 24: 929–936.

    Article  CAS  PubMed  Google Scholar 

  21. McIntyre OR, Pajak TF, Kyle RA, Cornwell III GG, Leone L . Response rate and survival in myeloma patients receiving prednisone alone. Med Pediatr Oncol 1985; 13: 239–243.

    Article  CAS  PubMed  Google Scholar 

  22. Alexanian R, Barlogie B, Dixon D . High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med 1986; 105: 8–11.

    Article  CAS  PubMed  Google Scholar 

  23. Friedenberg WR, Kyle RA, Knospe WH, Bennett JM, Tsiatis AA, Oken MM . High-dose dexamethasone for refractory or relapsing multiple myeloma. Am J Hematol 1991; 36: 171–175.

    Article  CAS  PubMed  Google Scholar 

  24. Palumbo A, Giaccone L, Bertola A, Pregno P, Bringhen S, Rus C et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 2001; 86: 399–403.

    CAS  PubMed  Google Scholar 

  25. Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002; 99: 3163–3168.

    Article  CAS  PubMed  Google Scholar 

  26. Salmon SE, Crowley JJ, Balcerzak SP, Roach RW, Taylor SA, Rivkin SE et al. Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol 1998; 16: 890–896.

    Article  CAS  PubMed  Google Scholar 

  27. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–1571.

    Article  CAS  PubMed  Google Scholar 

  28. Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N et al. 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 2001; 98: 492–494.

    Article  CAS  PubMed  Google Scholar 

  29. Rajkumar SV, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE et al. Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 2000; 75: 897–901.

    Article  CAS  PubMed  Google Scholar 

  30. Dimopoulos MA, Anagnostopoulos A, Weber D . Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 2003; 21: 4444–4454.

    Article  CAS  PubMed  Google Scholar 

  31. Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R . Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol 2003; 121: 768–771.

    Article  CAS  PubMed  Google Scholar 

  32. Alexanian R, Weber D, Anagnostopoulos A, Delasalle K, Wang M, Rankin K . Thalidomide with or without dexamethasone for refractory or relapsing multiple myeloma. Semin Hematol 2003; 40: 3–7.

    Article  CAS  PubMed  Google Scholar 

  33. Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20: 4319–4323.

    Article  CAS  PubMed  Google Scholar 

  34. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R . Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21: 16–19.

    Article  CAS  PubMed  Google Scholar 

  35. Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106: 35–39.

    Article  CAS  PubMed  Google Scholar 

  36. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR . Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 431–436.

    Article  CAS  PubMed  Google Scholar 

  37. Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P et al. Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma. Bone Marrow Transplant 2006; 37: 825–829.

    Article  CAS  PubMed  Google Scholar 

  38. Stewart AK, Chen CI, Howson-Jan K, White D, Roy J, Kovacs MJ et al. Results of a multicenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant. Clin Cancer Res 2004; 10: 8170–8176.

    Article  CAS  PubMed  Google Scholar 

  39. Brinker BT, Waller EK, Leong T, Heffner Jr LT, Redei I, Langston AA et al. Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma. Cancer 2006; 106: 2171–2180.

    Article  CAS  PubMed  Google Scholar 

  40. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L et al. Maintenance therapy with thalidomide improves survival in multiple myeloma patients. Blood 2006; 108: 3289–3294.

    Article  CAS  PubMed  Google Scholar 

  41. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354: 1021–1030.

    Article  CAS  PubMed  Google Scholar 

  42. Navas TA, Nguyen AN, Hideshima T, Reddy M, Ma JY, Haghnazari E et al. Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia 2006; 20: 1017–1027.

    Article  CAS  PubMed  Google Scholar 

  43. Hideshima T, Podar K, Chauhan D, Ishitsuka K, Mitsiades C, Tai YT et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 2004; 23: 8766–8776.

    Article  CAS  PubMed  Google Scholar 

  44. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 2005; 105: 2941–2948.

    Article  CAS  PubMed  Google Scholar 

  45. Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005; 106: 2837–2840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barosi G, Boccadoro M, Cavo M, Corradini P, Marchetti M, Massaia M et al. Management of multiple myeloma and related-disorders: guidelines from the Italian Society of Hematology (SIE), Italian Society of Experimental Hematology (SIES) and Italian Group for Bone Marrow Transplantation (GITMO). Haematologica 2004; 89: 717–741.

    CAS  PubMed  Google Scholar 

  47. Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J 2003; 4: 379–398.

    Article  PubMed  Google Scholar 

  48. Nguyen AN, Stebbins EG, Henson M, O'Young G, Choi SJ, Quon D et al. Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation. Exp Cell Res 2006; 312: 1909–1923.

    Article  CAS  PubMed  Google Scholar 

  49. Xin X, Abrams TJ, Hollenbach PW, Rendahl KG, Tang Y, Oei YA et al. CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Clin Cancer Res 2006; 12: 4908–4915.

    Article  CAS  PubMed  Google Scholar 

  50. Bommert K, Bargou RC, Stuhmer T . Signalling and survival pathways in multiple myeloma. Eur J Cancer 2006; 42: 1574–1580.

    Article  CAS  PubMed  Google Scholar 

  51. Menu E, Jernberg-Wiklund H, Stromberg T, De Raeve H, Girnita L, Larsson O et al. Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model. Blood 2006; 107: 655–660.

    Article  CAS  PubMed  Google Scholar 

  52. Wu KD, Zhou L, Burtrum D, Ludwig DL, Moore MA . Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis. Cancer Immunol Immunother 2007; 56: 343–357.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Lonial.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mihelic, R., Kaufman, J. & Lonial, S. Maintenance therapy in multiple myeloma. Leukemia 21, 1150–1157 (2007). https://doi.org/10.1038/sj.leu.2404633

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404633

Keywords

This article is cited by

Search

Quick links