Review Article

Stem cell transplantation for multiple myeloma: current and future status

Abstract

Stem cell transplantation (SCT) has been used in the treatment of multiple myeloma (MM) for decades and has become a standard of care for newly diagnosed MM patients. However, several important questions remain regarding the optimal use of SCT, particularly in light of the many recent advances in the treatment of MM. Bortezomib-based therapy or, in some cases, lenalidomide-based therapy should be considered as an induction therapy in transplantation-eligible patients. Efforts to improve upon the efficacy and safety of standard transplantation regimens (that is, high-dose melphalan) are also underway. Most published studies on the use of tandem autologous SCT were conducted before the advent of novel agents, such as thalidomide, lenalidomide and bortezomib, making it difficult to establish the current role of tandem SCT. Allogeneic SCT continues to be evaluated in clinical trials, and may have an important role in the treatment of transplantation-eligible patients with suitable donors. Post-transplantation consolidation and maintenance therapy using novel agents should be considered to improve outcomes in patients who fail to achieve a complete response following SCT. Patients in remission should be advised that continued therapy has been shown to prolong remission, improve quality of life and extend survival. Additional data on the optimal approach to post-transplantation therapy are needed. New strategies in development aimed at improving patient selection, safety and efficacy of SCT are likely to improve future outcomes.

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References

  1. 1

    McElwain TJ, Powles RL . High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 1983; 2: 822–824.

  2. 2

    Selby PJ, McElwain TJ, Nandi AC, Perren TJ, Powles RL, Tillyer CR et al. Multiple myeloma treated with high dose intravenous melphalan. Br J Hematol 1987; 66: 55–62.

  3. 3

    Barlogie B, Hall R, Zander A, Dicke K, Alexanian R . High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood 1986; 67: 1298–1301.

  4. 4

    Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagannath S et al. High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood 1987; 70: 869–872.

  5. 5

    Alexanian R, Dimopoulos MA, Hester J, Delasalle K, Champlin R . Early myeloablative therapy for multiple myeloma. Blood 1994; 84: 4278–4282.

  6. 6

    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 Français du Myélome. N Engl J Med 1996; 335: 91–97.

  7. 7

    Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010; 376: 2075–2085.

  8. 8

    Chanan-Khan A, Giralt S . Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol 2010; 28: 2612–2624.

  9. 9

    Macro M, Divine M, Uzunhan Y, Jaccard A, Bouscary D, Leblond V et al. Dexamethasone+thalidomide (Dex/Thal) compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma (MM): a randomized trial. Blood 2006; 108: (abstract 57).

  10. 10

    Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 2010; 28: 4621–4629.

  11. 11

    Sonneveld P, Schmidt-Wolf I, van der Holt B, el Jarari L, Bertsch U, Salwender H et al. HOVON-65/GMMG-HD4 Randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Blood 2010; 116: (abstract 40).

  12. 12

    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.

  13. 13

    Siegel DS, Jacobus S, Rajkumar VS, Abonour R, Callander NS, Katz MS et al. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in the ECOG E4A03 randomized clinical trial. Blood 2010; 116: (abstract 38).

  14. 14

    National Comprehensive Cancer Network. Guidelines for Multiple Myeloma. Version 1, 2011. Available at www.nccn.org.

  15. 15

    Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116: 679–686.

  16. 16

    Kumar S, Flinn IW, Richardson PG, Hari P, Callander NS, Noga SJ et al. Novel three- and four-drug combination regimens of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for previously untreated multiple myeloma: results from the multi center, randomized, phase 2 EVOLUTION study. Blood 2010; 116: (abstract 621).

  17. 17

    Hahn T, Wingard JR, Anderson KC, Bensinger WI, Berenson JR, Brozeit G et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant 2003; 9: 4–37.

  18. 18

    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.

  19. 19

    Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89: 789–793.

  20. 20

    Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG et al. Single versus double autologous stem cell transplantation for multiple myeloma. N Engl J Med 2003; 349: 2495–2502.

  21. 21

    Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 2007; 25: 2434–2441.

  22. 22

    Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol 2010; 28: 1209–1214.

  23. 23

    van Rhee F, Szymonifka J, Anaissie E, Nair B, Waheed S, Alsayed Y et al. Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy. Blood 2010; 116: 1220–1227.

  24. 24

    Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood 2002; 99: 731–735.

  25. 25

    Giralt S, Bensinger W, Goodman M, Podoloff D, Eary J, Wendt R et al. 166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials. Blood 2003; 102: 2684–2691.

  26. 26

    Dispenzieri A, Wiseman GA, Lacy MQ, Litzow MR, Anderson PM, Gastineau DA et al. A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma. Leukemia 2005; 19: 118–125.

  27. 27

    Anagnostopoulos A, Aleman A, Ayers G, Donato M, Champlin R, Weber D et al. Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Cancer 2004; 100: 2607–2612.

  28. 28

    Fenk R, Schneider P, Kropff M, Huenerlituerkoglu AN, Steidl U, Aul C et al. High-dose idarubicin, cyclophosphamide and melphalan as conditioning for autologous stem cell transplantation increases treatment-related mortality in patients with multiple myeloma: results of a randomised study. Br J Haematol 2005; 130: 588–594.

  29. 29

    Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood 2010; 115: 32–37.

  30. 30

    Ghobrial I, Stewart AK . ASH evidence-based guidelines: what is the role of maintenance therapy in the treatment of multiple myeloma? Hematology Am Soc Hematol Educ Program 2009, 587–589.

  31. 31

    Stewart AK, Trudel S, Bahlis NJ, White DJ, Sabry W, Belch A et al. A randomized phase III trial of thalidomide and prednisone as maintenance therapy following autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM): the NCIC CTG MY.10 trial. Blood 2010; 116: (abstract 39).

  32. 32

    Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 2009; 27: 1788–1793.

  33. 33

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

  34. 34

    Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 2010; 115: 1113–1120.

  35. 35

    Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 2008; 112: 3115–3121.

  36. 36

    Barlogie B, Annaissie E, van Rhee F, Shaughnessy Jr JD, Szymonifka J, Hoering A et al. Reiterative survival analyses of Total Therapy 2 for multiple myeloma elucidate follow-up time dependency of prognostic variables and treatment arms. J Clin Oncol 2010; 28: 3023–3027.

  37. 37

    Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1782–1791.

  38. 38

    McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1770–1781.

  39. 39

    Revlimid (lenalidomide). Summary of product characteristics. Available at: www.ema.europa.eu.

  40. 40

    Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107: 3474–3480.

  41. 41

    Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: 1110–1120.

  42. 42

    Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112: 3591–3593.

  43. 43

    Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea 3rd E et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011; 12: 1195–1203.

  44. 44

    Stadtmauer EA, Krishnan A, Pasquini MC, Ewell M, Alyea EP, Antin JH et al. Tandem autologous stem cell transplants (auto-auto) with or without maintenance therapy versus single autologous transplant followed by HLA-matched sibling non-myeloablative allogeneic stem cell transplant (auto-allo) for patients (pts) with high risk (HR) multiple myeloma (MM): results from the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 trial. Blood 2010; 116: (abstract 526).

  45. 45

    Lokhorst H, Einsele H, Vesole D, Bruno B, San Miguel J, Pérez-Simon JA et al. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 2010; 28: 4521–4530.

  46. 46

    Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L et al. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 2011; 29: 3016–3022.

  47. 47

    Crawley C, Iacobelli S, Björkstrand B, Apperley JF, Niederwieser D, Gahrton G . Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007; 109: 3588–3594.

  48. 48

    Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma who are candidates for autologous stem cell transplantation. Blood 2011; 117: 6063–6073.

  49. 49

    Waheed S, Shaughnessy JD, van Rhee F, Alsayed Y, Nair B, Anaissie E et al. International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with Total therapy 2 and 3 protocols. Cancer 2011; 117: 1001–1009.

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Acknowledgements

We thank Shanthi Jayawardena, PhD, and Eva Polk, PhD (Excerpta Medica), for the linguistic improvement of the manuscript. Editorial support in the preparation of this manuscript was funded by Celgene Corporation. WB is supported by the NIH fund: NIH/NCI 5R21CA155911.

SG and WB were fully responsible for all content and editorial decisions for this manuscript.

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Correspondence to W Bensinger.

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Competing interests

WB has participated in a speakers bureau and advisory board, and has received clinical research support from Celgene Corporation. He has also participated in an advisory board and has received clinical research support from Millennium and Onyx Pharmaceuticals. WB has also received grant support from AstraZeneca and Acetylon Pharmaceuticals. SG has had a consultancy role and received honoraria from Biokine Therapeutics, Miltenyi Biotech, Onyx, Celgene Corporation and Sanofi; he has also received lecture fees and grants from Celgene Corporation.

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Giralt, S., Bensinger, W. Stem cell transplantation for multiple myeloma: current and future status. Leukemia Suppl 2, S10–S14 (2013). https://doi.org/10.1038/leusup.2013.3

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Keywords

  • autologous stem cell transplantation
  • allogeneic stem cell transplantation
  • multiple myeloma
  • melphalan

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