Stem Cell Transplantation for Multiple Myeloma

  • Sharmilan Thanendrarajan
  • Tarun K. Garg
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


The introduction of high-dose chemotherapy and autologous stem cell transplantation more than 30 years has revolutionized the treatment landscape for patients with multiple myeloma. Multiple myeloma is a malignant plasma cell disorder which is characterized by accumulation of clonal plasma cells (myeloma cells) in the bone marrow and increased production of atypical immunoglobulins leading to end organ damage with bone destruction, renal insufficiency, anemia and/or hypercalcemia. In this chapter the author provides an overview of current and past innovations in treatment of multiple myeloma using stem cell transplantation as consolidation therapy. Moreover, the role of stem cell transplantation in the era of novel anti-myeloma agents is discussed, and controversial topics related to stem cell transplantation in myeloma are addressed, such as single versus tandem transplantation, stem cell transplantation in elderly or relapsed myeloma patients, and allogeneic transplantation.


Multiple myeloma Stem cell transplantation High-dose melphalan Stem cell collection Allogeneic transplantation Total therapy 


  1. 1.
    Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860–73.CrossRefPubMedGoogle Scholar
  2. 2.
    Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046–60.CrossRefPubMedGoogle Scholar
  3. 3.
    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–48. doi: 10.1016/S1470-2045(14)70442-5.CrossRefPubMedGoogle Scholar
  4. 4.
    Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kyle RA, San-Miguel JF, Mateos MV, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Hematol Oncol Clin North Am. 2014;28(5):775–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Weinhold N, Heuck CJ, Rosenthal A, Thanendrarajan S, Stein CK, Van Rhee F, et al. Clinical value of molecular subtyping multiple myeloma using gene expression profiling. Leukemia. 2016;30(2):423–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Lonial S, Boise LH, Kaufman J. How I treat high-risk myeloma. Blood. 2015;126(13):1536–43.CrossRefPubMedGoogle Scholar
  8. 8.
    Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Barlogie B, Hall R, Zander A, Dicke K, Alexanian R. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood. 1986;67(5):1298–301.PubMedGoogle Scholar
  10. 10.
    Shah N, Callander N, Ganguly S, Gul Z, Hamadani M, Costa L, et al. Hematopoietic stem cell transplantation for multiple myeloma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21(7):1155–66.CrossRefPubMedGoogle Scholar
  11. 11.
    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(10):1021–30.Google Scholar
  12. 12.
    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(2):158–64.CrossRefPubMedGoogle Scholar
  13. 13.
    Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24(11):1934–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;S0140-6736(15):01120–4.Google Scholar
  15. 15.
    Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609–17.CrossRefPubMedGoogle Scholar
  16. 16.
    Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458–64.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Richardson PG, Moreau P, Laubach JP, Gupta N, Hui AM, Anderson KC, et al. The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma. Future Oncol. 2015;11(8):1153–68.CrossRefPubMedGoogle Scholar
  18. 18.
    Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013;122(14):2331–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817–25.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114(27):5436–43.CrossRefPubMedGoogle Scholar
  21. 21.
    Mohty M, Richardson PG, McCarthy PL, Attal M. Consolidation and maintenance therapy for multiple myeloma after autologous transplantation: where do we stand? Bone Marrow Transplant. 2015;50(8):1024–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J. Curing myeloma at last: defining criteria and providing the evidence. Blood. 2014;124(20):3043–51.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Blokhin N, Larionov L, Perevodchikova N, Chebotareva L, Merkulova N. Clinical experiences with sarcolysin in neoplastic diseases. Ann N Y Acad Sci. 1958;68(3):1128–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Alexanian R, Bergsagel DE, Migliore PJ, Vaughn WK, Howe CD. Melphalan therapy for plasma cell myeloma. Blood. 1968;31(1):1–10.PubMedGoogle Scholar
  25. 25.
    Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969;208(9):1680–5.CrossRefPubMedGoogle Scholar
  26. 26.
    McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983;2(8354):822–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Selby P. High-dose chemotherapy. Chemioterapia. 1987;6(2 Suppl):675–7.PubMedGoogle Scholar
  28. 28.
    Cunningham D, Paz-Ares L, Gore ME, Malpas J, Hickish T, Nicolson M, et al. High-dose melphalan for multiple myeloma: long-term follow-up data. J Clin Oncol. 1994;12(4):764–8.CrossRefPubMedGoogle Scholar
  29. 29.
    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(3):869–72.PubMedGoogle Scholar
  30. 30.
    Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93(1):55–65.PubMedGoogle Scholar
  31. 31.
    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(2):91–7.CrossRefPubMedGoogle Scholar
  32. 32.
    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(19):1875–83.CrossRefPubMedGoogle Scholar
  33. 33.
    Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011;118(12):3205–11.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cavo M, Pantani L, Pezzi A, Petrucci MT, Patriarca F, Di Raimondo F, et al. Bortezomib-thalidomide-dexamethasone (VTD) is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma. Leukemia. 2015;29(12):2429–31.CrossRefPubMedGoogle Scholar
  35. 35.
    Ludwig H, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, et al. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015;171(3):344–54.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 Mar 21. pii: blood-2016-01-693580.Google Scholar
  37. 37.
    Sonneveld P, Goldschmidt H, Rosiñol L, Bladé J, Lahuerta JJ, Cavo M, et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol. 2013;31(26):3279–87.CrossRefPubMedGoogle Scholar
  38. 38.
    Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, et al. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015;126(11):1294–301.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, et al. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016;127(9):1109–16. doi: 10.1182/blood-2015-11-679415.. Epub 2016 Jan 22.CrossRefPubMedGoogle Scholar
  40. 40.
    Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16(16):1617–29.CrossRefPubMedGoogle Scholar
  41. 41.
    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(26):2495–502.CrossRefPubMedGoogle Scholar
  42. 42.
    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(17):2434–41.CrossRefPubMedGoogle Scholar
  43. 43.
    Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst. 2009;101(2):100–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood. 2009;114(9):1729–35.CrossRefPubMedGoogle Scholar
  45. 45.
    Naumann-Winter F, Greb A, Borchmann P, Bohlius J, Engert A, Schnell R. First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies. Cochrane Database Syst Rev. 2012;10:CD004626.PubMedGoogle Scholar
  46. 46.
    Grövdal M, Nahi H, Gahrton G, Liwing J, Waage A, Abildgaard N, et al. Autologous stem cell transplantation versus novel drugs or conventional chemotherapy for patients with relapsed multiple myeloma after previous ASCT. Bone Marrow Transplant. 2015;50(6):808–12.CrossRefPubMedGoogle Scholar
  47. 47.
    Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(8):874–85.CrossRefPubMedGoogle Scholar
  48. 48.
    Giralt S, Garderet L, Durie B, Cook G, Gahrton G, Bruno B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant. 2015;21(12):2039–51.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068–74.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Auner HW, Szydlo R, Hoek J, Goldschmidt H, Stoppa AM, Morgan GJ, et al. Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years. Bone Marrow Transplant. 2015;50(2):209–15.CrossRefPubMedGoogle Scholar
  51. 51.
    Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370(9594):1209–18.CrossRefPubMedGoogle Scholar
  52. 52.
    Badros A, Barlogie B, Siegel E, Morris C, Desikan R, Zangari M, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol. 2001;114(3):600–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Morris CL, Siegel E, Barlogie B, Cottler-Fox M, Lin P, Fassas A, et al. Mobilization of CD34+ cells in elderly patients (>/=70 years) with multiple myeloma: influence of age, prior therapy, platelet count and mobilization regimen. Br J Haematol. 2003;120(3):413–23.CrossRefPubMedGoogle Scholar
  54. 54.
    Afifi S, Adel NG, Devlin S, Duck E, Vanak J, Landau H, et al. Upfront plerixafor plus G-CSF versus cyclophosphamide plus G-CSF for stem cell mobilization in multiple myeloma: efficacy and cost analysis study. Bone Marrow Transplant. 2016;51(4):546–52.CrossRefPubMedGoogle Scholar
  55. 55.
    Silvennoinen R, Anttila P, Säily M, Lundan T, Heiskanen J, Siitonen TM, et al. A randomized phase II study of stem cell mobilization with cyclophosphamide + G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma. Bone Marrow Transplant. 2016;51(3):372–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Abuabdou A, Rosenbaum ER, Usmani SZ, Barlogie B, Cottler-Fox M. Analysis of CD34+ cell collection using two mobilization regimens for newly diagnosed multiple myeloma patients reveals the separate impact of mobilization and collection variables. J Clin Apher. 2014;29(5):251–5.CrossRefPubMedGoogle Scholar
  57. 57.
    Papanikolaou X, Rosenbaum ER, Tyler LN, Sawyer J, Heuck CJ, Barlogie B, et al. Hematopoietic progenitor cell collection after autologous transplant for multiple myeloma: low platelet count predicts for poor collection and sole use of resulting graft enhances risk of myelodysplasia. Leukemia. 2014;28(4):888–93.CrossRefPubMedGoogle Scholar
  58. 58.
    Uy GL, Rettig MP, Cashen AF. Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells. Expert Opin Biol Ther. 2008;8(11):1797–804.CrossRefPubMedGoogle Scholar
  59. 59.
    van Rhee F, Giralt S, Barlogie B. The future of autologous stem cell transplantation in myeloma. Blood. 2014;124(3):328–33.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Barlogie B, Anaissie E, van Rhee F, Pineda-Roman M, Zangari M, Shaughnessy J, et al. The Arkansas approach to therapy of patients with multiple myeloma. Best Pract Res Clin Haematol. 2007;20(4):761–81.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Koehne G, Giralt S. Allogeneic hematopoietic stem cell transplantation for multiple myeloma: curative but not the standard of care. Curr Opin Oncol. 2012;24(6):720–6.CrossRefPubMedGoogle Scholar
  62. 62.
    Laubach J, Garderet L, Mahindra A, Gahrton G, Caers J, Sezer O, et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia 2015 Dec 29.Google Scholar
  63. 63.
    Franssen LE, Raymakers RA, Buijs A, Schmitz MF, van Dorp S, Mutis T, et al. Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long-term follow-up in a single institution. Eur J Haematol 2016 Mar 29.Google Scholar
  64. 64.
    Auner HW, Szydlo R, van Biezen A, Iacobelli S, Gahrton G, Milpied N, et al. Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2013;48(11):1395–400.CrossRefPubMedGoogle Scholar
  65. 65.
    Kawamura K, Ikeda T, Hagiwara S, Mori T, Shinagawa A, Nishiwaki K, et al. Tandem autologous versus autologous/allogeneic transplantation for multiple myeloma: propensity score analysis. Leuk Lymphoma. 2016;9:1–7.Google Scholar
  66. 66.
    Gahrton G, Iacobelli S, Björkstrand B, Hegenbart U, Gruber A, Greinix H, et al. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013;121(25):5055–63.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Myeloma InstituteUniversity of Arkansas for Medical Sciences (UAMS)Little RockUSA

Personalised recommendations