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Novel Induction Regimens in Multiple Myeloma

  • Multiple Myeloma (R Nievszky, Section Editor)
  • Published:
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Abstract

Multiple myeloma is the second most common hematologic malignancy and predominantly affects the elderly. The introduction of novel agents such as thalidomide, lenalidomide, and bortezomib has improved progression-free survival, overall survival, and quality of life in myeloma patients. Next generation agents such as carfilzomib hold further promise for increased depth and length of remission. Autologous stem cell transplant remains a useful tool in the treatment of multiple myeloma, but not all patients are eligible for this procedure. As therapy becomes more effective, determination of the right therapy in the right patient becomes paramount. The focus of this review is a critical analysis of combinations of the novel agents in the treatment of newly diagnosed multiple myeloma in both transplant eligible and ineligible patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

    Article  PubMed  Google Scholar 

  2. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111(6):2962–72.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  3. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860–73.

    Article  PubMed  CAS  Google Scholar 

  5. Landau H, Giralt S. Treatment of transplant-eligible patients with multiple myeloma in 2014. Hematol Oncol Clin North Am. 2014;28(5):815–27.

    Article  PubMed  Google Scholar 

  6. Rajkumar SV. Multiple myeloma: the death of VAD as initial therapy. Blood. 2005;106(1):2–3.

    Article  CAS  Google Scholar 

  7. Gonzalez F, Trujillo JM, Alexanian R. Acute leukemia in multiple myeloma. Ann Intern Med. 1977;86(4):440–3.

    Article  PubMed  CAS  Google Scholar 

  8. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106(13):4050–3.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Cavo M, Tacchetti P, Patriarca F, 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(9758):2075–85.

    Article  PubMed  CAS  Google Scholar 

  10. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III hovon-65/ gmmg-Hd4 trial. J Clin Oncol. 2012;30(24):2946–55.

    Article  PubMed  CAS  Google Scholar 

  11. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23(7):1337–41.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679–86.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the apex trial. Blood. 2007;110(10):3557–60.

    Article  PubMed  CAS  Google Scholar 

  14. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906–17.

    Article  PubMed  CAS  Google Scholar 

  15. Niesvizky R, Jayabalan DS, Christos PJ, et al. Bird (biaxin [clarithromycin]/revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;111(3):1101–9.

    Article  PubMed  CAS  Google Scholar 

  16. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366(19):1759–69. This is a major large randomized study evaluating the roles of continuous lenalidomide therapy versus melphalan-prednisone treatment in non-transplant candidates.

    Article  PubMed  CAS  Google Scholar 

  17. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71.

    Article  PubMed  CAS  Google Scholar 

  18. Knight R. Imids: a novel class of immunomodulators. Semin Oncol. 2005;32(4 Suppl 5):S24–30.

    Article  PubMed  CAS  Google Scholar 

  19. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345–50.

    Article  PubMed  CAS  Google Scholar 

  20. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118(18):4771–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Broyl A, Kuiper R, van Duin M, et al. High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. Blood. 2013;121(4):624–7.

    Article  PubMed  CAS  Google Scholar 

  22. 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(3):431–6.

    Article  PubMed  CAS  Google Scholar 

  23. Cavo M, Zamagni E, Tosi P, 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(1):35–9.

    Article  PubMed  CAS  Google Scholar 

  24. Cavo M, Di Raimondo F, Zamagni E, et al. Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma. J Clin Oncol. 2009;27(30):5001–7.

    Article  PubMed  CAS  Google Scholar 

  25. Suppiah R, Srkalovic JG, Hussein MA. Immunomodulatory analogues of thalidomide in the treatment of multiple myeloma. Clin Lymphoma Myeloma. 2006;6(4):301–5.

    Article  PubMed  CAS  Google Scholar 

  26. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood. 2010;115(7):1343–50.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Anderson KC. Proteasome inhibitors in multiple myeloma. Semin Oncol. 2009;36(2 Suppl 1):S20–6.

    Article  PubMed  CAS  Google Scholar 

  28. Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica. 2006;91(11):1498–505.

    PubMed  CAS  Google Scholar 

  29. Rossi A, Mark T, Jayabalan D, et al. Bird (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood. 2013;121(11):1982–5.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (evolution) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119(19):4375–82. This randomized study establishes that a 4-drug regimen is not necessarily superior to 3-drugs in newly diagnosed transplant-eligible myeloma.

    Article  PubMed  CAS  Google Scholar 

  31. Parlati F, Lee SJ, Aujay M, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009;114(16):3439–47.

    Article  PubMed  CAS  Google Scholar 

  32. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801–9. This is the first published study of the activity of carfilzomib in the induction setting in transplant candidates.

    Article  PubMed  CAS  Google Scholar 

  33. Paiva B, van Dongen JJ, Orfao A. New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood. 2015. This is a review of the current status of minimal residual disease testing in myeloma.

  34. Giralt S, Stadtmauer EA, Harousseau JL, et al. International myeloma working group (imwg) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia. 2009;23(10):1904–12.

    Article  PubMed  CAS  Google Scholar 

  35. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007;21(9):2035–42.

    Article  PubMed  CAS  Google Scholar 

  36. Mazumder A, Kaufman J, Niesvizky R, et al. Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia. 2008;22(6):1280. author reply 1281-2.

    Article  PubMed  CAS  Google Scholar 

  37. Mark T, Stern J, Furst JR, et al. Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma. Bio Blood Marrow Transplant. 2008;14(7):795–8.

    Article  CAS  Google Scholar 

  38. Micallef IN, Ho AD, Klein LM, et al. Plerixafor (mozobil) for stem cell mobilization in patients with multiple myeloma previously treated with lenalidomide. Bone Marrow Transplant. 2011;46(3):350–5.

    Article  PubMed  CAS  Google Scholar 

  39. Giralt S, Costa L, Schriber J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant. 2014;20(3):295–308. Review of impact of induction chemotherapy on ability to harvest hematopoietic stem cells and recommendations.

    Article  PubMed  Google Scholar 

  40. Hurria A. Management of elderly patients with cancer. J Natl Compr Canc Netw. 2013;11(5 Suppl):698–701.

    PubMed  Google Scholar 

  41. Niesvizky R, Coleman M, Mark T. Best practices in the management of newly diagnosed multiple myeloma patients who will not undergo transplant. Oncology (Williston Park). 2010;24(3 Suppl 2):14–21.

    Google Scholar 

  42. Alexanian R, Bergsagel DE, Migliore PJ, Vaughn WK, Howe CD. Melphalan therapy for plasma cell myeloma. Blood. 1968;31(1):1–10.

    PubMed  CAS  Google Scholar 

  43. Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2005;80(10):1371–82.

    Article  PubMed  Google Scholar 

  44. Group MTC. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists’ collaborative group. J Clin Oncol. 1998;16(12):3832–42.

    Google Scholar 

  45. Facon T, Mary JY, Pegourie B, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006;107(4):1292–8.

    Article  PubMed  CAS  Google Scholar 

  46. Palumbo A, Sezer O, Kyle R, et al. International myeloma working group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia. 2009;23(10):1716–30.

    Article  PubMed  CAS  Google Scholar 

  47. Rajkumar SV, Rosinol L, Hussein M, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008;26(13):2171–7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Ludwig H, Hajek R, Tothova E, et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood. 2009;113(15):3435–42.

    Article  PubMed  CAS  Google Scholar 

  49. Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008;112(8):3107–14.

    Article  PubMed  CAS  Google Scholar 

  50. Facon T, Mary JY, Hulin C, 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.

    Article  PubMed  CAS  Google Scholar 

  51. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27(22):3664–70.

    Article  PubMed  CAS  Google Scholar 

  52. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31(4):448–55. Major randomized study evaluating the role of adding bortezomib to melphalan + prednisone for induction therapy in non-transplant candidates.

    Article  PubMed  CAS  Google Scholar 

  53. Moreau P, Kolb B, Attal M, et al. Phase I/II Study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood. 2015. Study evaluating the activity of carfilzomib + melphalan + prednisone in the elderly.

  54. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906–17. This is a major randomized trial establishing the superiority of continuous lenalidomide therapy in the upfront treatment of transplant-ineligible myeloma.

    Article  PubMed  CAS  Google Scholar 

  55. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, phase 3b upfront study. ASH Annu Meet Abstr. 2011;118(21):478. This study compares a 2 vs 3-drug bortezomib-based regimens as induction therapy for transplant-ineligible myeloma.

    Google Scholar 

  56. Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the international myeloma working group (Imwg). Leukemia. 2014;28(3):525–42.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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Conflicts of Interest

Karie D. Runcie declares that she has no conflict of interest.

Tomer M. Mark has received honoraria for speakers bureau activities from Celgene Inc., Onyx Inc., and Millennium Inc; research support from Celgene; and has done consultancy for Celgene, Janssen, and Takeda.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA

    Karie D. Runcie & Tomer M. Mark

  2. Department of Medicine, New York Presbyterian Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY, 10021, USA

    Karie D. Runcie

  3. Weill Cornell Medical College, Center for Myeloma, 428 E. 72nd street, Suite 300, New York, NY, 10021, USA

    Tomer M. Mark

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  1. Karie D. Runcie
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Correspondence to Tomer M. Mark.

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This article is part of the Topical Collection on Multiple Myeloma

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Runcie, K.D., Mark, T.M. Novel Induction Regimens in Multiple Myeloma. Curr Hematol Malig Rep 10, 388–394 (2015). https://doi.org/10.1007/s11899-015-0282-1

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