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.

  • Spotlight Review
  • Published:

Treatment of newly diagnosed myeloma

Abstract

The introduction of thalidomide, bortezomib and lenalidomide has dramatically changed the treatment paradigm of multiple myeloma (MM). In patients eligible for autologous stem cell transplant (ASCT), combinations including thalidomide/dexamethasone (Thal/Dex) or bortezomib/dexamethasone (Bort/Dex) or lenalidomide/dexamethasone (Rev/Dex) have been introduced as induction regimens in patients eligible for ASCT. New induction regimens have significantly increased complete response rate before and after ASCT with a positive impact on progression-free survival. Maintenance therapy with thalidomide, under investigation with lenalidomide, may further prolong remission duration. In patients not eligible for ASCT, randomized studies have shown that melphalan, prednisone, thalidomide (MPT) and melphalan, prednisone and bortezomib (MPV) are both superior to melphalan and prednisone (MP), and are now considered standard of care. Ongoing trials will soon assess if MP plus lenalidomide may be considered an attractive option. More complex regimens combining thalidomide or bortezomib or lenalidomide with cyclophosphamide or doxorubicin have been also tested. In small cohorts of patients bortezomib or lenalidomide may overcome the poor prognosis induced by deletion 13 or translocation t(4;14) or deletion 17p13. If these data will be confirmed, a cytogenetically risk-adapted strategy might become the most appropriate strategy.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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. Rajkumar SV, Kyle RA . Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 2005; 80: 1371–1382.

    Article  PubMed  Google Scholar 

  3. Ries LAG, Eisner MP, Kosary CL, Linet M, Tamra T, Young JL et al. (eds). SEER cancer statistics review, 1975–2000. National Cancer Institute. Available at: http://seer.cancer.gov//csr/1975_2001. Accessed on 7 September 2004.

  4. Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007; 356: 2582–2590.

    Article  CAS  PubMed  Google Scholar 

  5. Kumar SK, Dingli D, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK et al. Outcome after autologous stem cell transplantation for multiple myeloma in patients with preceding plasma cell disorders. Br J Haematol 2008; 141: 205–211.

    Article  PubMed  Google Scholar 

  6. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999; 163: 380–386.

    CAS  PubMed  Google Scholar 

  7. Dredge K, Marriott JB, Macdonald CD, Man HW, Chen R, Muller GW et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002; 87: 1166–1172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mitra-Kaushik S, Harding JC, Hess JL, Ratner L . Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 tax transgenic mice and tax tumor transplants. Blood 2004; 104: 802–809.

    Article  CAS  PubMed  Google Scholar 

  9. 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: 2516–2520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78: 21–33.

    Article  PubMed  Google Scholar 

  11. Van Rhee F, Bolejack V, Hollmig K, Pineda-Roman M, Anaissie E, Epstein J et al. High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis. Blood 2007; 110: 827–832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 

  13. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.

    Article  PubMed  Google Scholar 

  14. Gertz MA, Lacy MQ, Dispensieri 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 

  15. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S et al. The molecular classification of multiple myeloma. Blood 2006; 108: 2020–2028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 2007; 109: 3489–3495.

    Article  CAS  PubMed  Google Scholar 

  17. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906–917.

    Article  CAS  PubMed  Google Scholar 

  18. Bahlis NJ, Song K, Trieu Y, Roland B, Masih-Khan E, Chang H et al. Lenalidomide overcomes poor prognosis conferred by del13q and t(4;14) but Not del17p13 in multiple myeloma: results of the Canadian MM016 trial. Blood 2007; 110: (Abstract 3597).

  19. Stewart AK, Bergsagel PL, Greipp PR, Dispenzieri A, Gertz MA, Hayman SR et al. A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia 2007; 21: 529–534.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Rajkumar SV, Blood E, Vesole DH, Fonseca R, Greipp PR, Eastern Cooperative Oncology Group. 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 

  22. Fermand J-P, Jaccard A, Macro M, Uzunhan Y, Allard C, Castaigne S et al. A randomized comparison of dexamethasone+thalidomide (Dex/Thal) vs Dex+Placebo (Dex/P) in patients (pts) with relapsing multiple myeloma (MM). Blood 2006; 108: (Abstract 3563).

  23. 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).

  24. Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L 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: 2171–2177.

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Morgan G, Davies FE, Owen RG, Rawstron AC, Bell S, Cocks K et al. Thalidomide combinations improve response rates; results from the MRC IX study. Blood 2007; 110: (Abstract 3593).

  27. Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B et al. Prevention of thalidomide-associated thrombosis in myeloma. Leukemia 2008; 22: 414–423.

    Article  CAS  PubMed  Google Scholar 

  28. Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106: 4050–4053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, Kabat B et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc 2007; 82: 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  30. Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Greipp P . A randomized phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. Blood 2006; 108: (Abstract 799).

  31. Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S 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: 1101–1109.

    Article  CAS  PubMed  Google Scholar 

  32. Harousseau J, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM 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: 1498–1505.

    CAS  PubMed  Google Scholar 

  33. Rosinol L, Oriol A, Mateos MV, Sureda A, García-Sánchez P, Gutiérrez N et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics. J Clin Oncol 2007; 25: 4452–4458.

    Article  CAS  PubMed  Google Scholar 

  34. Harousseau JL, Mathiot C, Attal M, Marit G, Caillot D, Mohty MMM et al. VELCADE/Dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial. Blood 2007; 110: (Abstract 450).

  35. Cavo M, Patriarca F, Tacchetti P, Galli M, Perrone G, Petrucci MT et al. Bortezomib (VELCADE)-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM). Blood 2007; 110: (Abstract 73a).

  36. Palumbo A, Avonto I, Patriarca F, Crippa C, Petrucci MT, Rossini F et al. Bortezomib, pegylated-liposomal-doxorubicin and dexamethasone followed by melphalan 100 mg/m2 in elderly newly diagnosed patients: an interim analysis. Blood 2007; 110: (Abstract 448a).

  37. Richardson P, Jagannath S, Raje N, Jakubowiak A, Lonial S, Avigan D et al. Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) as front-line therapy for patients with multiple myeloma (MM): preliminary results of a phase 1/2 study. Blood 2007; 110: (Abstract 187).

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Spencer A, Prince M, Roberts AW, Bradstock KF, Prosse IW . First analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) trial of thalidomide and alternate day prednisolone following autologous stem cell transplantation (ASCT) for patients with multiple myeloma (ALLG MM6). Blood 2006; 108: (Abstract 58a).

  40. Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB et al. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 2008; 111: 1805–1810.

    Article  CAS  PubMed  Google Scholar 

  41. Schillera GJ, Liaoa M, Sohna JP, Malonea R, Bartonia K, Habtemariam B et al. Phase I/II trial of bortezomib maintenance following autologous peripheral blood progenitor cell transplantation as treatment for intermediate- and advanced-stage multiple myeloma. Biol Blood Marrow Transplant 2008; 14 (2 Suppl 1): (Abstract 176).

    Article  Google Scholar 

  42. Palumbo A, Bringhen S, Petrucci MT, Musto P, Rossini F, Nunzi M et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50–70: results of a randomized controlled trial. Blood 2004; 104: 3052–3057.

    Article  CAS  PubMed  Google Scholar 

  43. 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: 1209–1218.

    Article  CAS  PubMed  Google Scholar 

  44. Ludwig H, Tothova E, Hajek R, Drach J, Labar B, Egyed M et al. Thalidomide-dexamethasone versus melphalan-prednisolone as first line treatment in elderly patients with multiple myeloma: second interim analysis. Haematologica 2007; 92 (S1): (Abstract 446a).

  45. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367: 825–831.

    Article  CAS  PubMed  Google Scholar 

  46. Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM 01/01. Blood 2007; 110: (Abstract 75a).

  47. Waage A, Gimsing P, Juliusson G, Turesson I, Fayers P . Melphalan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo controlled randomized phase 3 trial. Blood 2007; 110: (Abstract 78a).

  48. Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N et al. Melphalan, Prednisone, and Lenalidomide Treatment for newly diagnosed myeloma: a report from the GIMEMA-Italian Multiple Myeloma Network. J Clin Oncol 2007; 25: 4459–4465.

    Article  CAS  PubMed  Google Scholar 

  49. Mateos MV, Hernandez JM, Hernandez MT, Gutiérrez NC, Palomera L, Fuertes M et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase I/II study. Blood 2006; 108: 2165–2172.

    Article  CAS  PubMed  Google Scholar 

  50. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906–917.

    Article  CAS  PubMed  Google Scholar 

  51. Terpos E, Dimopoulos MA, Sezer O . The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma. Leukemia 2007; 21: 1875–1884.

    Article  CAS  PubMed  Google Scholar 

  52. Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood 2007; 110: 334–338.

    Article  CAS  PubMed  Google Scholar 

  53. von Metzler I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth M et al. Bortezomib inhibits human osteoclastogenesis. Leukemia 2007; 21: 2025–2034.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Palumbo.

Additional information

Conflict of interest

SVR has received research support to cover cost of clinical trials at Mayo Clinic from Celgene Corporation. AP has received scientific advisory-board and lecture fees from Pharmion, Celgene and Janssen-Cilag. Also supported by CA 62242, CA107476, CA 100080 and CA 93842 to SVR; Università degli Studi di Torino; Compagnia di S Paolo, MIUR and CNR to AP.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palumbo, A., Rajkumar, S. Treatment of newly diagnosed myeloma. Leukemia 23, 449–456 (2009). https://doi.org/10.1038/leu.2008.325

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.325

Keywords

This article is cited by

Search

Quick links