SIE, SIES, GITMO evidence-based guidelines on novel agents (thalidomide, bortezomib, and lenalidomide) in the treatment of multiple myeloma

Abstract

In this project, we produced drug-specific recommendations targeting the use of new agents for multiple myeloma (MM). We used the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system which separates the judgments on quality of evidence from the judgment about strength of recommendations. We recommended thalidomide and bortezomib in MM patients candidates to autologous stem cell transplantation (ASCT) (weak positive). We did not recommend novel agents as maintenance therapy after ASCT (weak negative). In patients not candidate to ASCT, thalidomide or bortezomib (strong positive) associated with melphalan and prednisone were recommended. In these patients, no specific course of action could be recommended as for maintenance therapy. In patients who are refractory or relapsing after first-line therapy, we recommended bortezomib and pegylated liposomal doxorubicin, or lenalidomide and dexamethasone combinations (weak positive).

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

References

  1. 1.

    Brenner H, Gondos A, Pulte D (2008) Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111:2521–2526

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Kastritis E, Zervas K, Symeonidis A et al (2009) Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG). Leukemia 23:1152–1157

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Kumar SK, Rajkumar SV, Dispenzieri A et al (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516–2520

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Barosi G, Boccadoro M, Cavo M et al (2004) 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 89:717–741

    PubMed  CAS  Google Scholar 

  5. 5.

    Brouwers MC, Kho ME, Browman GP et al (2010) AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting, and evaluation in health care. Prev Med 51:421–424

    PubMed  Article  Google Scholar 

  6. 6.

    Atkins D, Best D, Briss PA et al (2004) Grading quality of evidence and strength of recommendations. BMJ 328:1490–1498

    PubMed  Article  Google Scholar 

  7. 7.

    Ferguson JH (1996) The NIH Consensus Development Program. The evolution of guidelines. Int J Technol Assess Health Care 12:460–474

    PubMed  CAS  Google Scholar 

  8. 8.

    William PL, Webb C (1994) The Delphi technique: a methodological discussion. J Adv Nurs 19:180–186

    Article  Google Scholar 

  9. 9.

    Delbecq AL, van de Ven AH, Gustafson DH (1975) Group Techniques for Program Planning: a guide to nominal group and Delphi processes. Scott Foresman and Co, Glenview

    Google Scholar 

  10. 10.

    Hicks L, Haynes A, Reece D et al (2008) A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. Cancer Treat Rev 34:442–452

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Lokhorst HM, van der Holt B, Zweegman S et al (2010) 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 115:1113–1120

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Harousseau JL, Attal M, Avet-Loiseau H et al (2010) Bortezomib–dexamethasone is superior to vincristine–doxorubicin–dexamethasone as induction prior to autologous stem cell transplantation in newly diagnosed multiple myeloma: results of the IFM2005-01 phase 3 trial. J Clin Oncol 28:4621–4629

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Sonneveld P, Schmidt-Wolf I, van der Holt B et al (2008) 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 112:653, suppl; abstr 307

    Google Scholar 

  14. 14.

    Rajkumar SV, Jacobus S, Callander NS et al (2010) 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 11:29–37

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Cavo M, Tacchetti P, Patriarca F et al (2010) 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 376:2075–2085

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Cavo M, Pantani L, Patriarca L et al (2011) Superior complete response rate (CR) and progression-free survival (PFS) with bortezomib–thalidomide–dexamethasone (VTS) versus thalidomide–dexamnethasopne (TD) as consolidation therapy after autologous stem-cell transplantation (ASCT) in multiple mueloma (MM). Blood 118:816, suppl; abstr 1871

    Article  Google Scholar 

  17. 17.

    Harousseau J-L, Avet-Loiseau H, Facon T et al (2009) Bortezomib plus dexamethasone (VD) versus reduced-dose bortezomib plus thalidomide plus dexamethasone (vTD) as induction treatment prior to autologous stem-cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM). Blood 114:150, suppl; abstr 354

    Google Scholar 

  18. 18.

    Rosiñol L, Cibeira MT, Mateos MV et al (2010) A Phase III PETHEMA/GEM study of induction therapy prior autologous stem cell transplantation (ASCT) in multiple myeloma: superiority of VTD (bortezomib/thalidomide/dexamethasone) over TD and VBMCP/VBAD plus bortezomib. Blood 116:139, suppl; abstr 307

    Article  Google Scholar 

  19. 19.

    Attal M, Harousseau JL, Leyvraz S et al (2006) Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108:3289–3294

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Barlogie B, Tricot G, Anaissie E et al (2006) Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354:1021–1030

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Spencer A, Prince HM, Roberts AW et al (2009) 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 27:1788–1793

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Stewart AK, Trudel S, Bahlis N et al (2010) 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 116:23, suppl; abstr 39

    Article  Google Scholar 

  23. 23.

    Morgan GJ, Gregory WM, Davies FE et al (2012) The role of maintenance therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 119:7–15

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Nooka AK, Begera M, Boise LH et al (2011) Thaldomide as maintenance therapy in multiple myeloma (MM) improves progression free survival (PFS) and overall survival (OS): a meta-analysis. Blood 118:807, suppl; abstr 1855

    Google Scholar 

  25. 25.

    Attal M, Lauwers VC, Marit G et al (2010) Maintenance treatment with lenalidomide after transplantation for myeloma: final analysis of the IFM 2005-02. Blood 116:141, suppl; abstr 310

    Google Scholar 

  26. 26.

    McCarthy PL, Owzar K, Anderson KC et al (2010) Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma: CALGB 100104. Blood 116:21, suppl; abstr 37

    Google Scholar 

  27. 27.

    Rosinol L, Cibeira MT, Masteros MV et al (2011) A phase III PETHEMA/GEM randomized trial of postransplant (ASCT) maintenance in multiple myeloma: superiority of bortezomib/thalidomide compared with thaluidomide and alpha-2b interferon. Blood 118:1694, suppl; abstr 3962

    Google Scholar 

  28. 28.

    Palumbo A, Bringhen S, Caravita T et al (2006) Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367:825–831

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Palumbo A, Bringhen S, Liberati AM et al (2008) Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized trial. Blood 112:3107–3114

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Facon T, Mary JY, Hulin C et al (2007) 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 370:1209–1218

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Hulin C, Facon T, Rodon P et al (2009) 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 27:3664–3670

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Waage A, Gimsing P, Fayers P et al (2010) Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 116:1405–1412

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Beksac M, Haznedar R, Firatli-Tuglular T et al (2011) Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol 86:16–22

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Wijermans P, Schaafsma M, Termorshuizen F et al (2010) Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol 28:3160–3166

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Fayers PM, Palumbo A, Hulin C et al (2011) Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood 118:1239–1247

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Rajkumar SV, Blood E, Vesole D et al (2006) 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 24:431–436

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Rajkumar SV, Rosinol L, Hussein M et al (2008) 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 26:2171–2177

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Ludwig H, Hajek R, Tothova E et al (2009) Thalidomide–dexamethasone compared to melphalan–prednisolone in elderly patients with multiple myeloma. Blood 13:3435–3442

    Article  Google Scholar 

  39. 39.

    Morgan GJ, Davies FE, Gregory WM et al (2011) Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood 118:1231–1238

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    San-Miguel J, Schlag R, Khuageva N et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Mateos MV, Richardson PG, Schlag R et al (2010) Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 28:2259–2266

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    San-Miguel J, Schlag R, Khuageva NK et al (2011) Continued overall survival benefit after 5 years’ follow-up with bortezomib–melphalan–prednisone (VMP) versus melphalan–prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial. Blood 118:221, suppl; abstr 476

    Google Scholar 

  43. 43.

    Palumbo A, Delforge M, Catalano J et al (2010) A phase 3 study evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients ≥ 65 years with newly diagnosed multiple myeloma (NDMM): continuous use of lenalidomide vs fixed-duration regimens. Blood 116:273, suppl; abstr 622

    Article  Google Scholar 

  44. 44.

    Zonder JA, Crowley J, Hussein MA et al (2010) Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood 116:5838–5841

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Mateos MV, Oriol A, Martínez-López J et al (2010) Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 11:934–941

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Palumbo A, Bringhen S, Rossi D et al (2010) Bortezomib–melphalan–prednisone–thalidomide followed by maintenance with bortezomib–thalidomide compared with bortezomib–melphalan–prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 28:5101–5109

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Bringhen S, Larocca A, Rossi D et al (2010) Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116:4745–4753

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Nievizky R, Flinn IW, Rifkin R et al (2011) 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. Blood 118:222, suppl; abstr 478

    Google Scholar 

  49. 49.

    Palumbo A, Adam Z, Kropff M et al (2011) A phase 3 study evaluating the efficacy and safety of lenalidomide (Len) combined with melphalan and prednisone followed by continuous lenalidomide maintenance (MPR-R) in patients (Pts) ≥ 65 years (Yrs) with newly diagnosed multiple myeloma (NDMM): updated results for Pts aged 65–75 < Yrs enrolled in MM-015. Blood 118:220, suppl; abstr 475

    Article  Google Scholar 

  50. 50.

    Mateos MV, Oriol A, Tereul A-I et al (2011) Maintenance therapy with bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP) in elderly myeloma patients included in the GEM2005MAS65 Spanish randomized trial. Blood 118:222, suppl; abstr 477

    Article  Google Scholar 

  51. 51.

    Ludwig H, Adam Z, Tóthová E et al (2010) Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica 95:1548–1554

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Richardson PG, Sonneveld P, Schuster MW et al (2005) Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Richardson PG, Sonneveld P, Schuster M et al (2007) Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110:3557–3560

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Lee SJ, Richardson PG, Sonneveld P et al (2008) Bortezomib is associated with better health-related quality of life than high dose dexamethasone in patients with relapsed multiple myeloma: results from the APEX study. Br J Haematol 143:511–519

    PubMed  CAS  Google Scholar 

  55. 55.

    Orlowski RZ, Nagler A, Sonneveld P et al (2007) Randomized phase III study of pegylated liposomal Doxorubicin plus Bortezomib compared with Bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 28:3892–3901

    Article  Google Scholar 

  56. 56.

    Sonnevel P, Hajek R, Nagler A et al (2008) Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer 112:1529–1537

    Article  Google Scholar 

  57. 57.

    Weber D, Chen C, Niesvizky R et al (2007) Lenalidomide plus Dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Dimopoulos M, Spencer A, Attal M et al (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123–2132

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Dimopoulos MA, Chen C, Spencer A et al (2009) Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 23:2147–2152

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Chen C, Reece DE, Siegel D et al (2009) Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Br J Haematol 146:164–170

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Dimopoulos MA, Hussein M, Swern AS et al (2011) Long-term outcomes and safety of continuous lenalidomide plus dexamethasone (Len + Dex) treatment in patients (Pts) with relapsed or refractory multiple myeloma (RRMM). Blood 118:1263, suppl; abstr 2929

    Article  Google Scholar 

  62. 62.

    Proposed evaluation tools for COMPUS (2005) http://www.cadth.ca/media/pdf/COMPUS_Evaluation_Methodology_draft_e.pdf. Accessed 15 June 2007

  63. 63.

    Schunemann HJ, Jaeschke R, Cook DJ et al (2006) An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J Respir Crit Care Med 174:605–614

    PubMed  Article  Google Scholar 

  64. 64.

    Kumar SK, Mikhael JR, Buadi FK et al (2009) Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 84:1095–1110

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma, version 1.2011

  66. 66.

    Bird JM, Owen RG, D’Sa S et al (2011) Guidelines for the diagnosis and management of multiple myeloma 2011. Br J Haematol 154:32–75

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Palumbo A, Sezer O, Kyle R et al (2009) IMWG International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia 23:1716–1730

    PubMed  Article  CAS  Google Scholar 

  68. 68.

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

  69. 69.

    De Palma R, Liberati A, Ciccone G et al (2008) Developing clinical recommendations for breast, colorectal, and lung cancer adjuvant treatments using the GRADE system: a study from the Programma Ricerca e Innovazione Emilia Romagna Oncology Research Group. J Clin Oncol 26:1033–1039

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

Funding of the project was provided by SIE, SIES, and GITMO societies and from at-arm’s-length contribution from Celgene, Janssen Cilag and Novartis (Italy) provided to the SIE. The SIE administered all aspects of the meetings. The funding sources had no role in identifying statements, abstracting data, synthesizing results, grading evidence, or preparing the manuscript or in the decision to submit the manuscript for publication.

Authorship contribution

GB and ST designed research; GB, AB, and MM performed the systematic review of literature, graded the evidence, and prepared the summary tables of evidence. GM, MB, PC, MM, PT, AP, MC, and ST formed the Panel of experts who discussed the summaries of evidence and produced recommendations. GB wrote the preliminary version of the paper. All authors participated in writing significant sections of the paper.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Giovanni Barosi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Barosi, G., Merlini, G., Billio, A. et al. SIE, SIES, GITMO evidence-based guidelines on novel agents (thalidomide, bortezomib, and lenalidomide) in the treatment of multiple myeloma. Ann Hematol 91, 875–888 (2012). https://doi.org/10.1007/s00277-012-1445-y

Download citation

Keywords

  • Multiple myeloma
  • Bortezomib
  • Thalidomide
  • Lenalidomide
  • Guideline
  • GRADE
  • Recommendations