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.

  • Original Article
  • Published:

Myeloma

Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies

Leukemia volume 24, pages 1769–1778 (2010)Cite this article

Subjects

Abstract

We prospectively studied the impact of several cytogenetic abnormalities (CAs) in patients with relapsed/refractory myeloma who received lenalidomide and dexamethasone (RD) with or without the addition of bortezomib (V). On the basis of the presence of previous neuropathy, 50 patients were treated with RD and 49, without preexisting neuropathy, with VRD. The overall response rate was 63%, similar for RD and VRD. Poor risk cytogenetics were associated with lower response rates in RD (P=0.01), but not in VRD (P=0.219). The median progression-free survival (PFS) was similar for RD (9 months) and VRD (7 months). The median overall survival (OS) for all patients was 16 months, with no differences between RD or VRD regimens. Poor risk cytogenetics, especially del17p, resistance to previous thalidomide, elevated lactate dehydrogenase (LDH) and presence of extramedullary disease were associated with inferior response to therapy and shorter PFS and OS. The impact of other CAs on OS was more pronounced in RD. In conclusion, the presence of CAs is an important adverse prognostic factor for patients with relapsed/refractory myeloma, but resistance to previous thalidomide, elevated LDH and presence of extramedullary disease remain of major prognostic importance. The outcome of patients with del17p remains extremely poor even with VRD combination.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357: 2123–2132.

    Article  CAS  PubMed  Google Scholar 

  2. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357: 2133–2142.

    Article  CAS  PubMed  Google Scholar 

  3. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T 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: 3557–3560.

    Article  CAS  PubMed  Google Scholar 

  4. Bruno B, Patriarca F, Sorasio R, Mattei D, Montefusco V, Peccatori J et al. Bortezomib with or without dexamethasone in relapsed multiple myeloma following allogeneic hematopoietic cell transplantation. Haematologica 2006; 91: 837–839.

    CAS  PubMed  Google Scholar 

  5. Prince HM, Adena M, Smith DK, Hertel J . Efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed or refractory multiple myeloma: a systematic comparison. Eur J Haematol 2007; 79: 93–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003; 101: 2377–2380.

    Article  CAS  PubMed  Google Scholar 

  7. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99: 4525–4530.

    Article  CAS  PubMed  Google Scholar 

  8. Richardson PG, Weller E, Jagannath S, Avigan DE, Alsina M, Schlossman RL . Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 2009; 27: 5713–5719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Anderson KC, Jagannath S, Jakubowiak A, Lonial S, Raje N, Alsina M et al. Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma (MM): Encouraging outcomes and tolerability in a phase II study. J Clin Oncol 2009; 27 (Suppl): 15s. (abstract 8536).

    Google Scholar 

  10. Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 2006; 24: 3113–3120.

    Article  CAS  PubMed  Google Scholar 

  11. Gertz MA, Lacy MQ, Dispenzieri 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 

  12. 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 

  13. 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 Myelome. Blood 2007; 109: 3489–3495.

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 2007; 21: 151–157.

    Article  CAS  PubMed  Google Scholar 

  16. Chang H, Trieu Y, Qi X, Xu W, Stewart KA, Reece D . Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res 2007; 31: 779–782.

    Article  CAS  PubMed  Google Scholar 

  17. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.

    Article  CAS  PubMed  Google Scholar 

  18. Reece D, Song KW, Fu T, Roland B, Chang H, Horsman DE et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood 2009; 114: 522–525.

    Article  CAS  PubMed  Google Scholar 

  19. Knop S, Gerecke C, Liebisch P, Topp MS, Platzbecker U, Sezer O et al. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood 2009; 113: 4137–4143.

    Article  CAS  PubMed  Google Scholar 

  20. Kapoor P, Kumar S, Fonseca R, Lacy MQ, Witzig TE, Hayman SR et al. Impact of risk stratification on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood 2009; 114: 518–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Avet Loiseau H, Moreau P, Mathiot C, Charbonnel C, Caillot D, Facon T et al. Induction with Velcade(R)/Dexamethasone partially overcomes the poor prognosis of t(4;14), but not that of del(17p), in young patients with multiple myeloma. Blood 2009; 114 (Suppl): 957. (abstract).

    Google Scholar 

  22. Wu KL, Beverloo B, Lokhorst HM, Segeren CM, van der Holt B, Steijaert MM et al. Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma. Br J Haematol 2007; 136: 615–623.

    Article  CAS  PubMed  Google Scholar 

  23. Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006; 108: 1724–1732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shaughnessy Jr JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109: 2276–2284.

    Article  CAS  PubMed  Google Scholar 

  25. Shaughnessy Jr JD, Haessler J, van Rhee F, Anaissie E, Pineda-Roman M, Cottler-Fox M et al. Testing standard and genetic parameters in 220 patients with multiple myeloma with complete data sets: superiority of molecular genetics. Br J Haematol 2007; 137: 530–536.

    Article  CAS  PubMed  Google Scholar 

  26. Wang M, Dimopoulos MA, Chen C, Cibeira MT, Attal M, Spencer A et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 2008; 112: 4445–4451.

    Article  CAS  PubMed  Google Scholar 

  27. Avet-Loiseau H, Soulier J, Fermand JP, Yakoub-Agha I, Attal M, Hulin C et al. Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia 2010; 24: 623–628.

    Article  CAS  PubMed  Google Scholar 

  28. Sonneveld P, Hajek R, Nagler A, Spencer A, Blade J, Robak T et al. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer 2008; 112: 1529–1537.

    Article  CAS  PubMed  Google Scholar 

  29. Dimopoulos MA, Barlogie B, Smith TL, Alexanian R . High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med 1991; 115: 931–935.

    Article  CAS  PubMed  Google Scholar 

  30. Anagnostopoulos A, Gika D, Symeonidis A, Zervas K, Pouli A, Repoussis P et al. Multiple myeloma in elderly patients: prognostic factors and outcome. Eur J Haematol 2005; 75: 370–375.

    Article  PubMed  Google Scholar 

  31. Terpos E, Katodritou E, Roussou M, Pouli A, Michalis E, Delimpasi S et al. High serum lactate dehydrogenase adds prognostic value to the International Myeloma Staging System even in the era of novel agents. Eur J Haematol 2010; 85: 114–119.

    PubMed  Google Scholar 

  32. Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M . Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol 2010; 21: 325–330.

    Article  CAS  PubMed  Google Scholar 

  33. Wu P, Davies FE, Boyd K, Thomas K, Dines S, Saso RM et al. The impact of extramedullary disease at presentation on the outcome of myeloma. Leuk Lymphoma 2009; 50: 230–235.

    Article  CAS  PubMed  Google Scholar 

  34. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH et al. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Cancer 2006; 106: 1316–1319.

    Article  CAS  PubMed  Google Scholar 

  35. Harousseau JL, Dimopoulos MA, Wang M, Corso A, Chen C, Attal M et al. The quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma. Haematologica 2010 (in press).

  36. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer 2006; 106: 1316–1319.

    Article  CAS  PubMed  Google Scholar 

  37. Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004; 127: 165–172.

    Article  CAS  PubMed  Google Scholar 

  38. 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: 3458–3464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dimopoulos MA, Christoulas D, Roussou M, Kastritis E, Migkou M, Gavriatopoulou M et al. Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol 2010; 85: 1–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece

    M A Dimopoulos, E Kastritis, D Christoulas, M Migkou, M Gavriatopoulou, M Gkotzamanidou, M Iakovaki, C Matsouka, D Mparmparoussi, M Roussou, E Efstathiou & E Terpos

Authors
  1. M A Dimopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Kastritis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Christoulas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Migkou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Gavriatopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Gkotzamanidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Iakovaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Matsouka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Mparmparoussi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Roussou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E Efstathiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E Terpos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Dimopoulos.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

The paper was presented as an oral presentation at ASH 2009 Annual Meeting in New Orleans (abstract No 958).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dimopoulos, M., Kastritis, E., Christoulas, D. et al. Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies. Leukemia 24, 1769–1778 (2010). https://doi.org/10.1038/leu.2010.175

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.175

Keywords

Search

Advanced search

Quick links