International Journal of Hematology

, Volume 97, Issue 6, pp 743–748 | Cite as

Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma

  • Takeshi Harada
  • Shuji Ozaki
  • Asuka Oda
  • Shiro Fujii
  • Shingen Nakamura
  • Hirokazu Miki
  • Kumiko Kagawa
  • Kyoko Takeuchi
  • Toshio Matsumoto
  • Masahiro Abe
Rapid Communication

Abstract

Transient inflammatory reactions have been reported in a subpopulation of patients with multiple myeloma (MM) during lenalidomide (Len) plus dexamethasone (DEX) therapy. Here, we examined serum levels of Th1 (IL-2 and IFN-γ) and Th2 cytokines (IL-6 and TNF-α) in nine refractory or relapsed MM patients treated with Len plus low-dose DEX. Six patients showed elevation of C-reactive protein (CRP) after the initiation of therapy. In these patients, IFN-γ and IL-6 were also elevated in two and three patients, respectively. The remaining three patients showed no appreciable changes in CRP or these cytokines. Furthermore, Len enhanced the production of both Th1 and Th2 cytokines in normal peripheral blood mononuclear cells and in patient bone marrow mononuclear cells containing primary myeloma cells and lymphocytes. These results suggest that the modulation of the Th1 and Th2 cytokine production by Len may contribute to transient inflammatory reaction in MM patients.

Keywords

Multiple myeloma Lenalidomide Inflammatory reaction 

Notes

Acknowledgments

The authors thank Celgene Corporation for providing lenalidomide.

Conflict of interest

None.

Supplementary material

12185_2013_1321_MOESM1_ESM.jpg (79 kb)

Supplementary Figure 1. Cytokine production by intracellular flow cytometric assay. RPMI 8226 and normal PBMCs in the co-culture setting (A) or patient BMMCs (B) were stimulated by Len for 48 h. Then, intracellular cytokine production was determined by flow cytometry. Representative data are shown from three independent experiments. (JPG 78.6 kb)

References

  1. 1.
    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(21):2133–42.PubMedCrossRefGoogle Scholar
  2. 2.
    Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. 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. 2010;11(1):29–37.PubMedCrossRefGoogle Scholar
  3. 3.
    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(13):4050–3.PubMedCrossRefGoogle Scholar
  4. 4.
    Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, et al. 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. 2009;23(11):2147–52.PubMedCrossRefGoogle Scholar
  5. 5.
    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(21):2123–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24(1):22–32.PubMedCrossRefGoogle Scholar
  7. 7.
    Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009;2(36):36.PubMedCrossRefGoogle Scholar
  8. 8.
    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(1):380–6.PubMedGoogle Scholar
  9. 9.
    Ozaki S, Harada T, Fujii S, Nakamura S, Miki H, Nakano A, et al. Transient inflammatory reaction during lenalidomide plus reduced-dose dexamethasone therapy in two patients with relapsed multiple myeloma. Int J Hematol. 2011;93(2):257–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Morita Y, Shimada T, Yamaguchi T, Rai S, Hirase C, Emoto M, et al. Cytokine profiles in relapsed multiple myeloma patients undergoing febrile reactions to lenalidomide. Int J Hematol. 2011;94(6):583–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412–20.PubMedCrossRefGoogle Scholar
  13. 13.
    Picker LJ, Singh MK, Zdraveski Z, Treer JR, Waldrop SL, Bergstresser PR, et al. Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood. 1995;86(4):1408–19.PubMedGoogle Scholar
  14. 14.
    Openshaw P, Murphy EE, Hosken NA, Maino V, Davis K, Murphy K, et al. Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations. J Exp Med. 1995;182(5):1357–67.PubMedCrossRefGoogle Scholar
  15. 15.
    Pelliniemi TT, Irjala K, Mattila K, Pulkki K, Rajamaki A, Tienhaara A, et al. Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group. Blood. 1995;85(3):765–71.PubMedGoogle Scholar
  16. 16.
    Gandhi AK, Kang J, Capone L, Parton A, Wu L, Zhang LH, et al. Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr Cancer Drug Targets. 2010;10(2):155–67.PubMedCrossRefGoogle Scholar
  17. 17.
    Hsu AK, Quach H, Tai T, Prince HM, Harrison SJ, Trapani JA, et al. The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood. 2011;117(5):1605–13.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferrajoli A, Lee BN, Schlette EJ, O’Brien SM, Gao H, Wen S, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008;111(11):5291–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Chanan-Khan AA, Chitta K, Ersing N, Paulus A, Masood A, Sher T, et al. Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo evidence of immune activation and antitumour response. Br J Haematol. 2011;155(4):457–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Aue G, Njuguna N, Tian X, Soto S, Hughes T, Vire B, et al. Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia. Haematologica. 2009;94(9):1266–73.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2013

Authors and Affiliations

  • Takeshi Harada
    • 1
  • Shuji Ozaki
    • 1
    • 3
  • Asuka Oda
    • 1
  • Shiro Fujii
    • 1
  • Shingen Nakamura
    • 1
  • Hirokazu Miki
    • 1
    • 2
  • Kumiko Kagawa
    • 1
  • Kyoko Takeuchi
    • 1
  • Toshio Matsumoto
    • 1
  • Masahiro Abe
    • 1
  1. 1.Department of Medicine and Bioregulatory Sciences, Graduate School of Medical SciencesUniversity of TokushimaTokushimaJapan
  2. 2.Division of Transfusion MedicineTokushima University HospitalTokushimaJapan
  3. 3.Department of HematologyTokushima Prefectural Central HospitalTokushimaJapan

Personalised recommendations