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Multiple Myeloma, Gammopathies

IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)


Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2–Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.

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  1. 1

    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.

    CAS  Article  Google Scholar 

  2. 2

    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.

    CAS  Article  Google Scholar 

  3. 3

    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.

    CAS  Article  Google Scholar 

  4. 4

    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.

    CAS  Article  Google Scholar 

  5. 5

    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.

    CAS  Article  Google Scholar 

  6. 6

    Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014; 371: 906–917.

    CAS  Article  Google Scholar 

  7. 7

    Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol 2014; 32: 2712–2717.

    CAS  Article  Google Scholar 

  8. 8

    Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1782–1791.

    CAS  Article  Google Scholar 

  9. 9

    McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1770–1781.

    CAS  Article  Google Scholar 

  10. 10

    Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012; 366: 1759–1769.

    CAS  Article  Google Scholar 

  11. 11

    Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y et al. Identification of a primary target of thalidomide teratogenicity. Science 2010; 327: 1345–1350.

    CAS  Article  Google Scholar 

  12. 12

    Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014; 343: 301–305.

    Article  Google Scholar 

  13. 13

    Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014; 343: 305–309.

    CAS  Article  Google Scholar 

  14. 14

    Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol 2014; 164: 811–821.

    CAS  Article  Google Scholar 

  15. 15

    Zhu YX, Braggio E, Shi CX, Kortuem KM, Bruins LA, Schmidt JE et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood 2014; 124: 536–545.

    CAS  Article  Google Scholar 

  16. 16

    Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012; 26: 2326–2335.

    CAS  Article  Google Scholar 

  17. 17

    Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011; 118: 4771–4779.

    CAS  Article  Google Scholar 

  18. 18

    Broyl A, Kuiper R, van Duin M, van der Holt B, el Jarari L, Bertsch U et al. High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. Blood 2013; 121: 624–627.

    CAS  Article  Google Scholar 

  19. 19

    Heintel D, Rocci A, Ludwig H, Bolomsky A, Caltagirone S, Schreder M et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol 2013; 161: 695–700.

    CAS  Article  Google Scholar 

  20. 20

    Schuster SR, Kortuem KM, Zhu YX, Braggio E, Shi CX, Bruins LA et al. The clinical significance of cereblon expression in multiple myeloma. Leuk Res 2014; 38: 23–28.

    CAS  Article  Google Scholar 

  21. 21

    Eichner R, Heider M, Fernandez-Saiz V, van Bebber F, Garz AK, Lemeer S et al. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat Med 2016; 22: 735–743.

    CAS  Article  Google Scholar 

  22. 22

    Ross FM, Avet-Loiseau H, Ameye G, Gutierrez NC, Liebisch P, O'Connor S et al. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica 2012; 97: 1272–1277.

    Article  Google Scholar 

  23. 23

    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.

    CAS  Article  Google Scholar 

  24. 24

    Sehgal K, Das R, Zhang L, Verma R, Deng Y, Kocoglu M et al. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets. Blood 2015; 125: 4042–4051.

    CAS  Article  Google Scholar 

  25. 25

    Gandhi AK, Mendy D, Waldman M, Chen G, Rychak E, Miller K et al. Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity. Br J Haematol 2014; 164: 233–244.

    CAS  Article  Google Scholar 

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This work was funded by the Deutsche Forschungsgemeinschaft (DFG; Emmy-Noether program Kr3886/2-1 to JK, KFO-216 to CL, RB, HE and LB). FK was supported in part by the Deutsche Krebshilfe (grant 109420, Max-Eder program). FB was supported by the European Research Commission (project BCM-UPS), the Deutsche Forschungsgemeinschaft (SFB 1243) and the Wilhelm Sander Stiftung (#2012.096.1). LB was supported in part by the Deutsche Forschungsgemeinschaft (Heisenberg-Professur BU 1339/8-1).

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Correspondence to J Krönke or C Langer.

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Competing interests

Celgene cooperation provided lenalidomide as study medication used in this trial. JK received honoraria from Celgene. SK received honoraria from Celgene, Amgen, Bristol-Myers Squibb, Janssen, Onyx. CL received honoraria from Celgene, Amgen, Bristol-Myers Squibb, Janssen, Novartis, Takeda Oncology.

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Krönke, J., Kuchenbauer, F., Kull, M. et al. IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM). Leukemia 31, 1363–1367 (2017).

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