IMiD: Immunomodulatory Drug Lenalidomide (CC-5013; Revlimid) in the Treatment of Lymphoma: Insights into Clinical Use and Molecular Mechanisms

  • Pashtoon Murtaza Kasi
  • Grzegorsz S. Nowakowski
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 17)


Immune modulation has been a focus of increasing interest particularly for patients with lymphoma through the new class of ‘immunomodulatory drugs’ called IMiDs. Lenalidomide is an oral thalidomide analogue drug that belongs to the second generation of IMiDs. The proposed mechanisms of action of lenalidomide and the IMiD class of drugs go beyond just traditional cytotoxicity. With further descriptions comes more knowledge of predictive markers as well as molecular mechanisms of resistance. These still are evolving areas of research. Furthermore, mechanisms of resistance to IMiDs and ways to overcome may be different in different tumor types. The goal of this chapter is to focus on the early descriptions and usage of the drug, and to the more recent understandings of mechanisms of resistance. The main focus is on lymphoma, particularly diffuse large B-cell lymphoma. Knowledge and molecular insights gained pertaining to potential methods of overcoming these methods of resistance from other tumor types are also presented.


Lenalidomide IMiD Lymphoma Immunomodulatory Revlimid DLBCL GCB Non-GCB Non-Hodgkin’s Lymphoma 



Activated B-cell subtype


Antibody-dependent cellular cytotoxicity


Cell of Origin


Common terminology criteria for adverse events


Circulating tumor DNA


Diffuse Large B-Cell Lymphoma


Germinal center B-cell-like type


Immunomodulatory Drug


Monoclonal antibodies


Non-Hodgkin’s Lymphoma


Non-germinal B-cell-like type


Combination chemoimmunotherapy regimen R-ICE with the addition of lenalidomide (Revlimid)


Combination chemoimmunotherapy regimen consisting of rituximab, ifosfamide, carboplatin and etoposide


Conflict of Interest

The authors declare no conflicts of interest.


  1. 1.
    Gibson AD, Klem J, Price N, Reddy GK. 45th annual meeting of the American Society of Hematology December 6–9, 2003. Clin Lymphoma. 2004;4(4):206–12.CrossRefPubMedGoogle Scholar
  2. 2.
    Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD, Multiple Myeloma Study I. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133–42.CrossRefPubMedGoogle Scholar
  3. 3.
    Knop S, Einsele H, Bargou R, Cosgrove D, List A. Adjusted dose lenalidomide is safe and effective in patients with deletion (5q) myelodysplastic syndrome and severe renal impairment. Leuk Lymphoma. 2008;49(2):346–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005;11(16):5984–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhu D, Corral LG, Fleming YW, Stein B. Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother. 2008;57(12):1849–59.CrossRefPubMedGoogle Scholar
  6. 6.
    Crane E, List A. Immunomodulatory drugs. Cancer Investig. 2005;23(7):625–34.CrossRefGoogle Scholar
  7. 7.
    Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, Roth M, Vaughn M, Knight J, Wallace P, Czuczman MS. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol. 2008;140(1):36–45.PubMedGoogle Scholar
  8. 8.
    Martinez-Høyer S, Docking R, Chan S, Jadersten M, Parker J, Karsan A. Mechanisms of resistance to Lenalidomide in Del (5q) myelodysplastic syndrome patients. Blood. 2015;126(23):5228–5228.Google Scholar
  9. 9.
    Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, Schafer P, Bartlett JB. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res. 2008;14(14):4650–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Martin MG, Vij R. Arterial thrombosis with immunomodulatory derivatives in the treatment of multiple myeloma: a single-center case series and review of the literature. Clin Lymphoma Myeloma. 2009;9(4):320–3.CrossRefPubMedGoogle Scholar
  11. 11.
    Niesvizky R, Martinez-Banos D, Jalbrzikowski J, Christos P, Furst J, De Sancho M, Mark T, Pearse R, Mazumdar M, Zafar F, Pekle K, Leonard J, Jayabalan D, Coleman M. Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma. Leuk Lymphoma. 2007;48(12):2330–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, Lam W, McBride K, Wride K, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Habermann TM. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(30):4952–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Habermann TM, Lossos IS, Justice G, Vose JM, Wiernik PH, McBride K, Wride K, Ervin-Haynes A, Takeshita K, Pietronigro D, Zeldis JB, Tuscano JM. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol. 2009;145(3):344–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Dueck G, Chua N, Prasad A, Finch D, Stewart D, White D, van der Jagt R, Johnston J, Belch A, Reiman T. Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma. Cancer. 2010;116(19):4541–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Escoubet-Lozach L, Lin IL, Jensen-Pergakes K, Brady HA, Gandhi AK, Schafer PH, Muller GW, Worland PJ, Chan KW, Verhelle D. Pomalidomide and lenalidomide induce p21 WAF-1 expression in both lymphoma and multiple myeloma through a LSD1-mediated epigenetic mechanism. Cancer Res. 2009;69(18):7347–56.CrossRefPubMedGoogle Scholar
  16. 16.
    Qian Z, Zhang L, Cai Z, Sun L, Wang H, Yi Q, Wang M. Lenalidomide synergizes with dexamethasone to induce growth arrest and apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leuk Res. 2011;35(3):380–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Klebig RR, Reeder CB, Witzig TE. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia. 2011;25(12):1877–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27(32):5404–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes AL, Czuczman MS. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol. 2011;22(7):1622–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Zinzani PL, Pellegrini C, Gandolfi L, Stefoni V, Quirini F, Derenzini E, Broccoli A, Argnani L, Pileri S, Baccarani M. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk. 2011;11(6):462–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA, Fenske TS, Hurd DD, Goy A, Schneider SE, Keppel CR, Wagner-Johnston ND, Carson KR, Bartlett NL. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011;118(19):5119–25.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, Goy A, Witzig TE, Czuczman MS. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117(22):5058–66.CrossRefPubMedGoogle Scholar
  23. 23.
    Czuczman MS, Vose JM, Witzig TE, Zinzani PL, Buckstein R, Polikoff J, Li J, Pietronigro D, Ervin-Haynes A, Reeder CB. The differential effect of lenalidomide monotherapy in patients with relapsed or refractory transformed non-Hodgkin lymphoma of distinct histological origin. Br J Haematol. 2011;154(4):477–81.CrossRefPubMedGoogle Scholar
  24. 24.
    Yang Y, Shaffer AL 3rd, Emre NC, Ceribelli M, Zhang M, Wright G, Xiao W, Powell J, Platig J, Kohlhammer H, Young RM, Zhao H, Yang Y, Xu W, Buggy JJ, Balasubramanian S, Mathews LA, Shinn P, Guha R, Ferrer M, Thomas C, Waldmann TA, Staudt LM. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723–37.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Amatangelo MD, Neri P, Ortiz M, Bjorklund CC, Gandhi AK, Klippel A, Bahlis NJ, Daniel T, Chopra R, Trotter M, Thakurta A. Resistance to Lenalidomide in multiple myeloma is associated with a switch in gene expression profile. Blood. 2015;126(23):1789–1789.Google Scholar
  26. 26.
    Bjorklund CC, Ma W, Wang ZQ, Davis RE, Kuhn DJ, Kornblau SM, Wang M, Shah JJ, Orlowski RZ. Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. J Biol Chem. 2011;286(13):11009–20.CrossRefPubMedGoogle Scholar
  27. 27.
    Ocio EM, Fernández-Lázaro D, San-Segundo L, Lopez-Corral L, Corchete LA, Gutiérrez NC, Garayoa M, Paíno T, García-Gómez A, Delgado M. In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone. Leukemia. 2015;29(3):705–14.CrossRefPubMedGoogle Scholar
  28. 28.
    Zaman S, Stellrecht CM, Orlowski RZ, Gandhi V. Abstract 1710: Bortezomib and lenalidomide resistant myeloma cells overexpress the hepatocyte growth factor/MET signaling axis and respond to MET kinase inhibitors. Cancer Res. 2014;74(19 Supplement):1710.CrossRefGoogle Scholar
  29. 29.
    Ghosh N, Tucker N, Zahurak M, Wozney J, Borrello I, Huff CA. Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma. Am J Hematol. 2014;89(8):E116–20.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Turturro F. Constitutive NF-κB activation underlines major mechanism of drug resistance in relapsed refractory diffuse large B cell lymphoma. Biomed Res Int. 2015;2015:5.CrossRefGoogle Scholar
  31. 31.
    Chanan-Khan AA, Swaika A, Paulus A, Kumar SK, Mikhael JR, Rajkumar SV, Dispenzieri A, Lacy MQ. Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma. Blood Cancer J. 2013;3:e143.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Verhelle D, Corral LG, Wong K, Mueller JH, Moutouh-de Parseval L, Jensen-Pergakes K, Schafer PH, Chen R, Glezer E, Ferguson GD, Lopez-Girona A, Muller GW, Brady HA, Chan KW. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res. 2007;67(2):746–55.CrossRefPubMedGoogle Scholar
  33. 33.
    Tempescul A, Ianotto JC, Morel F, Marion V, De Braekeleer M, Berthou C. Lenalidomide, as a single agent, induces complete remission in a refractory mantle cell lymphoma. Ann Hematol. 2009;88(9):921–2.CrossRefPubMedGoogle Scholar
  34. 34.
    Ramsay AG, Clear AJ, Kelly G, Fatah R, Matthews J, Macdougall F, Lister TA, Lee AM, Calaminici M, Gribben JG. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21):4713–20.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Blum W, Klisovic RB, Becker H, Yang X, Rozewski DM, Phelps MA, Garzon R, Walker A, Chandler JC, Whitman SP, Curfman J, Liu S, Schaaf L, Mickle J, Kefauver C, Devine SM, Grever MR, Marcucci G, Byrd JC. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J Clin Oncol. 2010;28(33):4919–25.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, Samaniego F, McLaughlin P, Fanale M, Younes A, Cabanillas F, Fowler N, Newberry KJ, Sun L, Young KH, Champlin R, Kwak L, Feng L, Badillo M, Bejarano M, Hartig K, Chen W, Chen Y, Byrne C, Bell N, Zeldis J, Romaguera J. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012;13(7):716–23.CrossRefPubMedGoogle Scholar
  37. 37.
    Boultwood J, Pellagatti A, McKenzie AN, Wainscoat JS. Advances in the 5q- syndrome. Blood. 2010;116(26):5803–11.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Pashtoon Murtaza Kasi
    • 1
  • Grzegorsz S. Nowakowski
    • 2
  1. 1.Division of OncologyCollege of Medicine and Oncology, Mayo ClinicJacksonvilleUSA
  2. 2.Division of HematologyMayo ClinicRochesterUSA

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