Skip to main content

Advertisement

Log in

Future directions in immunomodulatory therapy

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The role of immunomodulatory-based therapy with thalidomide or lenalidomide is clearly established in the management of patients with myeloma in all phases of their disease. Recent preclinical and clinical works have demonstrated that in addition to combination therapy with dexamethasone, there is significant activity when combined with the proteasome inhibitor bortezomib. More recent clinical studies have also demonstrated significant activity when combined with akt inhibitors, HDAC inhibitors, and even monoclonal antibodies. Further clinical development of immunomodulatory agents should continue to be based on preclinical rationale, which has resulted in a number of promising and clinically active combinations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20.

    Article  CAS  PubMed  Google Scholar 

  2. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–98.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, et al. 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. 2007;25(25):3892–901.

    Article  CAS  PubMed  Google Scholar 

  6. Jagannath S, Richardson P, Zeldenrust SR, Alsina M, Wride K, Zeldis J, et al. Long-term responses observed with lenalidomide therapy for patients with relapsed or refractory multiple myeloma. Chicago: ASCO; 2008. p. 8525.

    Google Scholar 

  7. Hideshima T, Anderson KC. Preclinical studies of novel targeted therapies. Hematol Oncol Clin North Am. 2007;21(6):1071–91. viii–ix.

    Article  PubMed  Google Scholar 

  8. Hideshima T, Richardson PG, Anderson KC. Current therapeutic uses of lenalidomide in multiple myeloma. Expert Opin Investig Drugs. 2006;15(2):171–9.

    Article  CAS  PubMed  Google Scholar 

  9. Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC. Thalidomide and lenalidomide: mechanism-based potential drug combinations. Leuk Lymphoma. 2008;49(7):1238–45.

    Article  CAS  PubMed  Google Scholar 

  10. Kumar S, Hayman S, Buadi F, Lacy M, Stewart K, Allred J, et al. Phase II trial of lenalidomide (RevlimidTM) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. ASH Annu Meet Abstr. 2008;112(11):91.

    Google Scholar 

  11. Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA–Italian multiple myeloma network. J Clin Oncol. 2007;25(28):4459–65.

    Article  CAS  PubMed  Google Scholar 

  12. Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K, et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol. 2006;17(12):1766–71.

    Article  CAS  PubMed  Google Scholar 

  13. Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006;108(2):618–21.

    Article  CAS  PubMed  Google Scholar 

  14. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98(1):210–6.

    Article  CAS  PubMed  Google Scholar 

  15. Tai YT, Catley LP, Mitsiades CS, Burger R, Podar K, Shringpaure R, et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res. 2004;64(8):2846–52.

    Article  CAS  PubMed  Google Scholar 

  16. Tai YT, Li X, Tong X, Santos D, Otsuki T, Catley L, et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res. 2005;65(13):5898–906.

    Article  CAS  PubMed  Google Scholar 

  17. Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J, et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005;65(24):11712–20.

    Article  CAS  PubMed  Google Scholar 

  18. Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775–84.

    Article  CAS  PubMed  Google Scholar 

  19. Tai YT, Soydan E, Song W, Fulciniti M, Kim K, Hong F, et al. CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells. Blood. 2009;113(18):4309–18.

    Article  CAS  PubMed  Google Scholar 

  20. Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112(4):1329–37.

    Article  CAS  PubMed  Google Scholar 

  21. Lonial S, Singhal A, Jagannath S, Vij R. Phase 1b study of elotuzumab (HuLuc63) in combination with lenalidomide in relapsed multiple myeloma. XII International Myeloma Workshop. Washington DC, USA: CIG Medical Group; 2009. p. s20.

  22. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, Roth M, Vaughn M, Knight J, et al. 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.

    CAS  PubMed  Google Scholar 

  23. Chanan-Khan A, Porter CW. Immunomodulating drugs for chronic lymphocytic leukaemia. Lancet Oncol. 2006;7(6):480–8.

    Article  CAS  PubMed  Google Scholar 

  24. Coluccia AM, Cirulli T, Neri P, Mangieri D, Colanardi MC, Gnoni A, et al. Validation of PDGFRbeta and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib. Blood. 2008;112(4):1346–56.

    Article  CAS  PubMed  Google Scholar 

  25. Wildes TM, Procknow E, Gao F, Dipersio JF, Vij R. Dasatinib in relapsed or plateau-phase multiple myeloma. Leuk Lymphoma. 2009;50(1):137–40.

    Article  CAS  PubMed  Google Scholar 

  26. Deng Q, Mitsiades N, Negri J, Wen Z, Rooney M, Hideshima T, et al. Dasatinib (BMS-354825): a multi-targeted kinase inhibitor with activity against multiple myeloma. ASH Annu Meet Abstr. 2005;106(11):1571.

    Google Scholar 

  27. Harvey RD, Lonial S. PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. Future Oncol. 2007;3(6):639–47.

    Article  CAS  PubMed  Google Scholar 

  28. Richardson P, Lonial S, Jakubowiak A, Krishnan A, Wolf J, Densmore J, et al. Multi-center phase II study of perifosine (KRX-0401) alone and in combination with dexamethasone (dex) for patients with relapsed or relapsed/refractory multiple myeloma (MM): promising activity as combination therapy with manageable toxicity. ASH Annu Meet Abstr. 2007;110(11):1164.

    Google Scholar 

  29. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107(10):4053–62.

    Article  CAS  PubMed  Google Scholar 

  30. Richardson P, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D, et al. Phase I/II of a multicenter trial of perifosine (KRX-0401) + bortezomib in relapsed or relapsed/refractory multiple myeloma patients previously relapsed from or refractory to bortezomib. International Myeloma Workshop. Washington, DC: CIG; 2009.

  31. Jakubowiak A, Richardson P, Zimmerman T, Alsina M, Kaufman J, Brozo C, et al. Multiple myeloma research consortium (MMRC) multicenter phase I results of perifosine (KRX-0401) in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). International Myeloma Workshop. Washington, DC: CIG; 2009.

  32. Lindemann RK, Gabrielli B, Johnstone RW. Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle. 2004;3(6):779–88.

    CAS  PubMed  Google Scholar 

  33. Kelly WK, Marks PA. Drug insight: histone deacetylase inhibitors—development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol. 2005;2(3):150–7.

    Article  CAS  PubMed  Google Scholar 

  34. Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006;108(10):3441–9.

    Article  CAS  PubMed  Google Scholar 

  35. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102(24):8567–72.

    Article  CAS  PubMed  Google Scholar 

  36. Nawrocki ST, Carew JS, Maclean KH, Courage JF, Huang P, Houghton JA, et al. Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. Blood. 2008;112(7):2917–26.

    Article  CAS  PubMed  Google Scholar 

  37. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101(2):540–5.

    Article  CAS  PubMed  Google Scholar 

  38. Siegel D, Weber D, Mitsiades CS, Rizvi S, Garcia-Vargas J, Howe J, et al. A phase I study of vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. ASH Annu Meet Abstr. 2008;112(11):3705.

    Google Scholar 

  39. Spencer A, Taylor K, Lonial S, Mateos M, Jalaluddin M, Hazell K, et al. Panoninostat plus lenalidomide and dexamethasone phase I trial in multiple myeloma (MM). Orlando, FL, USA: ASCO; 2009. p. 444s.

  40. Pineda-Roman M, Zangari M, van Rhee F, Anaissie E, Szymonifka J, Hoering A, et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia. 2008;22(7):1419–27.

    Article  CAS  PubMed  Google Scholar 

  41. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Ceccolini M, et al. Superior complete response rate and progression-free survival after autologous transplantation with up-front velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. ASH Annu Meet Abstr. 2008;112(11):158.

    Google Scholar 

  42. Richardson P, Jagannath S, Jakubowiak A, Lonial S, Raje N, Alsina M, et al. Lenalidomide, bortezomib, and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (MM): encouraging response rates and tolerability with correlation of outcome and adverse cytogenetics in a phase II study. ASH Annu Meet Abstr. 2008;112(11):1742.

    Google Scholar 

  43. Richardson P, Lonial S, Jakubowiak A, Jagannath S, Raje NS, Avigan D, et al. Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: encouraging efficacy in high risk groups with updated results of a phase I/II study. ASH Annu Meet Abstr. 2008;112(11):92.

    Google Scholar 

  44. Jagannath S, Vij R, Stewart AK, Somlo G, Jakubowiak A, Reiman T, et al. Initial results of PX-171–003, an open-label, single-arm, phase II studyof carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). ASH Annu Meet Abstr. 2008;112(11):864.

    Google Scholar 

  45. Vij R, Wang M, Orlowski R, Stewart AK, Jagannath S, Kukreti V, et al. Initial results of PX-171–004, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed myeloma (MM). ASH Annu Meet Abstr. 2008;112(11):865.

    Google Scholar 

  46. Streetly MJ, Gyertson K, Daniel Y, Zeldis JB, Kazmi M, Schey SA. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br J Haematol. 2008;141(1):41–51.

    Article  CAS  PubMed  Google Scholar 

  47. Schey SA, Fields P, Bartlett JB, Clarke IA, Ashan G, Knight RD, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22(16):3269–76.

    Article  CAS  PubMed  Google Scholar 

  48. Lacy MQ, Hayman SR, Gertz MA, Allred JB, Mandrekar SJ, Dispenzieri A, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. ASH Annu Meet Abstr. 2008;112(11):866.

    Google Scholar 

Download references

Acknowledgments

The author has received an honorarium for their participation in this supplement.

Conflict of interest statement

Dr Lonial is a consultant for Millennium, Celgene, Novartis, and BMS, and has received research support from Millennium.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sagar Lonial.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lonial, S. Future directions in immunomodulatory therapy. Med Oncol 27 (Suppl 1), 62–66 (2010). https://doi.org/10.1007/s12032-009-9376-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-009-9376-8

Keywords

Navigation