Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: Impact of immune activation and cereblon targets

Blood

Volumn 125, Issue 26, 2015, Pages 4042-4051

  Sehgal, Kartik ^a   Das, Rituparna ^a   Zhang, Lin ^a   Verma, Rakesh ^a   Deng, Yanhong ^b   Kocoglu, Mehmet ^a   Vasquez, Juan ^a   Koduru, Srinivas ^a   Ren, Yan ^c   Wang, Maria ^c   Couto, Suzana ^c   Breider, Mike ^c   Hansel, Donna ^c   Seropian, Stuart ^a,d   Cooper, Dennis ^a,d   Thakurta, Anjan ^c   Yao, Xiaopan ^b,d   Dhodapkar, Kavita M ^a,d   Dhodapkar, Madhav V ^a,d  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b YALE UNIVERSITY   (United States)

^c CELGENE CORPORATION   (United States)

^d YALE CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; CEREBLON; DEXAMETHASONE; GRANULOCYTE COLONY STIMULATING FACTOR; IKAROS TRANSCRIPTION FACTOR; POMALIDOMIDE; UNCLASSIFIED DRUG; ANGIOGENESIS INHIBITOR; THALIDOMIDE;

ADULT; ARTICLE; CD8+ T LYMPHOCYTE; CLINICAL ARTICLE; CONTROLLED STUDY; EVENT FREE SURVIVAL; FEMALE; GENE EXPRESSION PROFILING; HUMAN; IMMUNOMODULATION; MALE; MIDDLE AGED; MULTIPLE MYELOMA; NATURAL KILLER CELL; OVERALL SURVIVAL; PHARMACODYNAMICS; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROTEIN TARGETING; RANDOMIZED CONTROLLED TRIAL; T LYMPHOCYTE ACTIVATION; TREATMENT RESPONSE; ANALOGS AND DERIVATIVES; CLINICAL TRIAL; IMMUNOHISTOCHEMISTRY; IMMUNOLOGY; KAPLAN MEIER METHOD; MORTALITY; T LYMPHOCYTE; TUMOR MICROENVIRONMENT; TUMOR RECURRENCE;

ANGIOGENESIS INHIBITORS; FEMALE; HUMANS; IMMUNOHISTOCHEMISTRY; KAPLAN-MEIER ESTIMATE; KILLER CELLS, NATURAL; MALE; MIDDLE AGED; MULTIPLE MYELOMA; NEOPLASM RECURRENCE, LOCAL; T-LYMPHOCYTES; THALIDOMIDE; TUMOR MICROENVIRONMENT;

EID: 84933567284     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2014-11-611426     Document Type: Article

References (47)

1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060.
2. Lacy MQ, McCurdy AR. Pomalidomide. Blood. 2013;122(14):2305-2309.
3. Richardson PG, Mark TM, Lacy MQ. Pomalidomide: new immunomodulatory agent with potent antiproliferative effects. Crit Rev Oncol Hematol. 2013;88(Suppl 1):S36-S44.
4. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with lowdose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826-1832.
5. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24(11):1934-1939.
6. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008-5014.
7. Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013;121(11):1961-1967.
8. Schey SA, Fields P, Bartlett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22(16):3269-3276.
9. Leleu X, Attal M, Arnulf B, et al; Intergroupe Francophone du Myélome. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomiderefractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02. Blood. 2013;121(11):1968-1975.
10. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118(11):2970-2975.
11. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055-1066.
12. Dimopoulos MA, Leleu X, Palumbo A, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573-1585.
13. Li S, Pal R, Monaghan SA, et al. IMiD immunomodulatory compounds block C/EBPbeta translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 2011;117(19):5157-5165.
14. Escoubet-Lozach L, Lin IL, Jensen-Pergakes K, et al. 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):7347-7356.
15. Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99(12):4525-4530.
16. Mitsiades CS, Chen-Kiang S. Immunomodulation as a therapeutic strategy in the treatment of multiple myeloma. Crit Rev Oncol Hematol. 2013;88(Suppl 1):S5-S13.
17. Görgün G, Calabrese E, Soydan E, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood. 2010;116(17):3227-3237.
18. Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26(11):2326-2335.
19. ®immunomodulatory compounds lenalidomide and pomalidomide. Immunology. 2013;139(3):377-385.
20. Galustian C, Meyer B, Labarthe MC, et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother. 2009;58(7):1033-1045.
21. Gandhi AK, Kang J, Havens CG, 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(6):811-821.
22. Schafer PH, Gandhi AK, Loveland MA, et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomiderelated immunomodulatory drugs. J Pharmacol Exp Ther. 2003;305(3):1222-1232.
23. Hsu AK, Quach H, Tai T, et al. The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood. 2011;117(5):1605-1613.
24. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345-1350.
25. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118(18):4771-4779.
26. Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblondependent destruction of Ikaros proteins. Science. 2014;343(6168):305-309.
27. Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301-305.
28. LeBlanc R, Hideshima T, Catley LP, et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood. 2004;103(5):1787-1790.
29. Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006;108(2):618-621.
30. Richter J, Neparidze N, Zhang L, et al. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood. 2013;121(3):423-430.
31. Zhu YX, Braggio E, Shi CX, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124(4):536-545.
32. Gandhi AK, Mendy D, Waldman M, 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(2):233-244.
33. Sehgal K, Guo X, Koduru S, et al. Plasmacytoid dendritic cells, interferon signaling, and FcgammaR contribute to pathogenesis and therapeutic response in childhood immune thrombocytopenia. Sci Transl Med. 2013;5(193):193ra189.
34. McCarty KS Jr, Szabo E, Flowers JL, et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res. 1986;46(8 Suppl):4244s-4248s.
35. Budwit-Novotny DA, McCarty KS, Cox EB, et al. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986;46(10):5419-5425.
36. Haslett PA, Hanekom WA, Muller G, Kaplan G. Thalidomide and a thalidomide analogue drug costimulate virus-specific CD81 T cells in vitro. J Infect Dis. 2003;187(6):946-955.
37. Constantinides MG, Bendelac A. Transcriptional regulation of the NKT cell lineage. Curr Opin Immunol. 2013;25(2):161-167.
38. Huang SY, Lin CW, Lin HH, et al. Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomideand lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma. Ann Hematol. 2014;93(8):1371-1380.
39. Heintel D, Rocci A, Ludwig H, 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(5):695-700.
40. Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24(1):22-32.
41. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19(5):1021-1034.
42. Dhodapkar MV, Sznol M, Zhao B, et al. Induction of antigen-specific immunity with a vaccine targeting NYESO-1 to the dendritic cell receptor DEC-205. Sci Transl Med. 2014;6(232):232ra251.
43. Das R, Verma R, Sznol M, et al. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015;194(3):950-959.
44. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.
45. Thomas RM, Chen C, Chunder N, et al. Ikaros silences T-bet expression and interferongamma production during T helper 2 differentiation. J Biol Chem. 2010;285(4):2545-2553.
46. Thomas RM, Chunder N, Chen C, Umetsu SE, Winandy S, Wells AD. Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD41 T lymphocytes. J Immunol. 2007;179(11):7305-7315.
47. Fischer ES, Böhm K, Lydeard JR, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512(7512):49-53.