ELOTUZUMAB FOR THE TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA, WITH SPECIAL REFERENCE TO ITS MODES OF ACTION AND SLAMF7 SIGNALING
Main Article Content
Keywords
Elotuzumab, multiple myeloma, SLAMF7, SLAM-associated protein (SAP), EAT-2
Abstract
Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone (ELd) for relapsed/refractory multiple myeloma (MM) based on the findings of the phase III randomized trial ELOQUENT-2 (NCT01239797). Four-year follow-up analyses of ELOQUENT-2 have demonstrated that progression-free survival was 21% in ELd versus 14% in Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of action: natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and enhancement of NK cell activity. The ADCC is mediated through engagement between Fc portion of elotuzumab and FcgRIIIa/CD16 on NK cells. Enhanced NK cell cytotoxicity results fromm phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) that is induced via elotuzumab binding and recruits the SLAM-associated adaptor protein EAT-2.The coupling of EAT-2 to the phospholipase Cg enzymes SH2 domain leads to enhanced Ca2+. Influx and MAPK/Erk pathway activation, resulting in granule polarization and enhanced exocytosis inNK cells. Elotuzumab does not stimulate the proliferation of MM cells due to a lack of EAT-2.The inhibitory effects of elotuzumab on MM cell growth are not induced by the lack of CD45, even though SHP-2, SHP-1, SHIP-1, and Csk may be recruited to phosphorylated ITSM of SLAMF7. ELd improves PFS in patients with high-risk cytogenetics, i.e. t(4;14), del(17p), and 1q21 gain/amplification. Since the immune state is paralytic in advanced MM, the efficacy of ELd with minimal toxicity may bring forward for consideration of its use in the early stages of the disease.
Downloads
Abstract 4467
PDF Downloads 1408
HTML Downloads 1076
References
2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49:1374-403. doi: 10.1016/j.ejca.2012.12.027 https://www.ncbi.nlm.nih.gov/pubmed/23485231
3. Center for Cancer Control and Information Service, National Cancer Center, Japan. 25 December 2017?https://ganjoho.jp/reg_stat/statistics/stat/summary.html
4. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-20 https://www.ncbi.nlm.nih.gov/pubmed/17975015
5. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, Kapoor P, Dingli D, Hayman SR, Leung N, Lust J, McCurdy A, Russell SJ, Zeldenrust SR, Kyle RA, Rajkumar SV. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122-28?https://www.ncbi.nlm.nih.gov/pubmed/24157580
6. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-17?https://www.ncbi.nlm.nih.gov/pubmed/25184863
7. Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca A, Hardan I, Nagler A, Petrucci MT, Hajek R, Pezzatti S, Delforge M, Patriarca F, Donato F, Cerrato C, Nozzoli C, Yu Z, Boccadifuoco L, Caravita T, Benevolo G, Guglielmelli T, Vincelli D, Jacques C, Dimopoulos MA, Ciccone G, Musto P, Corradini P, Cavo M, Boccadoro M. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol. 2015;33:3459-66. https://www.ncbi.nlm.nih.gov/pubmed/26282661
8. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab Therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-31 https://www.ncbi.nlm.nih.gov/pubmed/26035255
9. Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-66 https://www.ncbi.nlm.nih.gov/pubmed/27557302
10. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-31??https://www.ncbi.nlm.nih.gov/pubmed/27705267
11. Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, Weiss BM, Krishnan A, Lentzsch S, Comenzo R, Wang J, Nottage K, Chiu C, Khokhar NZ, Ahmadi T, Lonial S. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974-81??https://www.ncbi.nlm.nih.gov/pubmed/28637662
12. Badros A, Hyjek E, Ma N, Lesokhin A, Dogan A, Rapoport AP, Kocoglu M, Lederer E, Philip S, Milliron T, Dell C, Goloubeva O, Singh Z. Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;130:1189-97???https://www.ncbi.nlm.nih.gov/pubmed/28461396
13. Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y, Rice AG, van Abbema A, Wong M, Liu G, Zhan F, Dillon M, Chen S, Rhodes S, Fuh F, Tsurushita N, Kumar S, Vexler V, Shaughnessy JD Jr, Barlogie B, van Rhee F, Hussein M, Afar DE, Williams MB. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14:2775-84 https://www.ncbi.nlm.nih.gov/pubmed/18451245
14. Tai Y-T, Dillon M, Song W, Leiba M, Li XF, Burger P, Lee AI, Podar K, Hideshima T, Rice AG, van Abbema A, Jesaitis L, Caras I, Law D, Weller E, Xie W, Richardson P, Munshi NC, Mathiot C, Avet-Loiseau H, Afar DE, Anderson KC. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112:1329-37?https://www.ncbi.nlm.nih.gov/pubmed/17906076
15. Iida S, Tobinai K, Taniwaki M, Shumiya Y, Nakamura T, Chou T. Phase I dose escalation study of high dose carfilzomib monotherapy for Japanese patients with relapsed or refractory multiple myeloma. Int J Hematol. 2016;104:596-604 https://www.ncbi.nlm.nih.gov/pubmed/27460677
16. Suzuki K, Sunami K, Ohashi K, Iida S, Mori T, Handa H, Matsue K, Miyoshi M, Bleickardt E, Matsumoto M, Taniwaki M. Randomized phase 3 study of elotuzumab for relapsed or refractory multiple myeloma: ELOQUENT-2 Japanese patient subanalysis. Blood Cancer J. 2017;7(3):e540. https://www.ncbi.nlm.nih.gov/pubmed/28282035
17. Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017;178:896-905 https://www.ncbi.nlm.nih.gov/pubmed/28677826
18. Zonder JA, Mohrbacher AF, Singhal S, van Rhee F, Bensinger WI, Ding H, Fry J, Afar DE, Singhal AK. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120:552-9 https://www.ncbi.nlm.nih.gov/pubmed/22184404
19. Jakubowiak AJ, Benson DM, Bensinger W, Siegel DS, Zimmerman TM, Mohrbacher A, Richardson PG, Afar DE, Singhal AK, Anderson KC. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2012;30:1960-5 https://www.ncbi.nlm.nih.gov/pubmed/22291084
20. Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30:1953-9?https://www.ncbi.nlm.nih.gov/pubmed/22547589
21. Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015;2(12):e516–e27.? https://www.ncbi.nlm.nih.gov/pubmed/26686406
22. Berenson J, Manges R, Badarinath S, Cartmell A, McIntyre K, Lyons R, Harb W, Mohamed H, Nourbakhsh A, Rifkin R. A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma. Am J Hematol. 2017;92:460-6?https://www.ncbi.nlm.nih.gov/pubmed/28213943
23. Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127:2833-40 https://www.ncbi.nlm.nih.gov/pubmed/27091875
24. Mateos MV, Granell M, Oriol A, Martinez-Lopez J, Blade J, Hernandez MT, Martín J, Gironella M, Lynch M, Bleickardt E, Paliwal P, Singhal A, San-Miguel J. Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma. Br J Haematol. 2016;175:448-56 https://www.ncbi.nlm.nih.gov/pubmed/27434748
25. Boles KS, Mathew PA. Molecular cloning of CS1, a novel human natural killer cell receptor belonging to the CD2 subset of the immunoglobulin superfamily. Immunogenetics. 2001;52:302-7??https://www.ncbi.nlm.nih.gov/pubmed/11220635
26. Lee JK, Mathew SO, Vaidya SV, Kumaresan PR, Mathew PA. CS1 (CRACC, CD319) induces proliferation and autocrine cytokine expression on human B lymphocytes. J Immunol. 2007;179:4672-8??https://www.ncbi.nlm.nih.gov/pubmed/17878365
27. Cannons JL, Tangye SG, Schwartzberg PL. SLAM family receptors and SAP adaptors in immunity. Annu Rev Immunol. 2011;29:665-705 https://www.ncbi.nlm.nih.gov/pubmed/21219180
28. Boles KS, Stepp SE, Bennett M, Kumar V, Mathew PA. 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol Rev. 2001;181:234-49 https://www.ncbi.nlm.nih.gov/pubmed/11513145
29. Schwartzberg PL, Mueller KL, Qi H, Cannons JL. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol. 2009;9:39-46 https://www.ncbi.nlm.nih.gov/pubmed/19079134
30. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol Hematol. 2013;88:168-7 https://www.ncbi.nlm.nih.gov/pubmed/23731618
31. Veillette A. SLAM-family receptors: immune regulators with or without SAP-family adaptors. Cold Spring Harb Perspect Biol. 2010;2(3):a002469. doi: 10.1101/cshperspect.a002469. https://www.ncbi.nlm.nih.gov/pubmed/20300214
32. Martin M, Romero X, de la Fuente MA, Tovar V, Zapater N, Esplugues E, Pizcueta P, Bosch J, Engel P. CD84 functions as a homophilic adhesion molecule and enhances IFN-gamma secretion: adhesion is mediated by Ig-like domain 1. J Immunol. 2001;167:3668-76 https://www.ncbi.nlm.nih.gov/pubmed/11564780
33. Bouchon A, Cella M, Grierson HL, Cohen JI, Colonna M. Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J Immunol. 2001;167:5517-21 https://www.ncbi.nlm.nih.gov/pubmed/11698418
34. Detre C, Keszei M, Romero X, Tsokos GC, Terhorst C. SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions. Semin Immunopathol. 2010;32:157-71 https://www.ncbi.nlm.nih.gov/pubmed/20146065
35. Cruz-Munoz ME, Dong Z, Shi X, Zhang S, Veillette A. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol. 2009;10:297-305 https://www.ncbi.nlm.nih.gov/pubmed/19151721
36. Wilson TJ, Garner LI, Metcalfe C, King E, Margraf S, Brown MH: Fine specificity and molecular competition in SLAM family receptor signaling. PLoS One. 2014;9:e92184. eCollection 2014 https://www.ncbi.nlm.nih.gov/pubmed/24642916
37. Chen J, Zhong MC, Guo H, Davidson D, Mishel S, Lu Y, Rhee I, Pérez-Quintero LA, Zhang S, Cruz-Munoz ME, Wu N, Vinh DC, Sinha M, Calderon V, Lowell CA, Danska JS, Veillette A. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature. 2017;544:493-7 https://www.ncbi.nlm.nih.gov/pubmed/28424516
38. Al-Alem U, Li C, Forey N, Relouzat F, Fondanèche MC, Tavtigian SV, Wang ZQ, Latour S, Yin L. Impaired Ig class switch in mice deficient for the X-linked lymphoproliferative disease gene Sap. Blood. 2005;106:2069-75?https://www.ncbi.nlm.nih.gov/pubmed/15941917
39. Kis LL, Nagy N, Klein G, Klein E. Expression of SH2D1A in five classical Hodgkin’s disease-derived cell lines. Int J Cancer. 2003;104:658-61 https://www.ncbi.nlm.nih.gov/pubmed/12594824
40. Roncador G, García Verdes-Montenegro JF, Tedoldi S, Paterson JC, Klapper W, Ballabio E, Maestre L, Pileri S, Hansmann ML, Piris MA, Mason DY, Marafioti T. Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica. 2007;92:1059-66 https://www.ncbi.nlm.nih.gov/pubmed/17640856
41. Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, Gullo C, Howie D, Rietdijk S, Thompson A, Coyle AJ, Denny C, Yaffe MB, Engel P, Eck MJ, Terhorst C. Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. EMBO J. 2001;20:5840-52?https://www.ncbi.nlm.nih.gov/pubmed/11689425
42. Calpe S, Erdos E, Liao G, Wang N, Rietdijk S, Simarro M, Scholtz B, Mooney J, Lee CH, Shin MS, Rajnavölgyi E, Schatzle J, Morse HC 3rd, Terhorst C, Lanyi A. Identification and characterization of two related murine genes, Eat2a and Eat2b, encoding single SH2-domain adapters. Immunogenetics. 2006;58:15-25?https://www.ncbi.nlm.nih.gov/pubmed/16425036
43. Chan B, Lanyi A, Song HK, Griesbach J, Simarro-Grande M, Poy F, Howie D, Sumegi J, Terhorst C, Eck MJ. SAP couples Fyn to SLAM immune receptors. Nat Cell Biol. 2003;5:155-60?https://www.ncbi.nlm.nih.gov/pubmed/12545174
44. Pérez-Quintero LA, Roncagalli R, Guo H, Latour S, Davidson D, Veillette A. EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase C?, Ca++, and Erk, leading to granule polarization. J Exp Med. 2014;211:727-42 https://www.ncbi.nlm.nih.gov/pubmed/24687958
45. Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, Cahn AP, Durham J, Heath P, Wray P, Pavitt R, Wilkinson J, Leversha M, Huckle E, Shaw-Smith CJ, Dunham A, Rhodes S, Schuster V, Porta G, Yin L, Serafini P, Sylla B, Zollo M, Franco B, Bolino A, Seri M, Lanyi A, Davis JR, Webster D, Harris A, Lenoir G, de St Basile G, Jones A, Behloradsky BH, Achatz H, Murken J, Fassler R, Sumegi J, Romeo G, Vaudin M, Ross MT, Meindl A, Bentley DR. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. 1998;20:129-35?https://www.ncbi.nlm.nih.gov/pubmed/9771704
46. Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, van Schaik S, Notarangelo L, Geha R, Roncarolo MG, Oettgen H, De Vries JE, Aversa G, Terhorst C. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature. 1998;395:462-9??https://www.ncbi.nlm.nih.gov/pubmed/9774102
47. Wu C, Sayos J, Wang N, Howie D, Coyle A, Terhorst C. Genomic organization and characterization of mouse SAP, the gene that is altered in X-linked lymphoproliferative disease. Immunogenetics. 2000;51:805-15??https://www.ncbi.nlm.nih.gov/pubmed/10970095
48. Calpe S, Wang N, Romero X, Berger SB, Lanyi A, Engel P, Terhorst C. The SLAM and SAP gene families control innate and adaptive immune responses. Adv Immunol. 2008;97:177-250??https://www.ncbi.nlm.nih.gov/pubmed/18501771
49. Nelson DL, Terhorst C. X–linked lymphoproliferative syndrome. Clin Exp Immunol. 2000;122:291-5 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905809/
50. Veillette A. NK cell regulation by SLAM family receptors and SAP-related adapters. Immunol Rev. 2006;214:22-34 https://www.ncbi.nlm.nih.gov/pubmed/17100873
51. Mattoo H, Mahajan VS, Maehara T, Deshpande V, Della-Torre E, Wallace ZS, Kulikova M, Drijvers JM, Daccache J, Carruthers MN, Castelino FV, Stone JR, Stone JH, Pillai S. Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease. J Allergy Clin Immunol. 2016;138:825-38 https://www.ncbi.nlm.nih.gov/pubmed/26971690
52. Xie Z, Gunaratne J, Cheong LL, Liu SC, Koh TL, Huang G, Blackstock WP, Chng WJ: Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T(4;14) multiple myeloma. Oncotarget. 2013;4:1008-18 https://www.ncbi.nlm.nih.gov/pubmed/23900284
53. Kim JR, Mathew SO, Mathew PA. Blimp-1/PRDM1 regulates the transcription of human CS1 (SLAMF7) gene in NK and B cells. Immunobiology. 2016;221:31-9 https://www.ncbi.nlm.nih.gov/pubmed/26310579
54. Tellier J, Shi W, Minnich M, Liao Y, Crawford S, Smyth GK, Kallies A, Busslinger M, Nutt SL. Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response. Nat Immunol. 2016;17:323-30 https://www.ncbi.nlm.nih.gov/pubmed/26779600
55. Matsumoto Y, Horiike S, Ohshiro M, Yamamoto M, Sasaki N, Tsutsumi Y, Kobayashi T, Shimizu D, Uchiyama H, Kuroda J, Nomura K, Shimazaki C, Taniwaki M. Expression of master regulators of helper T-cell differentiation in peripheral T-cell lymphoma, not otherwise specified, by immunohistochemical analysis. Am J Clin Pathol. 2010;133:281-90 https://www.ncbi.nlm.nih.gov/pubmed/20093238
56. Takeuchi A, Saito T. CD4 CTL, a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function. Front Immunol. 2017;8:194. doi: 10.3389/fimmu.2017.00194. eCollection 2017. https://www.ncbi.nlm.nih.gov/pubmed/28280496
57. Xie Y, Akpinarli A, Maris C, Hipkiss EL, Lane M, Kwon EK, Muranski P, Restifo NP, Antony PA. Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J Exp Med. 2010;207:651-67 https://www.ncbi.nlm.nih.gov/pubmed/20156973
58. Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, Blasberg R, Yagita H, Muranski P, Antony PA, Restifo NP, Allison JP. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med. 2010;207:637-50 https://www.ncbi.nlm.nih.gov/pubmed/20156971
59. Woo J, Vierboom MP, Kwon H, Chao D, Ye S, Li J, Lin K, Tang I, Belmar NA, Hartman T, Breedveld E, Vexler V, 't Hart BA, Law DA, Starling GC. PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis. Arthritis Res Ther. 2013;15:R207. doi: 10.1186/ar4400. https://www.ncbi.nlm.nih.gov/pubmed/24299175
60. Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, Starling GC, Ciarlariello D, Bhaskar S, Briercheck EL, Hughes T, Yu J, Rice A, Benson DM Jr. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62:1841-9 https://www.ncbi.nlm.nih.gov/pubmed/24162108
61. Guo H, Cruz-Munoz M-E, Wu N, Robbins M, Veillette A. Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. Mol Cell Biol. 2015;35:41-51 https://www.ncbi.nlm.nih.gov/pubmed/25312647
62. van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, Garg TK, Shi J, Moreno-Bost AM, Yun R, Balasa B, Ganguly B, Chao D, Rice AG, Zhan F, Shaughnessy JD Jr, Barlogie B, Yaccoby S, Afar DE. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Molecular Cancer Therapeutics. 2009;8: 2616-24 https://www.ncbi.nlm.nih.gov/pubmed/19723891
63. Balasa B, Yun R, Belmar NA, Fox M, Chao DT, Robbins MD, Starling GC, Rice AG. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-? pathways. Cancer Immunol Immunother. 2015;64:61-73 https://www.ncbi.nlm.nih.gov/pubmed/25287778
64. Dong Z, Cruz-Munoz ME, Zhong MC, Chen R, Latour S, Veillette A. Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells. Nat Immunol. 2009;10:973-80
65. Caraux A, Kim N, Bell SE, Zompi S, Ranson T, Lesjean-Pottier S, Garcia-Ojeda ME, Turner M, Colucci F. Phospholipase C-gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood. 2006;107:994-1002 https://www.ncbi.nlm.nih.gov/pubmed/16204312
66. Kageyama R, Cannons JL, Zhao F, Yusuf I, Lao C, Locci M, Schwartzberg PL, Crotty S. The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development. Immunity. 2012;36:986-1002 https://www.ncbi.nlm.nih.gov/pubmed/22683125
67. Zhao F, Cannons JL, Dutta M, Griffiths GM, Schwartzberg PL. Positive and negative signaling through SLAM receptors regulate synapse organization and thresholds of cytolysis. Immunity. 2012;36:1003-16. https://www.ncbi.nlm.nih.gov/pubmed/22683123
68. Lagrue K, Carisey A, Morgan DJ, Chopra R, Davis DM. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood. 2015;126:50-60 https://www.ncbi.nlm.nih.gov/pubmed/26002964
69. Sehgal K, Das R, Zhang L, Verma R, Deng Y, Kocoglu M, Vasquez J, Koduru S, Ren Y, Wang M, Couto S, Breider M, Hansel D, Seropian S, Cooper D, Thakurta A, Yao X, Dhodapkar KM, Dhodapkar MV. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets. Blood.2015;125:4042-51 https://www.ncbi.nlm.nih.gov/pubmed/25869284
70. Niu C, Jin H, Li M, Zhu S, Zhou L, Jin F, Zhou Y, Xu D, Xu J, Zhao L, Hao S, Li W, Cui J. Low-dose bortezomib increases the expression of NKG2D and DNAM-1 ligands and enhances induced NK and ?? T cell-mediated lysis in multiple myeloma. Oncotarget. 2017;l8:5954-64
71. Yang G, Gao M, Zhang Y, Kong Y, Gao L, Tao Y, Han Y, Wu H, Meng X, Xu H, Zhan F, Wu X, Shi J. Carfilzomib enhances natural killer cell-mediated lysis of myeloma linked with decreasing expression of HLA class I. Oncotarget. 2015;6:26982-94. https://www.ncbi.nlm.nih.gov/pubmed/26323098
72. García-Sanz R, González M, Orfão A, Moro MJ, Hernández JM, Borrego D, Carnero M, Casanova F, Bárez A, Jiménez R, Portero JA, San Miguel JF. Analysis of natural killer-associated antigens in peripheral blood and bone marrow of multiple myeloma patients and prognostic implications. Br J Haematol. 1996;93:81-8 https://www.ncbi.nlm.nih.gov/pubmed/8611480
73. Omedé P, Boccadoro M, Gallone G, Frieri R, Battaglio S, Redoglia V, Pileri A. Multiple myeloma: increased circulating lymphocytes carrying plasma cell-associated antigens as an indicator of poor survival. Blood. 1990;76:1375-9 https://www.ncbi.nlm.nih.gov/pubmed/2119828
74. Lopez-Verges S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, Norris PJ, Nixon DF, Lanier LL. CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood. 2010;116:3865-74 https://www.ncbi.nlm.nih.gov/pubmed/20733159
75. Tienhaara A, Pelliniemi TT. Peripheral blood lymphocyte subsets in multiple myeloma and monoclonal gammopathy of undetermined significance. Clin Lab Haematol. 1994;16:213-23 https://www.ncbi.nlm.nih.gov/pubmed/7828409
76. Pessoa de Magalhães RJ, Vidriales MB, Paiva B, Fernandez-Gimenez C, García-Sanz R, Mateos MV, Gutierrez NC, Lecrevisse Q, Blanco JF, Hernández J, de las Heras N, Martinez-Lopez J, Roig M, Costa ES, Ocio EM, Perez-Andres M, Maiolino A, Nucci M, De La Rubia J, Lahuerta JJ, San-Miguel JF, Orfao A; Spanish Myeloma Group (GEM); Grupo Castellano-Leones de Gammapatias Monoclonales, cooperative study groups. Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry. Haematologica. 2013;98:79-86 https://www.ncbi.nlm.nih.gov/pubmed/22773604
77. Pérez-Andres M, Almeida J, Martin-Ayuso M, Moro MJ, Martin-Nuñez G, Galende J, Hernandez J, Mateo G, San Miguel JF, Orfao A; Spanish Network on Multiple Myeloma; Spanish Network of Cancer Research Centers. Characterization of bone marrow T cells in monoclonal gammopathy of undetermined significance, multiple myeloma, and plasma cell leukemia demonstrates increased infiltration by cytotoxic/Th1 T cells demonstrating a squed TCR-Vbeta repertoire. Cancer. 2006;106: 1296-305 https://www.ncbi.nlm.nih.gov/pubmed/16475149
78. Jurisic V, Srdic T, Konjevic G, Markovic O, Colovic M. Clinical stage-depending decrease of NK cell activity in multiple myeloma patients. Med Oncol. 2007;24:312-7 https://www.ncbi.nlm.nih.gov/pubmed/17873307
79. Dosani T, Carlsten M, Maric I, Landgren O. The cellular immune system in myelomagenesis: NK cells and T cells in the development of MM and their uses in immunotherapies. Blood Cancer J. 2015;5:e321. doi: 10.1038/bcj.2015.49. https://www.ncbi.nlm.nih.gov/pubmed/26140429
80. Famularo G, D'Ambrosio A, Quintieri F, Di Giovanni S, Parzanese I, Pizzuto F, Giacomelli R, Pugliese O, Tonietti G. Natural killer cell frequency and function in patients with monoclonal gammopathies. J Clin Lab Immunol. 1992;37: 99–109 https://www.ncbi.nlm.nih.gov/pubmed/1285130
81. De Rossi G, De Sanctis G, Bottari V, Tribalto M, Lopez M, Petrucci MT Fontana L. Surface markers and cytotoxic activities of lymphocytes in monoclonal gammopathy of undetermined significance and untreated multiple myeloma. Increased phytohemagglutinin-induced cellular cytotoxicity and inverted helper/suppressor cell ratio are features common to both diseases. Cancer Immunol Immunother. 1987;25:133-6 https://www.ncbi.nlm.nih.gov/pubmed/3664530
82. Fauriat C, Mallet F, Olive D, Costello RT. Impaired activating receptor expression pattern in natural killer cells from patients with multiple myeloma. Leukemia. 2006;20:732-733 https://www.ncbi.nlm.nih.gov/pubmed/16437151
83. Costello RT, Boehrer A, Sanchez C, Mercier D, Baier C, Le Treut T, Sébahoun G. Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy. Immunology. 2013;139: 338-41 https://www.ncbi.nlm.nih.gov/pubmed/23360454
84. El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW, Cook G, Feyler S, Richards SJ, Davies FE, Morgan GJ, Cook GP. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res. 2007;67:8444-9 https://www.ncbi.nlm.nih.gov/pubmed/17875681
85. Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010;116:2286-94 https://www.ncbi.nlm.nih.gov/pubmed/20460501
86. Ray A, Das DS, Song Y, Richardson P, Munshi NC, Chauhan D, Anderson KC. Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia. 2015;29:1441-4 https://www.ncbi.nlm.nih.gov/pubmed/25634684
87. Bezman NA, Jhatakia A, Kearney AY, Brender T, Maurer M, Henning K, Jenkins MR, Rogers AJ, Neeson PJ, Korman AJ, Robbins MD, Graziano RF. PD-1 blockade enhances elotuzumab efficacy in mouse tumor models. Blood Advances 2017;1:753-65 http://www.bloodadvances.org/content/bloodoa/1/12/753.full.pdf
88. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M. Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood. 1997;90:1109-14 https://www.ncbi.nlm.nih.gov/pubmed/9242542
89. Wu J, Edberg JC, Redecha PB, Bansal V, Guyre PM, Coleman K, Salmon JE, Kimberly RP. A novel polymorphism of Fc?RIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest. 1997;100: 1059-70 https://www.ncbi.nlm.nih.gov/pubmed/9276722
90. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940-7 https://www.ncbi.nlm.nih.gov/pubmed/12975461
91. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99:754-8 https://www.ncbi.nlm.nih.gov/pubmed/11806974
92. Poulart V, Jou Y-M, Delmonte T, Robbins M (Abstract release date: May 19, 2016). Fc-gamma receptor polymorphisms and progression-free survival: Analysis of three clinical trials of elotuzumab in multiple myeloma. EHA Learning Center. Poulart V. Jun 9, 2016;132830 https://learningcenter.ehaweb.org/eha/2016/21st/132830/valerie.poulart.fc-gamma.receptor.polymorphisms.and.progression-free.survival.html?f=m3e968
93. dbSNP Short Genetic Variations. NCBI https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=396991
94. Leiba M, Duek A, Amariglio N, Avigdor A, Benyamini N, Hardan I, Zilbershats I, Ganzel C, Shevetz O, Novikov I, Cohen Y, Ishoev G, Rozic G, Nagler A, Trakhtenbrot L. Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable? Genes Chromosomes Cancer. 2016;55:710-8 https://www.ncbi.nlm.nih.gov/pubmed/27152944
95. Walker BA, Wardell CP, Brioli A, Boyle E, Kaiser MF, Begum DB, Dahir NB, Johnson DC, Ross FM, Davies FE, Morgan GJ. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J. 2014;4:e191. doi: 10.1038/bcj.2014.13 https://www.ncbi.nlm.nih.gov/pubmed/24632883
96. Glitza IC, Lu G, Shah R, Bashir Q, Shah N, Champlin RE, Shah J, Orlowski RZ, Qazilbash MH Chromosome 8q24.1/c-MYC abnormality: a marker for high-risk myeloma. Leuk Lymphoma. 2015;56:602-7 https://www.ncbi.nlm.nih.gov/pubmed/24844357
97. Nagoshi H, Taki T, Hanamura I, Nitta M, Otsuki T, Nishida K, Okuda K, Sakamoto N, Kobayashi S, Yamamoto-Sugitani M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Kuroda J, Taniwaki M. Frequent PVT1 rearrangement and novel chimeric genes PVT1-NBEA and PVT1-WWOX occur in multiple myeloma with 8q24 abnormality. Cancer Res. 2012;72:4954-62 https://www.ncbi.nlm.nih.gov/pubmed/22869583
98. Richardson P, Wong E, Stockerl-Goldstein K, Rosenbaum C, Dhodapkar M, Jou Y-M, Lynch M, Robbins M, Bleickardt E, Jagannath S (Abstract release date: May 19, 2016). A phase 2 open-label, multicenter study of elotuzumab monotherapy in patients with high-risk smoldering multiple myeloma. EHA Learning Center. Jagannath S. Jun 12, 2016; 135309 https://learningcenter.ehaweb.org/eha/2016/21st/135309/sundar.jagannath.a.phase.2.open-label.multicenter.study.of.elotuzumab.html?f=m3
99. Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, Corral LL, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Arguiñano JM, Quintana N, García JL, Bladé J, Lahuerta JJ, Miguel JF. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17:1127-36 https://www.ncbi.nlm.nih.gov/pubmed/27402145
100. Usmani SZ, Sexton R, Ailawadhi S, Shah JJ, Valent J, Rosenzweig M, Lipe B, Zonder JA, Fredette S, Durie B, Hoering A, Bartlett B, Orlowski RZ. Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211. Blood Cancer J. 2015;5:e334. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558587/
101. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, Offidani M, McCarthy P, Evangelista A, Lonial S, Zweegman S, Musto P, Terpos E, Belch A, Hajek R, Ludwig H, Stewart AK, Moreau P, Anderson K, Einsele H, Durie BG, Dimopoulos MA, Landgren O, San Miguel JF, Richardson P, Sonneveld P, Rajkumar SV: Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068-74. Correction in: Blood. 2016 Mar 3; 127(9): 1213. Correction in: Blood. 2016 Aug 18; 128(7): 1020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375104/
102. Ozaki S, Handa H, Saitoh T, Murakami H, Itagaki M, Asaoku H, Suzuki K, Isoda A, Matsumoto M, Sawamura M, Konishi J, Sunami K, Takezako N, Hagiwara S, Kuroda Y, Chou T, Nagura E, Shimizu K. Trends of survival in patients with multiple myeloma in Japan: A multicenter retrospective collaborative study of the Japanese Society of Myeloma. Blood Cancer J. 2015;5:e349. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648525/