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15-07-2016 | Multiple myeloma | Article

Elotuzumab for the treatment of multiple myeloma

Journal: Journal of Hematology & Oncology

Authors: Yucai Wang, Larysa Sanchez, David S. Siegel, Michael L. Wang

Publisher: BioMed Central

Abstract

Elotuzumab is one of the first two monoclonal antibodies that gained FDA approval for the treatment of multiple myeloma (MM). It targets SLAMF7, which is highly expressed in normal plasma and MM cells as well as natural killer (NK) cells. Elotuzumab demonstrated significant anti-myeloma activity in preclinical studies, and its mechanisms of action include mediating antibody-dependent cell-mediated cytotoxicity, enhancing cytotoxicity of NK cells, and inhibiting MM cell interaction with bone marrow stromal cells. In clinical trials, elotuzumab in combination with immunomodulatory drugs and proteasome inhibitors has demonstrated an excellent efficacy and safety profile in treating MM.
Literature
1.
Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71.CrossRefPubMed
2.
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100(9):3063–7.CrossRefPubMed
3.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609–17.CrossRefPubMed
4.
Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, Kapoor P, Dingli D, Hayman SR, Leung N, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–8.CrossRefPubMed
5.
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, Haessler J, Feather J, Hoering A, Moreau P, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–57.CrossRefPubMed
6.
El-Amm J, Tabbara IA. Emerging therapies in multiple myeloma. Am J Clin Oncol. 2015;38(3):315–21.CrossRefPubMed
7.
Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775–84.CrossRefPubMedPubMedCentral
8.
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(1):168–77.CrossRefPubMed
9.
Liu YC, Szmania S, van Rhee F. Profile of elotuzumab and its potential in the treatment of multiple myeloma. Blood Lymphat Cancer. 2014;2014(4):15–27.PubMedPubMedCentral
10.
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(10):5517–21.CrossRefPubMed
11.
Kumaresan PR, Lai WC, Chuang SS, Bennett M, Mathew PA. CS1, a novel member of the CD2 family, is homophilic and regulates NK cell function. Mol Immunol. 2002;39(1-2):1–8.CrossRefPubMed
12.
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(3):297–305.CrossRefPubMed
13.
Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, Lee AI, Podar K, Hideshima T, Rice AG, 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.CrossRefPubMedPubMedCentral
14.
Tai YT, Soydan E, Song W, Fulciniti M, Kim K, Hong F, Li XF, Burger P, Rumizen MJ, Nahar S, 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.CrossRefPubMedPubMedCentral
15.
Rice A, Dillon M, van Abbema A, Jesaitis L, Wong M, Lawson S, Liu G, Zhang Y, Powers D, Rhodes S, et al. Eradication of tumors in pre-clinical models of multiple myeloma by anti-CS1 monoclonal antibody HuLuc63: mechanism of action studies. Blood. 2006;108(11):3503–3.
16.
Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, Starling GC, Ciarlariello D, Bhaskar S, Briercheck EL, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62(12):1841–9.CrossRefPubMedPubMedCentral
17.
van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, Garg TK, Shi J, Moreno-Bost AM, Yun R, et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther. 2009;8(9):2616–24.CrossRefPubMedPubMedCentral
18.
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-alpha pathways. Cancer Immunol Immunother. 2015;64(1):61–73.CrossRefPubMed
19.
Sola C, Blery M, Bonnafous C, Bonnet E, Fuseri N, Graziano RF, Morel Y, André P. Lirilumab enhances anti-tumor efficacy of elotuzumab. Blood. 2014;124(21):4711–1.
20.
Robbins M, Jure-Kunkel M, Dito G, Andre P, Zhang H-f, Bezman N, Graziano RF. Effects of IL-21, KIR blockade, and CD137 agonism on the non-clinical activity of elotuzumab. Blood. 2014;124(21):4717–7.
21.
Garg TK, Szmania S, Shi J, Stone K, Moreno-Bost A, Malbrough P, Campana D, Barlogie B, Afar D, van Rhee F. Ex vivo activated natural killer (NK) cells from myeloma patients kill autologous myeloma and killing is enhanced by elotuzumab. Blood. 2008;112(11):3666–6.
22.
Szmania S, Lapteva N, Garg T, Greenway A, Lingo J, Nair B, Stone K, Woods E, Khan J, Stivers J, et al. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. J Immunother. 2015;38(1):24–36.CrossRefPubMedPubMedCentral
23.
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(3):552–9.CrossRefPubMedPubMedCentral
24.
Garcia MK, Cohen L, Guo Y, Zhou Y, You B, Chiang J, Orlowski RZ, Weber D, Shah J, Alexanian R, et al. Electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy in multiple myeloma: a feasibility study. J Hematol Oncol. 2014;7:41.CrossRefPubMedPubMedCentral
25.
Wang Y, Yang F, Shen Y, Zhang W, Wang J, Chang VT, Andersson BS, Qazilbash MH, Champlin RE, Berenson JR, et al. Maintenance therapy with immunomodulatory drugs in multiple myeloma:a meta-analysis and systematic review. J Natl Canc Inst. 2016;108(3):djv342.
26.
Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–9.CrossRefPubMed
27.
Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, et al. 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):e516–527.CrossRefPubMed
28.
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123–32.CrossRefPubMed
29.
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133–42.CrossRefPubMed
30.
Hou J, Du X, Jin J, Cai Z, Chen F, Zhou DB, Yu L, Ke X, Li X, Wu D, et al. A multicenter, open-label, phase 2 study of lenalidomide plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma: the MM-021 trial. J Hematol Oncol. 2013;6:41.CrossRefPubMedPubMedCentral
31.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, Rosinol L, Siegel DS, Mihaylov GG, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52.CrossRefPubMed
32.
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621–31.CrossRefPubMed
33.
Berdeja J, Jagannath S, Zonder J, Badros A, Kaufman JL, Manges R, Gupta M, Tendolkar A, Lynch M, Bleickardt E, et al. Pharmacokinetics and safety of elotuzumab combined with lenalidomide and dexamethasone in patients with multiple myeloma and various levels of renal impairment: results of a phase Ib study. Clin Lymphoma Myeloma Leuk. 2016;16(3):129–38.CrossRefPubMed
34.
Mateos MV, Granell M, Oriol Rocafiguera A, Martinez Lopez J, Blade J, Hernandez MT, Martin Sanchez J, Gironella M, Lynch M, Bleickardt E, et al. A phase II single-arm safety study of elotuzumab in combination with thalidomide and low dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. Haematologica. 2014;99(s1):361–2.
35.
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(16):1960–5.CrossRefPubMedPubMedCentral
36.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–98.CrossRefPubMed
37.
Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, 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.CrossRefPubMed
38.
Palumbo A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach JP, Mohrbacher A, et al. Elotuzumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma: 2-year follow-up. Blood. 2015;126(23):510–0.
39.
Jakubowiak A, Offidani M, Pegourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127(23):2833–40.CrossRefPubMedPubMedCentral
40.
Usmani SZ, Sexton R, Ailawadhi S, Shah JJ, Valent J, Rosenzweig M, Lipe B, Zonder JA, Fredette S, Durie B, et al. 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.CrossRefPubMedPubMedCentral
41.
Gupta N, Goh YT, Min CK, Lee JH, Kim K, Wong RS, Chim CS, Hanley MJ, Yang H, Venkatakrishnan K, et al. Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study. J Hematol Oncol. 2015;8:103.CrossRefPubMedPubMedCentral