ELOTUZUMAB FOR THE TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA, WITH SPECIAL REFERENCE TO ITS MODES OF ACTION AND SLAMF7 SIGNALING

Main Article Content

Masafumi Taniwaki *
Mihoko Yoshida
Yosuke Matsumoto
Kazuho Shimura
Junya Kuroda
Hiroto Kaneko
(*) Corresponding Author:
Masafumi Taniwaki | taniwaki@koto.kpu-m.ac.jp

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.


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Article Details

Author Biographies

Masafumi Taniwaki, Kyoto Prefectural University of Medicine

Center for Molecular Diagnostics and Therapeutics, Specially Appointed Professor

Mihoko Yoshida, Aiseikai Yamashina Hospital

Department of Hematology and Laboratory Medicine

Yosuke Matsumoto, Aiseikai Yamashina Hospital

Department of Hematology and Laboratory Medicine

Kazuho Shimura, Aiseikai Yamashina Hospital

Department of Hematology and Laboratory Medicine

Junya Kuroda, Kyoto Prefectural University of Medicine, Graduate School of Medical Science

Department of Hematology, Professor

Hiroto Kaneko, Aiseikai Yamashina Hospital

Department of Hematology and Laboratory Medicine, Vice-president

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