Elotuzumab for the Treatment of Relapsed or Refractory Multiple Myeloma, with Special Reference to its Modes of Action and SLAMF7 Signaling

Masafumi Taniwaki^1,2, Mihoko Yoshida², Yosuke Matsumoto², Kazuho Shimura², Junya Kuroda³ and Hiroto Kaneko²

¹ Center for Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Japan.
² Department of Hematology and Laboratory Medicine, General Incorporated Association Aiseikai Yamashina Hospital, Japan.
³ Department of Hematology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Japan.

Published: February 15, 2018
Received: December 26, 2017
Accepted: February 6, 2018
Mediterr J Hematol Infect Dis 2018, 10(1): e2018014 DOI 10.4084/MJHID.2018.014
This article is available on PDF format at: 

Introduction

Elotuzumab for the Treatment of RRMM

Efficacy and safety of elotuzumab in combination with lenalidomide and dexamethasone: Elotuzumab was approved in combination with lenalidomide and dexamethasone (Ld) for patients with RRMM based on the findings of the phase III, randomized, open-label, multicenter trial, ELOQUENT-2 (NCT01239797).[8] In ELOQUENT-2, the efficacy of elotuzumab combined with Ld (ELd) was evaluated for patients with RRMM who previously received one to three regimens. ELOQUENT-1 is still ongoing for patients with newly diagnosed MM (NDMM). ELOQUENT-2, in which 646 patients were randomized into ELd or Ld, demonstrated significant increase in overall response rate (ORR) and median PFS in ELd (Table 1).[8] Progression-free survival (PFS) has significantly improved in patients older than 75 years, particularly those with refractory disease and high-risk cytogenetic abnormalities (CA), i.e. t(4;14), del(17p), and 1q21 gain/amplification. A subanalysis of the Japanese population from ELOQUENT-2 revealed similar outcomes to the global study as well as to the Japanese phase I study; ORR were 84% in ELd vs 86% in Ld, and PFS rates at two years were 48% in ELd vs 18% in Ld.[15,16] A three-year follow-up and post-hoc analyses of ELOQUENT-2 recently confirmed that ELd provided a durable improvement in efficacy; ORR were 79% in ELd and 66% in Ld.[17] ELd reduced the risk of disease progression/death by 27% versus Ld. Interim overall survival (OS) at 3 years was 60% with ELd versus 53% with Ld. Serum M-protein dynamic modelling showed slower tumor regrowth with ELd.[17] An extended four-year follow-up of ELOQUENT-2 also demonstrated a sustained improvement in PFS in ELd versus Ld (21% vs 14%).[18] Patients with ≥ very good partial response (VGPR) had the greatest reduction (35%) in risk of progression/death. Median OS was 48% in ELd versus 40% in Ld.[18] These results further support the durable efficacy of ELd.

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Table 1. Antibody-containing novel combination regimens for RRMM.

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The safety, tolerability, and pharmacokinetics of intravenous elotuzumab have been assessed in a Phase I study of dose-escalation monotherapy at 10-20 mg/kg, demonstrating no maximum tolerated dose and modest activity with a best response of stable disease (SD).[19] The other two Phase I or Phase I/II studies also reported that the safety and tolerability of elotuzumab in combination with bortezomib or lenalidomide were acceptable.[20-22] Severe adverse events (AEs) in ELOQUENT-2 were 65% in ELd versus 57% in Ld; the most common grade 3/4 hematological AEs in ELd vs Ld were lymphocytopenia (77% vs 49%) followed by neutropenia (34% vs 44%), thrombocytopenia (19% vs 20%), and anemia (19% vs 21%).[8] Grade 3/4 hematological AEs, except for lymphocytopenia, were less frequent with ELd than with Ld, which may be of particular benefit for frail elderly patients. Common non-hematological grade 3/4 AEs were fatigue (8% in both arms), diarrhea (5% in ELd vs 4% in Ld), and pyrexia (5% and 3% in both arms). Lymphocytopenia may develop as a result of the migration of peripheral lymphocytes including NK cells into the involved tissue sites.[19] Infusion reactions (IRs) appearing as pyrexia, chills, and hypertension were very limited when compared with daratumumab, observed in 10% of ELd versus 45.3-50% of daratumumab-containing regimens.[9-11] Premedication with antihistamines, acetaminophen, and dexamethasone have successfully prevented IRs, and now are standard of care as part of the treatment with this antibody treatment. A phase II study demonstrated that a 1-hour infusion of elotuzumab provided convenient alternative dosing.[23]
Elotuzumab in combination with bortezomib or thalidomide: The efficacy of elotuzumab combined with bortezomib or thalidomide was also evaluated (Table 1).[24,25] A randomized Phase II study of elotuzumab combined with bortezomib and dexamethasone (EBd) versus bortezomib and dexamethasone (Bd), in which 152 patients with RRMM were randomized into EBd or Bd, has demonstrated slight increase in ORR and median PFS in EBd.[24] Grade 3/4 AEs were reported in 53 patients (71%) with EBd versus 45 patients (69%) with Bd; the most common grade 3 or higher AEs of EBd vs Bd were infections (21% vs 13%) and thrombocytopenia (9% vs 17%).[24] Grade 3/4 peripheral neuropathy (9% vs 12%), paresthesia (0% vs 5%), and thrombocytopenia were slightly less frequent in EBd than in Bd.[24] Grade 1/2 IRs were observed in 5% of EBd; there were no grade 3 or higher IRs.
The efficacy of 10 mg/kg elotuzumab combined with 50-200 mg thalidomide and 40 mg dexamethasone (ETd) (with or without 50 mg cyclophosphamide), was also evaluated in a Phase II single-arm study with minimal additional toxicity.[25] IRs were observed in 15% of ETd. This clinical trial showed ORR of 38% in 40 RRMM patients with a median of three prior regimens including bortezomib (98%) and lenalidomide (73%); median PFS and OS were 3.9 months and 16.3 months, respectively.[25] These findings suggest that the combination of elotuzumab with bortezomib or thalidomide has potential as treatment option for patients with RRMM.

Biological Characteristics of SLAMF7 and its Adaptor Proteins.

Biological characteristics of SLAMF receptors: SLAMF7 is one of the nine SLAMF receptors (SLAMF1-9) belonging to the CD2 subset of the immunoglobulin superfamily. It was originally identified as CS1 (CD2 subunit 1) by a subtractive hybridization between naïve B cell cDNA and that of memory B cells and plasma cells.[13] Molecular cloning revealed that CS1 is a novel human NK cell receptor.[26] SLAMF7 may also play a growth-promoting role and be involved in the autocrine expression of cytokines in normal B cells,[27] whereas its function in normal plasma cells currently remains unknown.
SLAMF receptors are type I transmembrane glycoproteins, except a glycosylphosphatidylinositol-anchored protein SLAMF2, which is widely expressed in hematopoietic cells but not in other tissues (Table 2). The genes encoding SLAMF receptors are reported to be clustered within an approximately 350-kb region at 1q23.[3.28,29] Our fluorescence in situ hybridization (FISH) study assigned SLAMF7 to 1q21.3 using the BAC clone RP11-404F10 containing SLAMF2, SLAMF7, and SLAMF3 (Sakamoto N, Taniwaki M et al., unpublished) (Figures 1A and 1B). SLAMF7 is also included in the amplicon of chromosome 1q gain/amplification, which is a high-risk CA frequently detected in RRMM (Sakamoto N, Taniwaki M et al., unpublished) (Figures 1C and 1D).

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Table 2.  Cytogenetic abnormalities valuable to predict prognosis of MM with candidate genes.

Figure 1. Fluorescence in situ hybridization mapping of SLAMF7 gene on normal metaphase and MM cells (Sakamoto N, Taniwaki M et al., unpublished). FISH is performed as described as previously.98  (A) Representative mapping finding of SLAMF7 gene on a partial metaphase cell using BAC clone RP11-404F10 containing SLAMF2, SLAMF7, and SLAMF3. (B) An enlarged view of chromosomes 1 shown in (A). SLAMF7 gene is assigned to 1q21.3 in our FISH study, although reportedly to be at the chromosomal band 1q23.3. (C) (D) Amplification of SLAMF7 gene in a metaphase spread and interphase nuclei obtained from a MM patient harboring pseudodiploid karyotype with 1q gain.

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SLAMF receptors are structurally characterized by distal Ig variable-like (IgV) and proximal C2-like (IgC2) domains within an extracellular portion and one or more immunoreceptor tyrosine-based switch motifs (ITSMs) within the cytoplasmic portion. The exception is that SLAMF3 has duplicated IgV-IgC2 sequences, and SLAMF8 and SLAMF9 lack tyrosine motifs.[28,30,31] SLAMF receptors 1, 3, 5 to 7, and 9, are “self-ligands” that recognize the same receptor molecule on another cell as a ligand; SLAMF2 and SLAMF4 are “co-ligands” that recognize each other.[27,28,32] Interactions between SLAMF receptors occur at their IgV domains between identical or different types of hematopoietic cells. The engagement of SLAMF receptors mediates regulatory effects on immune cells in the presence of the SLAM-associated protein (SAP) family of adaptors.[26,33,34] Two SAP family adaptors have been identified in humans: SAP (SH2D1A) and EWS-Fli1-activated transcript-2 (EAT-2, SH2D1B), which are intracellular proteins containing the Src homology2 (SH2) domain devoid of enzymatic activity.[28,31,35] Although most SLAMF receptors bind SAP and EAT-2, SLAMF7 is reported to be functionally controlled by EAT-2 only.[33,36] However, RNA interference experiments have demonstrated that SLAMF7 may interact with SAP when the concentration of SAP is significantly higher than that of EAT-2 in cells.[37] Hence, the selective binding of SLAMF7 to EAT-2 is due to its greater affinity to EAT-2 than SAP by nearly two orders of magnitude.[37] Moreover, a recent study reported that SLAMF7 interacted with integrin Mac-1 instead of SAP adaptors utilizing signals involving immunoreceptor tyrosine-based activation motifs (ITAMs), which induced the promotion of phagocytosis.[38] Further studies are needed in order to elucidate the exact role of SLAMF7 in myeloma cell pathophysiology.　
SLAM-associated adaptor proteins and downstream signal transduction: SLAMF functions as an either inhibitory or activating receptor depending on the availability of the SAP-related adaptor proteins, SAP and EAT-2. SAP is expressed in T, NK, NKT, and germinal center B cells. SAP expression has been reported in some Epstein-Barr virus (EBV)-transformed B cells, Hodgkin’s lymphoma, and angioimmunoblastic T-cell lymphoma.[39-41] EAT-2 is expressed in NK cells and a range of antigen-presenting cells including monocytes.[42,43] When the SLAMF receptor is engaged, tyrosine (Y) 281 located in ITSMs is phosphorylated, recruiting SAP or EAT-2.[28,32] Through the SH2 domain, SAP or EAT-2 binds SLAMF at the phosphorylated ITSMs with overlapping specificities for activating and inhibitory binding partners. SAP contains an arginine-based motif in the SH domain, which mediates binding to the Src family protein Fyn, thereby stabilizing immune synapses (Figure 2).[44] SAP also enhances adhesion between NK and target cells. On the other hand, EAT-2 controls NK cell function through the phospholipase Cγ enzymes (PLC-γ), Ca²⁺ fluxes, and the MAPK/Erk pathway, leading to granule polarization and the exocytosis of cytotoxic granules toward target cells (Figure 3).[45] SAP and EAT-2 both prevent SLAMF receptors from interacting with inhibitory effectors such as SH2-domain-containing tyrosine phosphatase (SHP)-2, SHP-1, SH2 domain-containing 5’ inositol phosphatase (SHIP)-1, or C-terminal Src kinase (Csk).[36,41] Hence, SLAMF receptors become inhibitory in the absence of SAP-related adaptors, suppressing the function of activating NK-cell receptors such as CD16, natural-killer group-2 member-D (NKG2D), and DNAX accessory molecule-1 (DNAM-1).[32]

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Figure 2.  Structure and function of SLAMF receptor in an immune synapse. The SLAMF receptors are structurally characterized by IgV and IgC2 domains within an extracellular portion and one or more ITSMs, depicted as a closed rectangle, within the cytoplasmic portion. The mostly homophilic interactions between SLAMF receptors result in their costimulatory effects on TCR/CD3 complex signaling pathway. When the SLAMF receptor is engaged by its ligand, cytoplasmic domain ITSMs with tyrosine-based motifs undergo phosphorylation, recruiting adaptors proteins, SAP or EAT-2. SAP can then recruit the Src family protein tyrosine kinase Fyn or Lck, which is important for activation via SLAM family receptors. The coupling of EAT-2 carboxyl-terminal tail to the PLC-γ SH2 domains leads to an additional activation pathway. ITSM-like motif (non-ITSM) depicted as an unfilled rectangle does not bind SAP or EAT-2. SAP is mostly expressed in T cells, while EAT-2 is primarily expressed in antigen-presenting cells.

Figure 3. Effect of elotuzumab to NK, NKT, and MM cells. The primary mechanism of action of elotuzumab is NK cell-mediated ADCC against MM cells. Elotuzumab also directly activates NK and NKT cells, but not MM cells, by its engagement with SLAMF7. This effect results in phosphorylation of tyrosine 281 (Y281) located in ITSMs, thereby recruiting a SLAM-associated adaptor EAT-2. EAT-2 binds to the SH2 domains of PLC-γ, and leads to enhanced Ca2+ influx and MAPK/Erk pathway activation, finally resulting in granule polarization and enhanced exocytosis in NK cells. Tyrosine 261 (Y261), needed for the inhibitory function of mouse SLAMF7, is conserved in human SLAMF7.[31] NKT cells are also activated via elotuzumab binding, resulting in the accelerated secretion of IL2 and TNFα, which induces the cytotoxicity of NK cells against MM cells.[64] Elotuzumab binds to the proximal IgC2 domain of SLAMF 7.

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The SAP gene located at Xq25 was identified as the causative gene altered in X-linked lymphoproliferative syndrome (XLP).[46,47] Germline mutations or deletions in SAP have been implicated in XLP, resulting in aberrant functions of SLAMF1.[48,49] Aberrant functions of SLAMF1, 2, and 6 caused by SAP mutations result in extreme sensitivity to EBV infection in patients with XLP. EBV-specific cytotoxic CD8+ T cells in XLP exhibit defects in the cytolysis of EBV-infected B cells. They escape an apoptotic death, which results in the uncontrolled proliferation of B cells and T cells, thereby causing fulminant infectious mononucleosis (60%), lymphomas (30%), and dysgammaglobulinemia (30%).[48,50]

Expression of SLAMF7 in Normal Cells, MM, and other Hematological Malignancies

Expression of SLAMF7 in normal cells and MM cells: SLAMF7 is expressed on NK cells, NKT cells, a subset of cytotoxic T-lymphocytes (CTLs) including CD8+ and CD4+ cells, mature dendritic cells (DCs), and activated B cells, regulating T- and B-cell functions. (Table 2).[27,31-33,51,52] Normal plasma cells also highly express SLAMF7 at the mRNA and protein levels.[13,14] SLAMF7 is not expressed in resting B cells, monocytes, granulocytes, or hematopoietic stem cells.[13,14,36] On the other hand, SLAMF7 is highly expressed in neoplastic plasma cells from more than 95% of patients with MM, plasmacytoma[13,14] and plasma cell leukemia (PCL). It is also expressed in CD138 purified plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM).[14] There have been no studies describing the higher expression of SLAMF7 in MM than in normal plasma cells. Soluble SLAMF7 (sSLMF7) lacking transmembrane and cytoplasmic domains was detected in patients with MM, particularly at advanced stages, but not in those with MGUS or healthy individuals.[14] The role of sSLMF7 in myeloma cell pathophysiology remains to be elucidated.

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Table 2. Cytogenetic abnormalities valuable to predict prognosis of MM with candidate genes.

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Although SLAMF7 expression level in MM cells were independent of the cytogenetic subtypes of MM, one of the highest expression levels was found in t(4;14)-positive MM.[13] A recent study demonstrated that the knockdown of SLAMF7 induced cell cycle G1 arrest or apoptosis, and also reduced colony formation in t(4;14) MM cells.[53] Overexpressed SLAMF7 in t(4;14)-positive MM cell lines was down-regulated by MMSET shRNAs.[53] These findings suggest a direct effect on the transcription of SLAMF7 by the MMSET protein. Although the mechanisms underlying the upregulation in plasma cells and MM cells currently remain unclear, a recent study demonstrated that SLAMF7 transcription was positively regulated by Blimp-1 (B lymphocyte-induced maturation protein-1) in NK cells and B cells.[54] Blimp-1 is a known transcriptional repressor in macrophages, NK cells, B cells, T cells, and skin epithelial cells. Plasma cell function is controlled by Blimp-1 through the regulation of immunoglobulin secretion and the unfolded protein response.[55]
Expression of SLAMF7 in other hematological malignancies: Most of B-cell lymphomas including various histological subtypes and Hodgkin lymphoma do not express SLAMF7, as assessed by immunohistochemistry (IHC). Neither acute myeloid leukemias nor lymphoblastic leukemias express SLAMF7.[13] The SLAMF7 protein was detected in 25% of peripheral T-cell lymphomas (PTCL) at a modest level using IHC. PTCL is a heterogeneous disease, but generally shows the CD4-positive phenotype. Using IHC, we identified various CD4+ Th subsets (Th1, Th2, Th17, and Treg) as possible normal counterparts of PTCL based on the expression of master regulators such as T-bet, GATA3, BCL6, RORγt, and FOXP3.[56] These findings suggest that some functional subsets of CD4+ T cells expressing SLAMF7 exist. Recent studies demonstrated the clonal expansion of CD4+ CTLs expressing SLAMF7, granzyme A, IL-1β, and TGF-β1, at inflamed tissue sites of IgG4-related disease.[52] Although CD4+ CTLs may develop from naïve T (Th0) and various Th subsets, Th1 cells regulated by T-bet represent the majority of CD4+ CTLs secreting IFN-γ.[57] CD4+ CTLs have been detected among peripheral blood lymphocytes under conditions of chronic viral infections and during antitumor responses.[58,59]

Dual Immunotherapeutic Mechanism of Elotuzumab

Optimal use of ELd for the Treatment of RRMM

Three factors need to be considered in order to achieve better outcomes using ELd: risk of the disease, frailty of the patients, and the quantity and quality of effector cells. Prior to introducing elotuzumab, many patients were treated with lenalidomide-based regimens until disease progression as first-line therapy, and were lenalidomide refractory at the time of first relapse. Since elotuzumab is approved in combination with Ld for the treatment of RRMM, there are two possible conditions under which to administer elotuzumab: starting ELd as second-line later treatment or adding elotuzumab to Ld ongoing as first-line or later treatment. In the case of second-line or later treatment, patients with PR, VGPR, or CR using Ld may be the ideal candidates for the addition of elotuzumab. This is because PFS by tumor responses between the ELd and Ld groups was significantly better in patients who achieved PR or better than in patients with a minor response or SD in ELOQUENT-2.[8]
According to the ELOQUENT-2 study, elotuzumab is beneficial for patients with high-risk CA including del(17p), 1q21 gain/amplification, and particularly t(4;14). A direct effect on SLAMF7 transcription by the MMSET protein has provided the rationale to use elotuzumab for t(4;14)-positive MM patients.[53] Secondary CA may impact adversely on treatment outcomes and survival in both NDMM and RRMM regardless of the primary high-risk CA (Table 3). For example, t(11;14) is not necessarily associated with a good, but with a poor prognosis when identified concomitantly with a high-risk secondary CA, such as 1q21 gain/amplification and del(17p) (Figure 4).[95] In the novel agent era, chromosomal rearrangements at 8q24 is also high-risk CA.[96,97] We previously detected 8q24 rearrangements involving MYC or PVT1 (plasmacytoma variant translocation 1) loci in 24% of patients with MM.[98]

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Table 3.  SLAM family receptors: their expression and interaction with adaptor proteins.

Figure 4. Chromosomal abnormalities in a patient with t(11;14)-positive primary refractory PCL detected by multicolor spectral karyotyping (SKY) (Goto M, Taniwaki M, et al. unpublished). SKY is performed as described as previously.[98] Arrows indicate a balanced translocation t(11;14)(q13;q32). Three secondary CA are detected in this patient: der(1)t(1;16)(q10;p10) indicated by an arrowhead, monsomy 13 (-13), and der(17)t(4;17)(?;p13) indicated by a double arrowhead. Unbalanced translocations, der(1)t(1;16)(q10;p10) and der(17)t(4;17)(?;p13), result in 1q gain and 17p deletion, respectively, which are high-risk secondary CA in MM (Goto M, Taniwaki M, et al. unpublished).

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Taking the modes of action of elotuzumab into consideration, the counts and functions of immune cells, particularly NK cells are crucial as already mentioned. In this regard, the findings of Phase II and III trails in patients with SMM have been encouraging. Elotuzumab monotherapy may delay progression to MM in patients with SMM, resulting in favorable PFS, because most patients achieved the best overall response of SD or MR, with ≥MR in 29% including PR in 10%.[99] Early treatments with Ld in patients with high-risk SMM provided a significant benefit over observations in terms of time to progression.[100] Since elotuzumab is well tolerated with minimal toxicity, elderly or frail patients who are ineligible for PI/MiD-based triplet therapy or transplantation are suitable candidates for ELd treatment. Moreover, the addition of elotuzumab to bortezomib, lenalidomide, and dexamethasone (LBd) is feasible without major additive AEs beyond what is already known about LBd, as demonstrated in SWOGS1211 trial.[101] However, the efficacy of elotuzumab in combination with LBd needs to be studied.

Conclusions

Acknowledgments

1. Cancer Stat Facts: Myeloma. National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Accessed 25 December 2017 https://seer.cancer.gov/statfacts/html/mulmy.html   
   
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. https://doi.org/10.1016/j.ejca.2012.12.027 
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://doi.org/10.1182/blood-2007-10-116129 PMid:17975015 PMCid:PMC2254544 
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://doi.org/10.1038/leu.2013.313 PMid:24157580 PMCid:PMC4000285 
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://doi.org/10.1056/NEJMoa1402551 PMid: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. 
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://doi.org/10.1056/NEJMoa1505654 PMid: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://doi.org/10.1056/NEJMoa1606038 PMid: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://doi.org/10.1056/NEJMoa1607751  PMid: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://doi.org/10.1182/blood-2017-05-785246 PMid:28637662 PMCid:PMC5570682 
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://doi.org/10.1182/blood-2017-03-775122 PMid: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://doi.org/10.1158/1078-0432.CCR-07-4246 PMid:18451245 PMCid:PMC4433038 
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://doi.org/10.1182/blood-2007-08-107292 PMid:17906076 PMCid:PMC2515112 
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://doi.org/10.1007/s12185-016-2070-7 PMid: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://doi.org/10.1038/bcj.2017.18 PMid:28282035 PMCid:PMC5380903 
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://doi.org/10.1111/bjh.14787 PMid:28677826  
18. Dimopoulos MA, Lonial S, White D, Moreau P, Mateos MV, San-Miguel J, Anderson KC, Shpilberg O, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Belch A, Reece DE, Beksac M, Mekan S, Sy O, Anil K. Singhal AK, Richardson PG , Weisel K (Abstract release date: May 18, 2017). Phase 3 ELOQUENT-2 Study: Extended 4-year follow-up of elotuzumab plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone in relapsed/refractory multiple myeloma. EHA Learning Center. Dimopoulos M. Jun 24, 2017; 181743 https://learningcenter.ehaweb.org/eha/2017/22nd/181743/meletios.a.dimopoulos.phase.3.eloquent-2.study.extended.4-year.follow-up.of.html
    
19. 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://doi.org/10.1182/blood-2011-06-360552 PMid:22184404 PMCid:PMC4467882 
20. 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://doi.org/10.1200/JCO.2011.37.7069 PMid:22291084 PMCid:PMC4874204 
21. 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://doi.org/10.1200/JCO.2011.37.2649 PMid:22547589    
22. 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://doi.org/10.1016/S2352-3026(15)00197-0  
23. 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://doi.org/10.1002/ajh.24687 PMid:28213943    
24. 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://doi.org/10.1182/blood-2016-01-694604 PMid:27091875 PMCid:PMC4900953 
25. 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://doi.org/10.1111/bjh.14263 PMid:27434748    
26. 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://doi.org/10.1007/s002510000274  
27. 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://doi.org/10.4049/jimmunol.179.7.4672 PMid:17878365  
28. Cannons JL, Tangye SG, Schwartzberg PL. SLAM family receptors and SAP adaptors in immunity. Annu Rev Immunol. 2011;29:665-705 https://doi.org/10.1146/annurev-immunol-030409-101302 PMid:21219180   
29. 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://doi.org/10.1034/j.1600-065X.2001.1810120.x PMid:11513145  
30. 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://doi.org/10.1038/nri2456 PMid:19079134   
31. 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://doi.org/10.1016/j.critrevonc.2013.04.003 PMid:23731618    
32. Veillette A. SLAM-family receptors: immune regulators with or without SAP-family adaptors. Cold Spring Harb Perspect Biol. 2010;2(3):a002469. https://doi.org/10.1101/cshperspect.a002469  
33. 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://doi.org/10.4049/jimmunol.167.7.3668 PMid:11564780    
34. 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://doi.org/10.4049/jimmunol.167.10.5517 PMid:11698418    
35. 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://doi.org/10.1007/s00281-009-0193-0 PMid:20146065 PMCid:PMC2868096 
36. 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://doi.org/10.1038/ni.1693 PMid:19151721    
37. 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 
38. 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://doi.org/10.1038/nature22076  PMid:28424516 PMCid:PMC5565268 
39. 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://doi.org/10.1182/blood-2004-07-2731 PMid:15941917 
40. 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://doi.org/10.1002/ijc.10986  PMid:12594824 
41. 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://doi.org/10.3324/haematol.10864 PMid:17640856    
42. 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://doi.org/10.1093/emboj/20.21.5840 PMid:11689425 PMCid:PMC125701 
43. 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://doi.org/10.1007/s00251-005-0056-3 PMid:16425036  
44. 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://doi.org/10.1038/ncb920 PMid:12545174    
45. 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://doi.org/10.1084/jem.20132038 PMid:24687958 PMCid:PMC3978279 
46. offey 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://doi.org/10.1038/2424 PMid:9771704    
47. 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://doi.org/10.1038/26683 PMid:9774102   
48. 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://doi.org/10.1007/s002510000215 PMid:10970095   
49. 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://doi.org/10.1016/S0065-2776(08)00004-7 
50. Nelson DL, Terhorst C. X–linked lymphoproliferative syndrome. Clin Exp Immunol. 2000;122:291-5 https://doi.org/10.1046/j.1365-2249.2000.01400.x PMCid:PMC1905809 
51. Veillette A. NK cell regulation by SLAM family receptors and SAP-related adapters. Immunol Rev. 2006;214:22-34 https://doi.org/10.1111/j.1600-065X.2006.00453.x PMid:17100873   
52. 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://doi.org/10.1016/j.jaci.2015.12.1330 PMid:26971690 PMCid:PMC5014627 
53. 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://doi.org/10.18632/oncotarget.1049 PMid:23900284 PMCid:PMC3759662 
54. 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://doi.org/10.1016/j.imbio.2015.08.005 PMid:26310579   
55. 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://doi.org/10.1038/ni.3348 PMid:26779600 PMCid:PMC4757736 
56. 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://doi.org/10.1309/AJCP0SBHYVLY5EML PMid:20093238   
57. 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://doi.org/10.3389/fimmu.2017.00194 
58. 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://doi.org/10.1084/jem.20091921 PMid:20156973 PMCid:PMC2839147 
59. 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://doi.org/10.1084/jem.20091918 PMid:20156971 PMCid:PMC2839156 
60. 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://doi.org/10.1186/ar4400 
61. 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://doi.org/10.1007/s00262-013-1493-8 PMid:24162108 PMCid:PMC4134870 
62. 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://doi.org/10.1128/MCB.01107-14 PMid:25312647 PMCid:PMC4295394 
63. 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://doi.org/10.1158/1535-7163.MCT-09-0483 PMid:19723891 PMCid:PMC2748787 
64. 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-a pathways. Cancer Immunol Immunother. 2015;64:61-73 https://doi.org/10.1007/s00262-014-1610-3 PMid:25287778 PMCid:PMC4282702 
65. 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 https://doi.org/10.1038/ni.1763 PMid:19648922   
66. 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://doi.org/10.1182/blood-2005-06-2428 PMid:16204312    
67. 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://doi.org/10.1016/j.immuni.2012.05.016 PMid:22683125 PMCid:PMC3389310 
68. 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://doi.org/10.1016/j.immuni.2012.05.017 PMid:22683123 PMCid:PMC3389133 
69. 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://doi.org/10.1182/blood-2015-01-625004 PMid:26002964 PMCid:PMC4551357 
70. 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://doi.org/10.1182/blood-2014-11-611426 PMid:25869284 PMCid:PMC4481593 
71. 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 ?d T cell-mediated lysis in multiple myeloma. Oncotarget. 2017;l8:5954-64 
72. 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://doi.org/10.18632/oncotarget.4831 
73. 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://doi.org/10.1046/j.1365-2141.1996.4651006.x PMid:8611480  
74. 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 PMid:2119828    
75. 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://doi.org/10.1182/blood-2010-04-282301 PMid:20733159 PMCid:PMC2981540 
76. 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://doi.org/10.1111/j.1365-2257.1994.tb00414.x PMid:7828409  
77. 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://doi.org/10.3324/haematol.2012.067272 PMid:22773604 PMCid:PMC3533663 
78. Pérez-Andres M, Almeida J, Martin-Ayuso M, Moro MJ, Martin-Nu-ez 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://doi.org/10.1002/cncr.21746 PMid:16475149    
79. 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://doi.org/10.1007/s12032-007-0007-y PMid:17873307    
80. 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://doi.org/10.1038/bcj.2015.49 
81. 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 PMid:1285130    
82. 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://doi.org/10.1007/BF00199953 PMid:3664530   
83. 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://doi.org/10.1038/sj.leu.2404096 PMid:16437151   
84. 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://doi.org/10.1111/imm.12082 PMid:23360454 PMCid:PMC3701180 
85. 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://doi.org/10.1158/0008-5472.CAN-06-4230 PMid:17875681   
86. 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://doi.org/10.1182/blood-2010-02-271874  PMid:20460501 PMCid:PMC3490105 
87. 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://doi.org/10.1038/leu.2015.11 PMid:25634684 PMCid:PMC5703039 
88. 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  
89. 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 PMid:9242542   
90. 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://doi.org/10.1172/JCI119616 PMid:9276722 PMCid:PMC508280 
91. 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://doi.org/10.1200/JCO.2003.05.013 PMid:12975461    
92. 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://doi.org/10.1182/blood.V99.3.754 PMid:11806974  
93. 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
    
94. dbSNP Short Genetic Variations. NCBI  https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=396991
95. 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://doi.org/10.1002/gcc.22372 PMid:27152944  
96. 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://doi.org/10.1038/bcj.2014.13  
97. 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://doi.org/10.3109/10428194.2014.924116 PMid:24844357 PMCid:PMC4333105 
98. 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://doi.org/10.1158/0008-5472.CAN-12-0213 PMid:22869583  
99. 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
    
100. Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, Corral LL, Rosi-ol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Argui-ano 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://doi.org/10.1016/S1470-2045(16)30124-3  
101. 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://doi.org/10.1038/bcj.2015.62 PMid:26252787 PMCid:PMC4558587 
102. 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://doi.org/10.1182/blood-2014-12-615187 PMid:25628469 PMCid:PMC4375104 
103. 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://doi.org/10.1038/bcj.2015.79 PMid:26383822 PMCid:PMC4648525