Table 2.

Summary of current treatments with novel agents for multiple myeloma (MM) potentially affecting natural killer (NK) cell activity.

Agent	Mechanism of action on NK cells	Clinical trials	Reference
PD-1/PD-L1 checkpoint inhibitors	Block of the recognition of PD-L1 by PD-1 on NK cells PD1 blockade may neutralize competitive negative signals resulting in enhanced trafficking, immune complex formation, and cytotoxicity of NK cells (Figures 1A,B)	Phase I trial of pembrolizumab with lenalidomide and dexamethasone. Two Phase I trials involving nivolumab showed acceptable tolerability. Efficacy assessment of nivolumab, alone or in combination is ongoing.	Benson et al. (125); San Miguel et al. (132); Suen et al. (133); Lesokhin et al. (134)
HLA-KIR checkpoint inhibitors	Prevent inhibitory KIR recognition of cognate HLA class I ligands Blockade of KIR-HLA interactions may neutralize negative signals transduced by inhibitory KIR2DL1/2/3 (Figure 2A)	Anti-KIR monoclonal antibody IPH2101 (1-7F9) determined the full saturation of NK inhibitory KIR in a phase I trial enrolling patients with RR MM. Full KIR occupancy was also achieved in a study combining lenalidomide and IPH2101. In this study, 5 (33%) patients had a response. In a single arm two-stage phase II trial, IPH2101 was employed in 9 patients with smoldering MM. The study was stopped before planned second stage due to lack of patients meeting the primary objective (50% decline in M-protein). A phase I study combining elotuzumab with lirilumab, a recombinant version of IPH2101, is currently in progress	Frohn et al. (136); Benson et al. (139); Benson et al. (140); Benson et al. (141); Korde et al. (142); Carlsten et al. (143)
Daratumumab (DARA)	ADCC to CD38+ MM cells Cytolytic activity to MM cells triggered by CD16 signaling upon recognition of antibody tagged to CD38 antigen. NK cell-mediated cytotoxicity induced by DARA could be enhanced by lenalidomide and KIR blockade. Other mechanisms: complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis (Figure 2B)	DARA was tested in combination with bortezomib and dexamethasone in RRMM. The primary end point was progression-free survival. DARA in combination with bortezomib and dexamethasone resulted in a significantly longer progression-free survival than bortezomib and dexamethasone alone	Palumbo et al. (156)
Elotuzumab	Direct effect: ADCC to MM cells expressing SLAMF7 Indirect effect: activation of SLAMF7+ NK cells Dual mechanism of action: (1) NK cell activation via SLAMF7 binding and recruitment of the EAT-2 adaptor proteins; (2) NK-mediated ADCC to SLAMF7+ MM cells (Figure 3)	Elotuzumab showed activity in combination with lenalidomide and dexamethasone in a phase I and a phase IIb-II clinical studies in RRMM. In a phase III study, patients with RRMM patients were treated with either elotuzumab with lenalidomide and dexamethasone, or lenalidomide and dexamethasone alone. Patients treated with the combination of elotuzumab, lenalidomide, and dexamethasone had a significantly reduced risk of disease progression or death. In a phase II study in RRMM patients, elotuzumab showed clinical benefit without significant toxicity when combined with bortezomib	Lonial et al. (167); Lonial et al. (169); Jakubowiak et al. (170)
IDO inhibitors	Inhibition of l-tryptophan degradation Reversal of NK immunosuppression by increased availability of l-tryptophan and reduced accumulation of l-kyreunine	IDO inhibitors are currently used as single agent or in combination in a number of solid tumors. This class has not yet been evaluated in clinical trials in myeloma patients	Uyttenhove et al. (172); Fallarino et al. (173); Bonanno et al. (182)

PD-1/PD-L1, programmed cell death protein 1/programmed cell death protein ligand 1; KIRs, killer immunoglobulin-like receptors; RR MM, relapsed/refractory MM; ADCC, antibody-dependent cellular cytotoxicity; SLAMF7, signaling lymphocytic activation molecule family 7; IDO, indoleamine 2,3-dioxygenase.