Profile of elotuzumab and its potential in the treatment of multiple myeloma

Figures & data

Table 1 Monoclonal antibodies in various stages of clinical investigation for the treatment of multiple myeloma

Mechanisms of action	Target	Agent	Trial phase
Targeting proteins expressed on myeloma cells or involving myeloma cell adhesion	CSI	Elotuzumab	III
	CD38	Daratumumab	II
		MOR03087	I/II
		SAR650984	I
	CDI38	BT062 (nBT062-SPBD-DM4 conjugate)	I/II
	CD40	Dacetuzumab (SGN-40)	I
		Lucatumumab (HCDI22, CHIR 12.12)	II
	CD56	Lorvotuzumab (IMGN90I, huN90I-DMI conjugate)	I
	CD74	Milatuzumab (hLLI, IMMU-II5)	I/II
		Milatuzumab-Dox (hLLI-DOX, milatuzumab-doxorubicin conjugate)	I/II
	CD200	ALXN6000	I/II
	ICAM-I (CD54)	BI-505	I
Neutralizing growth factors in bone marrow microenvironment or inhibiting growth-promoting receptors	IL6	Siltuximab (CNTO-328)	II
	VEGF	Bevacizumab	II
	IGF-IR	AVE1642	I
		Figitumumab (CP-751,871)	I
		MK0646	I
	BAFF	Tabalumab (LY2127399)	II
Targeting mediators of bone disease	RANKL	Denosumab	III
	DKKI	BHQ880	I/II
Improving antimyeloma immune responses	PD-I	CT-011	I
	KIR	IPH2101 (1-7F9)	II
Others	TRAIL-RI	Mapatumumab	II

Abbreviations: BAFF, B-cell activating factor; IGF-1R, insulin-like growth factor 1 receptor; IL6, interleukin 6; KIR, killer-cell immunoglobulin-like receptor; PD-1, programmed cell death 1; RANKL, receptor activator of nuclear factor kappa-B ligand; VEGF, vascular endothelial growth factor; DKK1, dickkopf-1; ICAM-1, intercellular adhesion molecule-1; TRAIL-R1, tumor necrosis factor-related apoptosis inducing ligand-receptor 1.

Figure 1 CS1 expression quantified by gene expression (A), and immunohistochemistry (B).

Notes: (A) CS1 is highly expressed in CD138+ NPC (n=24), patients with MGUS (n=14), SMM (n=35), and MM BS (n=532) and MM REL (n=79), while expression in MMCL (n=45) is lower. CS1 is expressed in NK cells but at a lower level (NK, n=16), and is nearly negligible in other NT (15 tissue samples). (B) Strong CS1 expression in plasma cells from BM samples of two patients with MM by immunohistochemical staining with mAb IG9 (400×). Images shown in (B) are reproduced from Hsi et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775–2784.¹⁸ Copyright © 2008, American Association for Cancer Research.
Abbreviations: mAb, monoclonal antibody; MGUS, monoclonal gammopathy of undetermined significance; MM BS, multiple myeloma treated on Total Therapy 2 and 3 protocols at baseline; MM REL, multiple myeloma treated on Total Therapy 2 and 3 protocols at relapse; MM, multiple myeloma; MMCL, myeloma cell lines; NK, natural killer; NPC, normal plasma cells from healthy donors; NT, normal healthy tissue; SMM, smoldering multiple myeloma.

Figure 2 Mechanisms of action of elotuzumab. The primary mechanism of action of elotuzumab against myeloma cells is NK cell-mediated ADCC. Elotuzumab can also interfere with the adhesion of myeloma cells to BMSC, or can induce NK cell activation directly through binding CS1 expressed on NK cells.

Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; BMSC, bone marrow stromal cells; NK, natural killer.

Figure 3 Elotuzumab enhanced both ex vivo expanded NK cell-mediated, and to a lesser extent, resting NK cell-mediated killing of autologous myeloma cells in a standard 4-hour ⁵¹Cr release assay.

Abbreviations: E:T ratio, effector:target ratio; ENK, expanded natural killer cells; NK, natural killer; RNK, resting natural killer cells.

Table 2 Ongoing clinical trials using elotuzumab for the treatment of multiple myeloma

Study agents	Population	Treatment protocols	Phase	Estimated enrollment	Primary endpoint	Registry number
Lenalidomide + dexamethasone with or without elotuzumab (ELOQUENT-2)	RRMM (1-3 prior therapies)	Arm A: lenalidomide 25 mg PO daily Days 1–21 + dexamethasone 40 mg PO weekly on Days 1,8, 15, 22; every 28 days	III	640	PFS	NCT01239797
		Arm B: same as Arm A^a + elotuzumab 10 mg/kg IV Days 1,8, 15, 22 in cycles 1–2;
		Days 1, 15 in cycles 3 and beyond; every 28 days
Lenalidomide + dexamethasone with or without elotuzumab (ELOQUENT-1)	Newly diagnosed MM, not HSCT candidates	Arm A: lenalidomide 25 mg PO daily Days 1-21 + dexamethasone 40 mg PO weekly on Days 1,8, 15, 22; every 28 days	III	750	PFS	NCT01335399
		Arm B: same as Arm A^a + elotuzumab 10 mg/kg IV Days 1,8, 15, 22 in cycle 1-2;
		Days 1, 15 in cycles 3-18; 20 mg/kg on Day 1 in cycles 19 and beyond; every 28 days
ELOQUENT-1 substudy	Same as ELOQUENT-1	Same as ELOQUENT-1	Same as ELOQUENT-1		Efficacy (change of CS1 expression in MM cells)	NCT0189 1643
Bortezomib + dexamethasone with or without elotuzumab	RRMM (1-3 prior therapies)	Arm A: bortezomib 1.3 mg/m^Citation2 IV Days 1, 4, 8, II in cycles 1-8 every 21 days;	II	150	PFS	NCT01478048
		Days 1,8, 15 in cycles 9 and beyond every 28 days + dexamethasone 20 mg PO
		Days 1, 2, 4, 5, 8, 9, II, 12 in cycles 1-8 every 21 days; Days 1, 2, 8, 9, 15, 16 in cycles 9 and beyond every 28 days
		Arm B: same as Arm A^b + elotuzumab 10 mg/kg IV Days 1,8, 15 in cycles 1-2 every
		21 days; Days 1, 1 1 in cycles 3-8 every 21 days; Days 1, 15 in cycles 9 and beyond every 28 days
Bortezomib + lenalidomide + dexamethasone with or without elotuzumab (SI 21 1)	Newly diagnosed high-risk MM^C	Arm A: induction: bortezomib SC or IV on Days 1, 4, 8, 11+ lenalidomide PO daily	I/ll	122	Safety profile in Phase 1 stage, PFS in Phase II stage	NCT01668719
		Days 1-14 + dexamethasone PO or IV Days 1, 2, 4, 5, 8, 9, II, 12 every 21 days for 8 cycles. Maintenance: bortezomib SC or IV on Days 1,8, 15 + lenalidomide PO daily
		Days 1-21 + dexamethasone PO or IV Days 1,8, 15, 22 every 28 days
		Arm B: same as Arm A+ elotuzumab IV on Days 1,8, 15 in cycles 1-2; Days 1, II in cycles 3-8 every 21 Days for 8 cycles in induction; elotuzumab IV Days 1,15 every 28 days in maintenance
Thalidomide + dexamethasone + elotuzumab	RRMM (5 or less prior therapies)	Thalidomide 50 mg PO Days 1-14 and 100 mg Days 15-28 in cycle 1; 200 mg daily in cycles 2 and beyond + dexamethasone 40 mg PO weekly^Citation3 + elotuzumab 10 mg/kg	II	40	Safety profile	NCT01632150
		IV weekly in cycles 1-2 and every other week thereafter (+ cyclophosphamide 50 mg
		PO daily if applicable, in subjects not achieving partial response by end of cycle 4)
Lenalidomide + dexamethasone + elotuzumab	RRMM in Japanese (1–4 prior therapies)	Elotuzumab IV 10 or 20 mg/kg weekly in cycles 1-2; biweekly in cycles 3 and beyond + lenalidomide + dexamethasone	I	20	Safety profile	NCT01241292
Elotuzumab	High-risk SMM^d	Elotuzumab 20 mg/kg IV Days 1, 8 in cycle 1; Day 1 in cycles 2 and beyond, every 28 days (first 1 5 patients)	II	40	Efficacy (with biomarker study)	NCT01441973
		Elotuzumab 10 mg/kg IV Days 1,8, 15, 22 in cycles 1-2; Days 1, 15 in cycles 3 and beyond, every 28 days (second 15 patients)

Notes:

a Dexamethasone will be administered at dosages of 28 mg PO and 8 mg IV on weeks with elotuzumab;

b dexamethasone will be administered at dosages of 8 mg PO + 8 mg IV on days of elotuzumab;

c high-risk MM is defined by GEP70, t(14;16), t(14;20), del(17p) by FISH or cytogenetics, primary plasma cell leukemia, serum LDH ≥2 times of institutional upper limit of normal value;

d high-risk SMM is defined by 1) serum M protein ≥3 g/dL and BMPC ≥10%, 2) serum M protein 1–3 g/dL and BMPC ≥10% and abnormal FLC ratio of <0.125 or >8.0, 3) urine M protein >200 mg/24 hours, and BMPC ≥10% and abnormal FLC ratio of ≤0.125 or ≥8.0. Data from http://clinicaltrials.gov.

Abbreviations: FISH, fluorescence in situ hybridization; HSCT, hematopoietic stem cell transplantation; IV, intravenous; LDH, lactate dehydrogenase; MM, multiple myeloma; PFS, progression-free survival; PO, per os; RRMM, relapsed/refractory multiple myeloma; SC, subcutaneous; SMM, smoldering multiple myeloma; BMPC, bone marrow plasma cell; GEP, gene expression profiling; FLC, free light chain.

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