Spotlight on elotuzumab in the treatment of multiple myeloma: the evidence to date

Figures & data

Figure 1 Binding and intracellular signaling of SLAMF7 receptors.

Notes: Following receptor engagement by self-adhesion of SLAMF7 or elotuzumab binding, SLAMF7 can mediate both activating and inhibitory signals based on the presence or absence of intracellular EAT-2. In NK cells, EAT-2 binds to a specific phosphorylated tyrosine-based motif in the cytoplasmic domain of SLAMF7, triggering downstream activation.
Abbreviations: EAT-2, Ewing’s sarcoma-associated transcript 2; ITSM, immunoreceptor tyrosine-based switch motif; NK, natural killer; SLAMF7, signaling lymphocytic activation molecule F7; TM, transmembrane domain; C2 and V, Ig superfamily domains.

Figure 2 Dual mechanism of action of elotuzumab to induce myeloma cell death.

Notes: (A) Elotuzumab binds to SLAMF7 on myeloma cells, targeting them for ADCC-mediated destruction. Through the CD16 receptors, NK cells bind to the Fc part of elotuzumab and become activated, finally leading to ADCC. (B) Elotuzumab binds to SLAMF7 on NK cells, directly activating them and resulting in increased cytokine production and release of cytotoxic granules.
Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; EAT-2, Ewing’s sarcoma-associated transcript 2; NK, natural killer; SLAMF7, signaling lymphocytic activation molecule F7.

Figure 3 SLAMF7 saturation of BM CD38⁺ cells.

Notes: BM samples were collected from patients with RRMM treated with elotuzumab during Study 1701. MM cells isolated from these samples were analyzed for SLAMF7 saturation. Symbols indicate observed data from individual patients at elotuzumab dose levels of 0.5–20 mg/kg. The vertical line indicates the target level of serum elotuzumab concentration (70 μg/mL) based on preclinical studies. Reprinted with permission from: Zonder et al²⁹; © 2012 by The American Society of Hematology.
Abbreviations: BM, bone marrow; E_max, maximum effect; MM, multiple myeloma; RRMM, relapsed and/or refractory MM; SLAMF7, signaling lymphocytic activation molecule F7.

Table 1 Clinical studies with E alone or in combination with established MM therapies

Study/Phase	Patient population and treatment	Previous treatments	Key efficacy parameters	Key safety parameters	References
E single-agent therapy
NCT00425347 (Study 1701) Phase I	35 pts with RRMM E dose: 0.5–20 mg/kg  Enrolled: 35  Treated: 34	m: 4.5 (range 2–10) T: 79.4% L: 82.4% B: 82.4%	ORR: 0% SD: 26.5%	2 DLTs (increased serum creatinine, hypersensitivity) MTD not reached Infusion reactions: 52% (without premedication) Infections: 29.4% Most common related AEs: chills, pyrexia, flushing	^Citation28
E/L combination therapy
NCT00742560 (Study 1703) Phase I/II	102 pts with RRMM Phase I part: E–L/d E dose: 5–20 mg/kg  Enrolled: 29  Treated: 28 Phase II part: E–L/d E dose: 10 versus 20 mg/kg  Enrolled: 73  Treated: 73	m: na (range: 1–3) T: 62% L: na B: 60%	Phase I:  ORR: 82%  mPFS: 29 months Phase II:  ORR: 84%  mPFS: 28.6 months	No DLTs, MTD not reached Phase II: Infusion reactions: 11% Most frequent AEs: diarrhea, muscle spasms, and fatigue Most frequent grade 3/4 AEs: lymphopenia (21%), neutropenia (19%)	^Citation33,Citation38
NCT01239797 (CA204-004; ELOQUENT-2) Phase III	646 pts with RRMM E dose: 10 mg/kg E–L/d: Enrolled: 321  Treated: 318 L/d: Enrolled: 325  Treated: 317	m: 2 (range: 1–4) T: 48% L: 6% B: 70%	ORR: 78.5% versus 66.5% mPFS: 19.4 versus 14.9 months (HR: 0.70) Prelim. mOS: 43.7 versus 39.6 months (HR: 0.77)	Infusion reactions: 10% Infections: 81% versus 74% (198 vs 192 events/100 patient-years) Most frequent grade 3/4 AEs: lymphopenia (77% vs 49%) neutropenia (34% vs 44%)	^Citation39,Citation46
NCT01241292 (CA204-005) Japanese pts	Six Japanese pts with RRMM Treatment: E–L/d E dose: 10 or 20 mg/kg  Enrolled/treated: 6	na	ORR: 83% (5 of 6 pts)	Most frequent AEs: leukopenia, lymphopenia, neutropenia, dysgeusia, constipation, pyrexia, nasopharyngitis, and rash	(not published yet) For results, see www.ClinicalTrials.gov
NCT01393964 (CA204-007) Phase Ib	26 MM pts with different levels of renal impairment Treatment: E–L/d E dose: 10 mg/kg  Enrolled: 26  Treated: 26	m: 2 (range: 1–7) T: 42% L: 35% B: 81%	PK: E serum levels comparable across all treatment groups ORR: 75% in NRF, 67% in SRI, 56% in ESRD	Infusion reactions: 12% AEs comparable across all treatment groups Most common AEs: fatigue, diarrhea, back pain, constipation, and anemia Dose adjustments for renal dysfunction were not required	^Citation37
E/B combination therapy
NCT00726869 (Study 1702) Phase I	28 pts with RRMM Treatment: E–B E dose: 2.5–20 mg/kg  Enrolled: 28  Treated: 28	m: 2 (range: 1–3) T: na L: 46% B: 39%	ORR: 48%, including two (67%) of three pts refractory to B mTTP: 9.5 months	No DLTs, MTD not reached Infusion reactions: 71% Hypersensitivity: 7% (grade 3/4: 4%) Most frequent AEs: fatigue, anemia, diarrhea, thrombocytopenia Most frequent grade 3/4 AEs: lymphopenia (25%), fatigue (14%)	^Citation32
NCT01478048 (CA204-009) Phase II	152 pts with RRMM E dose: 10 mg/kg E–B/d  Enrolled: 77  Treated: 75 B/d:  Enrolled: 75  Treated: 75	m: na (range: 1–3) T: na L: na B: 51%	ORR: 66% versus 63% mPFS: 9.7 versus 6.9 months (HR: 0.72)	Infusion reactions: 5% Most frequent AEs: infections (67% vs 53%), diarrhea (44% vs 33%) Most frequent grade 3/4 AEs: infections (21% vs 13%), thrombocytopenia (9% vs 17%), peripheral neuropathy (9% vs 12%)	^Citation53,Citation54

Abbreviations: AE, adverse event; B, bortezomib; d, dexamethasone; DLT, dose-limiting toxicity; E, elotuzumab; ESRD, end-stage renal disease; HR, hazard ratio; L, lenalidomide; m, median; mPFS, median progression-free survival; MTD, maximum tolerated dose; mTTP, median time to progression; na, not available; NRF, normal renal function; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; pts, patients; RRMM, relapsed/refractory multiple myeloma; SD, stable disease; SRI, severe renal impairment; T, thalidomide; TTP, time to progression.

Table 2 Efficacy results of E–L/d versus L/d in treated patients with RRMM (Study ELOQUENT-2)

Parameter	E–L/d (N=318)	L/d (N=317)	References
ORR, % (95% CI)	78.5 (73.6, 82.9)	65.5 (60.1, 70.7)	^Citation39 (primary analysis)
mPFS, months (95% CI)	19.4 (16.6, 22.2)	14.9 (12.1, 17.2)	^Citation39
PFS hazard ratio (95% CI), significance	0.70 (0.57, 0.85), P=0.0004		^Citation39
1-year PFS rate, %	68	39	^Citation39
2-year PFS rate, %	41	39	^Citation39
3-year PFS rate, %	26	18	^Citation46 (3-year follow-up)
3-year follow-up PFS hazard ratio (95% CI)	0.73 (0.60, 0.89)		^Citation46
mTTNT, months (95% CI)	33 (26.15, 40.21)	21 (18.07, 23.20)	^Citation46
TTNT hazard ratio (95% CI)	0.62 (0.50, 0.77)		^Citation46
Interim mOS, months (95% CI)	43.7 (40.3, NE)	39.6 (33.3, NE)	^Citation46
Interim OS hazard ratio (95% CI), significance	0.77 (0.61, 0.97), P=0.0257		^Citation46

Abbreviations: CI, confidence interval; d, dexamethasone; E, elotuzumab; L, lenalidomide; mOS, median overall survival; mPFS, median progression-free survival; mTTNT, median time to next treatment; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TTNT, time to next treatment; RRMM, relapsed and/or refractory multiple myeloma.

Figure 4 Association of patient FcγRIIIa receptor genotype and PFS in Study CA204-009 (treatment groups: E–B/d vs B/d).

Notes: Median PFS was analyzed in patient subgroups based on genetic polymorphisms of the FcγRIIIa (CD16) receptor expressed on NK cells. In the E–B/d treatment group, longer PFS was observed for patients homozygous for the high-affinity FcγRIIIa V allele (VV) compared with the low-affinity (FF) subgroups. The data were based on all randomized patients with FcγRIIIa genotypes being homozygous VV or FF (data cut-off: Aug 10, 2015). Reprinted with permission from: Jakubowiak et al⁵³; © 2016 by The American Society of Hematology.
Abbreviations: B, bortezomib; Bd, bortezomib plus dexamethasone; CI, confidence interval; d, dexamethasone; E, elotuzumab; EBd, elotuzumab with bortezomib plus dexamethasone; NK, natural killer; PFS, progression-free survival.

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