A Phase 2 Study of Elotuzumab in Combination
With Lenalidomide and Low-Dose
Dexamethasone in Patients With
Relapsed/Refractory Multiple Myeloma
Sagar Lonial,1,2 Andrzej J. Jakubowiak,1,3 Sundar Jagannath,1,4 Marc S. Raab,5
Thierry Facon,6 Ravi Vij,1,7 Philippe Moreau,8 Donna E. Reece,9 Darrell White,10
Lotfi Benboubker,11 Jeffrey Zonder,12 Jean-Francois Rossi,13 Claire Tsao,14
Teresa Parli,14 Glenn Kroog,15 Anil K. Singhal,14 Paul G. Richardson,1,16 on
behalf of the 1703 Study Investigators
1Multiple Myeloma Research Consortium, Norwalk, CT, USA; 2Winship Cancer Institute, Emory University School of Medicine,
Atlanta, GA, USA; 3University of Michigan, Ann Arbor, MI, USA; 4Mount Sinai Medical Center, New York, NY, USA;
5Universitaetsklinikum Heidelberg, Heidelberg, Germany; 6Hopital Claude Huriez, Service des Maladies du Sang, Lille, France;
7Washington University School of Medicine, St. Louis, MO, USA; 8Hematology Department, University Hospital, Nantes, France;
9Princess Margaret Hospital, Toronto, Ontario, Canada; 10Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia,
Canada; 11CHU Tours-Hopital Bretonneau, Tours, France; 12Karmanos Cancer Institute, Detroit, MI, USA; 13CHU de Montpellier-
Hopital Saint-Eloi, Montpellier, France; 14Abbott Biotherapeutics Corporation, Redwood City, CA, USA; 15Bristol-Myers Squibb,
Princeton, NJ, USA; 16Dana-Farber Cancer Institute, Boston, MA, USA
1
Elotuzumab Background
· Elotuzumab is a humanized IgG1 mAb targeting · MoA of elotuzumab is primarily through NK
human CS1, a cell surface glycoprotein1,2
cell-mediated ADCC against myeloma cells1,2
· CS1 is highly expressed on >95% of MM cells1-3 · In a MM xenograft mouse model, the
combination of elotuzumab + lenalidomide
Lower expression on NK cells
significantly reduced tumor volume
Little to no expression on normal tissues
compared with either agent alone4
Normal plasma cells
Plasmacytoma
600
500
Lenalidomide dosing (50 mg/kg)
)3
Elotuzumab (1 mg/kg) or control
(mm 400
IgG1 dosing
Control IgG1 + DMSO
lume 300
oV
Elotuzumab + DMSO
200
mor
Lenalidomide + control IgG1
Tu 100
Elotuzumab + lenalidomide
0
14
21
28
35
42
Lymphoplasmacytic Myeloma cells in bone
lymphoma
marrow
Study Day
ADCC = antibody-dependent cellular cytotoxicity; DMSO = dimethyl sulfoxide;
mAb = monoclonal antibody; MED = maximum efficacious dose; MM = multiple myeloma; MoA = mechanism of action; NK = natural killer
1. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784; 2. Tai YT et al. Blood. 2008;112:1329-1337
3. Van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624; 4. Lonial S et al. Blood. 2009;114:Abstract 432
2
1
Summary of 1703 Phase 1 Data*
· 28 patients received elotuzumab 5, 10, or 20 mg/kg in combination
with lenalidomide and low-dose dexamethasone
· The ORR was 82% with 43% VGPR
· At median follow-up of 16.4 mos (2.232.5 mos), median PFS had
not been reached
100
PFS rate was ~70%
) 90
(% 80
70
· No DLT was observed and of 60
Patients
MTD was not reached
50
40
30
Proportion
20
· The combination was
10
Progression-Free
generally well tolerated
0
0 1 23 45678 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 2526 27 28 29 30 31 32 33
in heavily pretreated
Months
patients with MM
Number at Risk:
20 mg/kg
22
17
16
14
13
13
10
10
8
4
2
0
*Data as of October 26, 2011
DLT = dose-limiting toxicity; ORR = objective response rate; MM = multiple myeloma; MTD = maximum tolerated dose
PFS = progression-free survival; VGPR = very good partial response
3
Study Objectives
· Primary objective
Efficacy (ORR: PR) of the combination in relapsed and/or
refractory MM pts with 1-3 prior therapies
· Secondary objectives
Safety, immunogenicity, and PK/PD of the combination
· Effectiveness of premedication regimen for minimizing infusion
reactions
PFS
Determine optimum dose of elotuzumab (10 mg/kg or 20 mg/kg)
for Phase 3 studies
MM = multiple myeloma; MTD = maximum tolerated dose; ORR = objective response rate; PFS = progression-
free survival; PR = partial response; PK/PD = pharmacokinetics/pharmacodynamics
4
2
Study Design
Response Assessments
Elotuzumab
Dosing
CYCLE 1
CYCLE 2
CYCLE 3
CYCLE 5
CYCLE 6
CYCLE 1
CYCLE 2
CYCLE 3
CYCLE 4
CYCLE N-1
CYCLE N
Lenalidomide
daily dose
daily dose
daily dose
daily dose
daily dose
daily dose
Cycle day
1
8
15
22
1
8
15
22
1
8
15
22
1
8
15
22
1
8
15
22
1
8
15
22
28
Dexamethasone
· Patients randomized to elotuzumab 10 or 20 mg/kg IV in combination with
· Lenalidomide 25 mg PO
· Low-dose dexamethasone 40 mg PO
· Treatment continued until disease progression or unacceptable toxicity
5
Premedication Regimen
· Administered 30-60 minutes prior to each elotuzumab
infusion
Methylprednisolone 50 mg IV or dexamethasone 8 mg IV
Diphenhydramine 25-50 mg PO or IV (or equivalent)
Ranitidine 50 mg IV (or equivalent)
Acetaminophen 650-1000 mg PO
6
3
Key Eligibility Criteria
· Inclusion
Relapsed and/or refractory MM with 1-3 prior therapies
Measurable disease by M protein
Creatinine clearance 50 mL/min (Cockcroft-Gault method)
· Exclusion
Prior lenalidomide
Thalidomide, bortezomib, or corticosteroids within 2 weeks of the
first elotuzumab dose
7
Baseline Characteristics (N=73)
Elotuzumab
Elotuzumab
Attribute
10 mg/kg
20 mg/kg
Total
Patients, n
36
37
73
Age, median years (range)
63 (39-77)
63 (41-82)
63 (39-82)
Years since first diagnosis, median (range)
4.7 (1.2-12.6)
4.4 (0.7-13.6)
4.5 (0.7-13.6)
2 prior therapies, n (%)
20 (56)
20 (54)
40 (55)
Prior transplant (autologous), n (%)
32 (89)
28 (76)
60 (82)
Refractory to last therapy, n (%)
12 (33)
12 (32)
24 (33)
High-risk cytogenetics*, n (%)
8 (22)
2 (5)
10 (14)
2 microglobulin 3.5 mg/L, n (%)
18 (50)
15 (41)
33 (45)
Prior bortezomib, n (%)
22 (61)
22 (60)
44 (60)
Prior thalidomide, n (%)
21 (58)
24 (65)
45 (62)
Data as of October 26, 2011
*Defined as del13q by metaphase or t(4;14), t(14;16) or del17p by fluorescence in situ hybridization
8
4
Patient Disposition
Elotuzumab
Elotuzumab
Total
Attribute
10 mg/kg
20 mg/kg
Total enrolled (ITT population), n
36
37
73
Number of cycles*, median (range)
16 (3-23)
12 (1-23)
15 (1-23)
Still on study (receiving study drugs), n (%)
20 (56)
18 (49)
38 (52)
Treatment cessation, n (%)
16 (44)
19 (51)
35 (48)
Disease progression
10
8
18
Adverse event
2
8
10
Other
437
*28 days per cycle
ITT = intent-to-treat; MM = multiple myeloma
9
Efficacy
Best Response (IMWG Criteria)
Elotuzumab
Elotuzumab
10 mg/kg
20 mg/kg
Total
Patients, n
36
37
73
ORR (PR), n (%)
33 (92)
27 (73)
60 (82)
CR/stringent CR, n (%)
5 (14)
4 (11)
9 (12)
VGPR, n (%)
14 (39)
12 (32)
26 (36)
PR, n (%)
14 (39)
11 (30)
25 (34)
<PR, n (%)
3 (8)
10 (27)
13 (18)
· Median time to response: 1 month (range, 0.7-5.8)
· Median time to best response: 2.2 months (range, 0.7-17.5)
CR = complete response; IMWG = International Myeloma Working Group; PR = partial response;
VGPR = very good partial response
10
5
Best Response by Number of Prior Therapies at
Screening (IMWG Criteria)
No. of Prior
Elotuzumab
Elotuzumab
Therapies
Parameter
10 mg/kg
20 mg/kg
Total
Patients, n
16
17
33
1
ORR (PR), n (%)
16 (100)
14 (82)
30 (91)
VGPR, n (%)
9 (56)
6 (35)
15 (45)
Patients, n
20
20
40
2
ORR (PR), n (%)
17 (85)
13 (65)
30 (75)
VGPR, n (%)
10 (50)
10 (50)
20 (50)
IMWG = International Myeloma Working Group; ORR = objective response rate; PR = partial response;
VGPR = very good partial response
11
Progression-free Survival
100
90
)
80
(%
70
of
60
on
Patients
ti
ree
50
opor
40
Pr
Median Time to Progression/Death:
Median Follow-up:
30
10 mg/kg (n=36): NA
10 mg/kg: 14.0 mos (range 2.6-21.2 mos)
20 mg/kg (n=37): NA
20 mg/kg: 14.3 mos (range 2.1-20.5 mos)
Progression-f
20
10
0
01
23
4
5
6
7
89 10 11 12 13 14 15 16 17 18 19 20 21 22
Number at Risk:
Months
10 mg/kg
36
32
30
29
21
13
4
1
0
20 mg/kg
37
29
26
23
19
14
4
0
0
At a median follow-up of 14.1 months, the median PFS was not reached
PFS rate was 75% (10 mg/kg) and 65% (20 mg/kg)
12
6
Treatment-emergent AEs*
(All Grade 25% or Grade 3/4 5%)
Total, N=73
Elotuzumab
Elotuzumab
Preferred Term, n (%)
10 mg/kg, n=36
20 mg/kg, n=37
Any Grade
Grade 3/4
Muscle spasms
19 (53)
21 (57)
40 (55)
2 (3)
Diarrhea
20 (56)
19 (51)
39 (53)
4 (5)
Fatigue
19 (53)
16 (43)
35 (48)
5 (7)
Constipation
14 (39)
19 (51)
33 (45)
0
Nausea
16 (44)
15 (41)
31 (42)
1 (1)
Upper respiratory tract infection
17 (47)
13 (35)
30 (41)
2 (3)
Pyrexia
14 (39)
14 (38)
28 (38)
1 (1)
Anemia
13 (36)
10 (27)
23 (32)
8 (11)
Insomnia
9 (25)
13 (35)
22 (30)
1 (1)
Peripheral edema
12 (33)
9 (24)
21 (29)
1 (1)
Back pain
11 (31)
8 (22)
19 (26)
2 (3)
Hyperglycemia
7 (19)
12 (32)
19 (26)
7 (10)
Neutropenia
11 (31)
8 (22)
19 (26)
12 (16)
Thrombocytopenia
11 (31)
7 (19)
18 (25)
12 (16)
Lymphopenia
10 (28)
7 (19)
17 (23)
12 (16)
Leukopenia
7 (19)
5 (14)
12 (16)
6 (8)
Hypokalemia
5 (14)
6 (16)
11 (15)
4 (5)
AE = adverse event
*Events emerging from treatment with elotuzumab plus lenalidomide/low-dose dexamethasone (not present at baseline)
Grade 5: 1 patient, pneumonia complicated by cellulitis and sepsis leading to multi-organ failure
The 4 most common AEs of any Grade and Grade 3/4 are highlighted
13
Peri-infusion AEs*
· Peri-infusion AEs (all Grades) reported in 49 of 73 (67%) patients
Nausea, headache, pyrexia, cough, dizziness (10%)
Dyspnea, erythema, rash, vomiting, chills, flushing, hyperhidrosis,
edema, palpitations (5.0%-9.9%)
Grade 3 peri-infusion AEs reported in 2 of 73 (3%) patients
· 1 rash and 1 nausea
There were no Grade 4 peri-infusion AEs
*Peri-infusion AEs predefined as: 110 AE terms of potential signs/symptoms of infusion
reaction occurring the day of / day after elotuzumab infusion regardless of investigator
assessed causality
14
7
Investigator-designated Infusion Reactions
· Investigator-designated infusion reactions are AEs identified by the
investigator as a sign or symptom of an elotuzumab-related infusion
reaction
· AEs that occurred in 2 subjects included nausea, pyrexia and rash
Elotuzumab
10 mg/kg
20 mg/kg
Total
Parameter, n (%)
n=36
n=37
N=73
Any AE
5 (14)
4 (11)
9 (12)
Grade 1
3 (8)
2 (5)
5 (7)
Grade 2
1 (3)
2 (5)
3 (4)
Grade 3*
1 (3) Rash
0
1(1)
AE = adverse event
*There were no Grade 4 infusion reaction AEs
15
Conclusions
· Elotuzumab plus lenalidomide and low-dose dexamethasone has a
high ORR in relapsed and relapsed/refractory MM
82% for all patients (91% in patients who had received only 1 prior therapy)
92% for patients treated with elotuzumab 10 mg/kg
· At a median follow-up of 14.1 months, the median PFS was not
reached
PFS rate was 65% to 75%
· The combination was generally well tolerated
Most common Grade 3/4 treatment-emergent AEs were neutropenia (16%),
thrombocytopenia (16%), and lymphopenia (16%)
Premedication regimen decreased incidence and mitigated severity of
infusion reactions*
*Richardson PG et al. J Clin Oncol 29: 2011 (suppl; abstr 8014)
16
8
Future Directions
· 10 mg/kg elotuzumab is the recommended Phase 3 dose
High ORR and similar safety profile for 10 and 20 mg/kg dose
· Two Phase 3 trials of 10 mg/kg elotuzumab plus lenalidomide and
low-dose dexamethasone are ongoing
ELOQUENT1 in previously untreated MM patients (CA204-006; NCT01335399)
ELOQUENT2 in relapsed/refractory MM patients (CA204-004; NCT01239797)
Poster Presentation Monday December 12
Poster 3968
Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone
in High-Risk and/or Stage 2-3 Relapsed and/or Refractory Multiple Myeloma: A
Retrospective Subset Analysis of the Phase 2 Study
Presenter: Sundar Jagannath
Hall GH, 6:00 8:00 PM
17
Acknowledgments
· The investigational drug elotuzumab is being developed in a
partnership between Abbott Biotherapeutics Corp. and
Bristol-Myers Squibb
· This study was sponsored by Abbott Biotherapeutics Corp.
and Bristol-Myers Squibb
· The authors and sponsors wish to thank the patients and
their families, as well as the 1703 study investigators and the
Multiple Myeloma Research Consortium for their
participation in this study
· Editorial support and graphic services were provided by
StemScientific and funded by both companies
18
9
Acknowledgments
· CHU de Montpellier-Hôpital Saint-Eloi, Montpellier, France
· CHU Tours-Hôpital Bretonneau, Tours, France
· Dana-Farber Cancer Institute, Boston, MA
· Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA
· Hôpital Claude Huriez, Service des Maladies du Sang, Lille, France
· Karmanos Cancer Institute, Detroit, MI
· Mount Sinai Medical Center, New York, NY
· Princess Margaret Hospital, Toronto, Ontario, Canada
· Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada
· Universitaetsklinikum Heidelberg, Heidelberg, Germany
· University Hospital, Nantes, France
· University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
· Washington University School of Medicine, St. Louis, MO
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