PowerPoint Presentation

Two Phase III Randomized,
Double-Blind, Placebo-Controlled
Trials of Lenalidomide-
Dexamethasone Vs.
Dexamethasone for Refractory or
Relapsed Multiple Myeloma
MM 009: (48 Centers North America) USA, Canada
(PI: Weber, Houston, USA)
MM 010: (51 Centers International) Europe, Australia,
Israel (PI: Dimopoulos, Athens, Greece)

Lenalidomide for Myeloma
Resistant MM
Total # Pts. Response(%)
Phase1
24
29
(Richardson et al, Blood
98(11): abst 3225, 2001
Phase1
15
30
(Zangari et al, Blood 98(11):
abst 3226, 2001)
Phase 2
83
24
(Richardson et al, Blood:
33
abst 825, 2003

CC-5013 25 mg d 1-21
Placebo d 22-28
TTP
Dex 40 mg, d 1-4, 9-12, 17-20
OS
Same except
X 4 COURSES
Dex d 1-4
RR
Continue until PD
Safety
Placebo d 1-28
1st SRE
Dex 40 mg, d 1-4, 9-12, 17-20
PS
PI: International (MM010): Dimopoulos (351pts)
North America (MM009) (354 pts)

Inclusion Criteria
· Refractory or relapsing MM
· < 3 previous regimens
Exclusion Criteria
· Resistance to > 200 mg Dexamethasone/ 1mo
· Liver Enzymes < 3x normal
· Creatinine < 2 mg/dL

Randomization/Stratification
· B M ( < 2.5 mg/L Vs. > 2.5 mg/L)
2
· Prior Transplant ( 0 Vs. > 1)
· No. Prior Anti-MM Regimens
( < 1 Vs > 1)

Patient Characteristics
MM-009
MM-010
Len/Dex Dex Len/Dex Dex
No. Pts.
170
171
176
175
Male (%)
60
59
59
59
Med. Age (yrs)
63
63
62
63
ECOG PS < 1 (%) 89
95
85
82

Patient Characteristics
MM-009
MM-010
Len/Dex Dex Len/Dex Dex
No. Pts.
170
171
176
175
DS Stage III (%)
66
67
65
63
Lytic Lesions (%)
69
77
77
80
Mean % Marrow
33
31
33
30
Plasmacytosis

Patient Characteristics
MM-009
MM-010
Len/Dex Dex Len/Dex Dex
No. Pts.
170
171
176
175
Mean Time from
Dx (yrs)
3.6
3.9
4.2
4.8
Prior Anti-MM
regimens > 2 (%) 56
54
64
64
Prior SCT > 1 (%) 61
58
56
54

Prior Therapies
Bort
Thal
Dex
SCT
70
50
Patients 30
%
10
009
009
009
009
010
010
010
010

MM- 009/010 Interim Analysis
· Planned when 50% of subjects (111
patients) progressed
· MM- 009 Patients enrolled from
Feb 2003 May 2004 (50% prog:
07/04)
· MM-010 Patients enrolled from
Sep 2003 Aug 2004 (50% prog:
09/2004)

Response Criteria
Partial Remission (PR):
> 50% decrease in serum M-protein
> 90% decrease in Bence Jones protein
Complete Remission (CR):
No serum M-protein
By Immunofixation
No Bence Jones protein
< 5% marrow plasma cells

Response Criteria
Minimal Response (MR):
> 25% - 49% decrease in serum M-protein
> 50% - < 89% decrease in Bence Jones pro.
Stable Disease (SD):
No More than a 25% change in M-protein
(over at least 3 month period)

Response Criteria
Progressive Disease (PD)
> 25% increase in nadir M-protein
(must be >0.5 g/dL increase in M-prot for PR
or reappearance for CR relapse)
New Lytic Bone Lesion/plasmacytoma
Hypercalcemia due to MM
Growth of soft tissue plasmacytoma
> 25% BM plasma cells

Response 1
PR+CR
80
PR (>50%)
CR (IF-)
61.2%*
(%)
60
57.9%
* p<0.001
Rate
40
34.7%
22.8%*
21.7%
Response
20
44.3%
26.5%
18.7%
17.7%
13.6%
0
4.1%
4.0%
Len/dex
Len/dex
Dex
Dex
009
010
009
010
1 Blade Criteria

Time To Progression
1.0
Len/Dex
Dex alone
0.8
P < .000001
Patients 0.6
of
0.4
010
009
0.2
Proportion
009
010
0
2.5
5
7.5
10 12.5 15 17.5 20 22.5
Time to Progression (months)

Summary of Efficacy
MM-009 MM-010 MM-009 MM-010
Len/Dex Len/Dex
Dex
Dex
CR + PR (%)
61.2
58.0
22.8
21.7
p<.001
CR (%)
26.5
13.6
4.1
4.0
PR (%)
34.7
44.3
18.7
17.7
SD (%)
28.2
33.5
57.9
64.6
PD (%)
2.9
2.8
12.3
7.4
Med TTP (mos) 15
13.3
5.1
5.1 p<.000001

Grade 3/4 Hematologic Toxicity
70%
50%
30%
10%
LD D LD D LD D LD D LD D LD D LD D LD D
009
010
009
010
009
010
009
010
Anemia Thrombocytopenia Neutropenia Neutropenic
Fever

Len-Dex: Thrombocytopenia
30%
20%
10%
LD D LD D LD D LD D LD D LD D LD D LD D
009
010
009
010
009
010
009
010
Grade 1
Grade 2
Grade 3
Grade 4
LLN-75,000
50-74,000
25-49,000
< 25,000

Grade 3/4 Toxicity
70%
60%
50%
40%
30%
20%
10%
0% LD D LD D LD D LD D LD D LD D LD D LD D
009
010
009
010
009
010
009
010
Fatigue
Neuropathy
Constipation
Pneumonia

Thromboembolic Events
70%
50%
30%
15.3
13.5
10%
8.5
3.5 4.5 3.4
2.9
4.5
0.6 4.0 1.1
3.5
LD D LD D
LD D
LD
D
LD D LD
D
009
010
009
010
009
010
DVT
PE
Total TE

Other G 3/4 Adverse Events
MM-009
MM-010
Len/Dex
Dex
Len/Dex
Dex
N = 170
N =170
N = 176
N =175
Atrial Fibrillation
4.7
0
0.6
1.8
CHF
2.4
0
0.6
0
Diarrhea
2.4
0
2.4
1.2
AE leading to dose
32.4
22.4
43.8
29.1
reduction, %
AE leading to
22.4
15.3
18.8
13.7
discontinuation, %

Reasons for Discontinuation
MM-009
MM-010
Len/Dex
Dex
Len/Dex
Dex
N = 170
N =170
N = 176
N =175
Discontinued (%)
57
88
50
79
PD
29
67
26
59
AE
14
9
7
6
Pt Decline
65
11
5
SD
23
0
2
Death
20.6
6
6
Other
43
0
0.6

Conclusions
· Neuropathy, constipation, fatigue <
thalidomide
· Myelosuppression > thalidomide,
manageable with dose reduction
· Thrombosis must be clarified,
anticoagulation appears probable
· High response, CR, and prolonged
TTP (in both trials) justify lenalidomide's
role for ref. MM & investigation in
untreated MM

Chen, Christine
Burris, Howard
Dobbs, Tracy
Dimopoulos, Meletios
Blade, Joan
Fanin, Renato
Niesvizky, Ruben
Jakubowiak, Andrzej J
Shustik, Chaim
Spencer, Andrew
Pilipenko, Galina
Lentzsch, Suzanne
Wang, Michael
Vij, Ravi
Silverman-DeMagalhaes, M
Attal, Michael
Delforge, Michel
Morra, Enrica
Belch,
Prince,
Andrew
Abonour, Rafat
Singhal, Seema
Miles
Lahuerta, Juan -Jose
Yong, Kwee
Stadtmauer,
Dmoszynska, Edward
Moreb, Jan
Chu, Luis
Anna
Rowe, Jacob M.
Baccarani, Michele
Siegel, Davi
Harousseau, dJean
-Luke
Bertoli, Luigi
Schey, Stephen
Farag, Sherif
Hitz, Felicitas
Wade, James
Hellmann,
C.
Andrezej
Brown, Archie
Fenk, Roland
Gregory, Stephanie
Prosper, A
Felipe
Borrell
San
o, Ivan
Miguel, Jesus
Roodman, G. David
Karamanesht,
E
Lambert-Fa
S lls,
zer,Rose
Jeffmary
Rajkumar,
Facon,
S.
ThierryVincent
Jagannath, Sundar
Nagler, Arnon
Moreno, Alvaro Aspitia
Wood, Peter
Chanan-Khan,
Mandelli,
Asher
Franco
Richardson, Paul
Taylor, Kerry
Seropian, Stuart
Baro, Julio
Lonial
Masliak, , Sagar
Zvenyslava
White, Darrell
Fermand, Jean
-P
Stuart,
ierre
Robert
Bird, Jenny
Alsina,
Konopka, Melissa
Lech
Ballester,
K
Oscar
aplan, Polina
Tirumali, Negandra
Coiffer, Bertrand
de Castro,
Alegre,
Carlos
Adrian
Coutre, Steven
Kropff, Martin
Wiernik, Peter
Drake, Mary
Hurd, David
Catalano, John
Gentile, Teresa
Ludwig, Heinz
Barton, Kevin
Ferrant, A
Zonder, Jeffrey
Goldschmidt, Hartmut
Martin, Thomas
Maschmeuyer, G
Fernandez,
G Hugo
obbi, Marco
Lazzarino, Mario
Schiller, Gary
Yehuda, Dina Ben
Geils, George
Guenther, Andreas
Lysaya, Tamila
Somlo, George
Taverna, Christian

MDs
R Alexanian, M Wang
Research nurses, PAs
M Gavino, P Sanjorjo
C.A. Nguyen, T Richards, V Mathai
Celgene
Data Coordinators
J Zeldis, R Knight
Kim Rankin, Kay Delasalle
M Olesnyckyi, Zhinuan Yu