A Phase
Phase III Study to Determine the
the Efficacy
and Safety of Lenalidomide in Combination
With Melphalan and
and Prednisone Followed by
by
Lenalidomide (MPR-R) in Patients 65 Years
With Newly Diagnosed
Diagnosed Multiple
Multiple Myeloma
Myeloma
(NDMM)
Antonio Palumbo1 Meletios Dimopoulos2 Michel Delforge3 Martin Kropff4
Antonio Palumbo1, Meletios Dimopoulos2, Michel Delforge3, Martin Kropff ,
Robin Foa5, Zhinuan Yu6, Lindsay Herbein6, Jay Mei6, Christian Jacques6,
John Catalano7
1Division of Hematology, University of Torino, Torino, Italy; 2Department of Clinical Therapeutics, Alexandra Hospital, University of Athens
School of Medicine, Athens, Greece; 3University Hospital Leuven, Leuven, Belgium; 4Department of Medicine (Hematology/Oncology),
University of Muenster, Muenster, Germany; 5Division of Hematology, University, Rome, Italy; 6Celgene Corporation, Summit, NJ;
7Haematology Dept and Dorevitch Pathology, Frankston Hospital, Frankston, Australia
1

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Rationale for Continuous Lenalidomide
· Tumoricidal and immunomodulatory effects
· Favorable tolerability
tolerability profile
profile
Continuous Lenalidomide
MPT Induction
In RR Multiple Myeloma4
PFS
PFS
p-value
Discontinue
Continue
Median
HR
Len
Len
(months)
IFM 99-061
Median TTP
13.6
Not reached
· MP
17.8
0.51
<0.0001
(mo)
(>16.2)
· MPT
27.5
IFM 01-012
Median OS
29.5
Not reached
· MP
18 5
.
06
0. 2
62
0 001
.
(mo)
(>39 0
. )
0)
· MPT
24.1
GIMEMA3
· MP
14.5
0.63
0.0004
· MPT
21 8
.
1. Facon et al. Lancet 2007; 2. Hulin et al JCO 2009; 3. Palumbo et al. Blood 2008; 4. San Miguel, ASH 2008
2

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Phase I/II Study
Cycles (28-day) 1-9
Cycles 10+
MPR-R
Lenalidomide
M: 0.18 mg/kg, days 1-4
Continued Tx
P: 2 mg/kg, days 1-4
10 mg/day,
R: 10 mg/day po, days 1-21
days 1-21
100
50
OS
80
40
33
29
PFS
60
30
(%)
(%)
24
20
tients
40
tients
aP
Median PFS 28.5 months
Pa
10
20
2-Year OS 91%
1
0
0
0
0
5
10
15
20
25
30
35
CR
VGPR
PR
MR
PD or
Time (months)
SD
Palumbo A, et al. Clin Lymphoma Myeloma. 2009;9:145-50.
3

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Phase III Study Schema
N=459, 82 centers in Europe, Australia and Israel
Cycles (28-day) 1-9
Cycles 10+
MPR-R
Lenalidom
Lenalido ide
m
M:
Continued Tx
0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
10 mg/day,
R: 10 mg/day po, days 1-21
ION
days 1-21
T
MPR
Lenalidomide
Disease
Primary
M: 0.18
Comparison
mg/kg, days 1-4
MISA
progression
(25 mg/day)
P: 2 MPR-R
mg/kg,
vs.
days MP
1-4
Placebo
+/-
O
R: 10 mg/day po, days 1-21
dexamethasone
Secondary
MP
Comparison
AND
M: MPR-R
0.18
vs.
mg/kg, MPR
days 1-4
R
Addition
P: 2
of
mg/kg, MPR
days arm
1-4
per
Placebo
PBO: EMEA
days
advice
1-21
Open-Label Extension/
Double-Blind Treatment Phase
Follow-Up Phase
Stratified by age ( 75 vs. > 75 years) and stage (ISS 1,2 vs. 3)
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.
4

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Phase III Study: First Interim Analysis
Intent to Treat Analysis
· Registration trial for newly diagnosed patients 65 yrs old
· Primary endpoint: PFS
­ Powered to show a 50% improvement in PFS for MPR-R (22.5 months)
vs. MP (15 months)
months)
· Independent adjudication committee confirmed responses
and progressions
progressions
· DMC suggested to unblind the study
­ Significant difference of MPR-R vs. MP (p<0.001)
­ Patients will be unblinded but will continue treatment in the current
treatment arms
· Presentation will focus on
on primary
primary comparison: MPR-Rv
R s
vs. MP
MP
­ Data cut-off 15 April 2009
­ Median follow-up 9.4 months for PFS
5

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Patient Characteristics
· 459 patients randomised between Feb 2007 and Sept 2008
­ 180 patients ongoing (MPR-R: 73; MPR: 54; MP: 53)
MPR-R
MPR
MP
N = 152
N = 153
N = 154
71
71
72
Median age, years (range)
(65-87)
(65-86)
(65-91)
Age distribution
> 75 years
24%
24%
25%
ISS Stage I / II / III
18 / 33 / 49%
21 / 31 / 48%
18 / 31 / 51%
Median BM plasma cells
35%
38%
35%
ISS, International Staging System
6

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Best Response
MPR-R
MPR
MP
P Value
Best Overall Responsea
(MPR-R
N = 152
N = 153
N = 154
vs. MP)
ORR
77%
67%
49%
<0.001
CRb
CR
18%
13%
5%
<0.001
VGPRc
32%
33%
11%
<0.001
PR
45%
34%
37%
---
Progressive Disease
0%
1%
0%
---
Median time to first response, months
1.9
1.9
2.8
<0.001
a. As measured using EBMT criteria1
b. Immunofixation negative with or without bone marrow confirmation
c. VGPR: >90% reduction in M-protein
1. Bladé J et al. Br J Haematol. 1998;102:1115-1123.
7

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Time to First Response
100
90
MPR-R
80
at least PR
70
s(%) 60
MP
50
at least PR
Patient 40
MPR-R
30
at least VGPR
VG
20
MP
10
at least VGPR
0
12345
6789
10
11
12
13
14
15
16
17
18
Treatment Cycle
· Within
Within first 3 months of therapy, 60% achieved PR
· Improvement to VGPR noted after 17 months of treatment
8

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Progression-Free Survival
First Interim Analysis
50% Reduced Risk in PFS
100
)
Median PFS
(%
MPR-R
Not reached
75
MP
13.0 months
tEvent
Medi
ed an
a foll
o ow
o up
u :
p 9.4
9 mos
50
withoutsn 25 HR 0.499
95% CI [0.330, 0.755]
Patie
Logrank P<0.001
0
0
5
10
1
15
20
25
30
PFS Tim
T
e (mont
mon hs)
No. at Risk
MPR-R
152
115
70
36
11
2
1
MP
154
114
77
21
4
1
1
9

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Time to Next Treatment
63% Reduced Risk for Next Treatment
100
MPR-R
75
ts(%)
MP
t
Even
50
ithw
25
HR 0.369
95% CI [0.243, 0.559]
Patients
Logrank P<0
P<0 001
.
0
0
10
20
30
Months
MPR-R
MP
N = 152
N = 154
n
n
Received next treatment
32
74
Lenalidomide
11
43
Bortezomib
11
9
Others
10
22
10

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Overall Survival
100
)
(%
75
MPR-R
tEvent
MP
50
92% 1-year Overall Survival
withoutsn
Patie 25
Total number of deaths: 37
0
0
5
10
15
20
25
30
OS time (months)
11

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MPR-R vs. MPR
Secondary Comparison
yp
Cycles (28-day) 1-9
Cycles 10+
MPR-R
Lenalidom
Lenalido ide
m
M:
Continued Tx
0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
10 mg/day,
R: 10 mg/day po, days 1-21
ION
days 1-21
T
MPR
Disease
Primary
M: 0.18
Analysis
mg/kg, days 1-4
MISA
progression
P:
O
MPR
2 mg/kg,
MPR-Rv
days
R s
vs. M
1-4
Placebo
O
P
MP
R: 10 mg/day po, days 1-21
AND
Secondary Comparison
R
MPR-R vs. MPR
R
Addition of MPR arm per
EMEA advice
Double-Blind Treatment Phase
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.
12

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MPR-R vs. MPR
47% Reduced Risk in PFS
100
Median PFS
MPR-
MPR R
Not reached
reached
MPR
13.2 months
(%) 75
ventE
50
swithout
25
HR 0.530
Patient
95% CI [0.350, 0.802]
Logrank P=
P 0.002
0.002
0
05
10
15
20
25
30
PFS Time (months)
No. at Risk
MPR-R
152
115
70
36
11
2
1
MPR
153
122
78
20
5
1
1
13

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MPR-R vs. MPR
Landmark PFS Analysis After Cycle 9
75% Reduced Risk in PFS
100
MPR-
MPR R
MPR
(%) 75
ventE
50
swithout
25
HR 0.245
Patient
95% CI [0.126, 0.476]
Logrank P<0.001
P<0.001
0
0
5
10
15
20
PFS Time (months)
No. at Risk
MPR-R
75
40
17
3
1
MPR
81
21
8
1
1
14

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Grade 3/4 Hematologic Adverse Events
MP
G4
G3
MPR-R
G4
G3
Anemia
Thrombocyt
Thrombocy openia
Neutropenia
Febrile neutropenia
0
102030
40506070
80
Patients (%)
· G-CSF administration (49% MPR-R vs. 29% MP)
· Platelet transfusion (6% MPR
MPR-R5
R vs. %
5% MP)
MP)
15

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Grade 3/4 Non-Hematologic Adverse Events
MP
G3/4
DVT/PE
MPR-R
G3/4
Rash
Fatigue
Peripheral
neuropathy
Infections
05
10
15
20
25
Patients (%)
· Overall discontinuation due to AEs (16% MPR-R vs. 7% MP)
­ Disconti
i
nuat on due to h
l
emato
i
og c AEs (7% MPR-R2
R vs. %
2% MP)
MP)
DVT, deep vein thrombosis; PE, pulmonary embolism.
16

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Grade 3/4 AEs After Cycle 9
(Continuous Len
e ali
a domi
do
de)
MPR-R
MP
N=
N = 75
75
N=9
N = 4
94
Anemia
0%
5%
Thrombocytopenia
3%
1%
Neutropenia
1%
0%
DVT
3%
0%
Rh
Rash
0%
0%
Fatigue
1%
0%
Peripheral neuropathy
neuropathy
0%
0%
DVT, deep vein thrombosis
17

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Conclusions
MPR-R in
in Elderly
Elderly NDMM
· Continuous lenalidomide is superior to regimens
of limited duration
· MPR-R is superior to MP
­ Higher and more
id
rap
responses
­ 50% reduced risk of progression
· Favorable safety profile
profile
­ Grade 4 neutropenia: 36% (febrile neutropenia: <7%)
­ No Grade 3/4
3/4 peripheral neuropathy
neuropathy (Grade
(Grade 2:
2: 1%
1% )
­ Low discontinuation due to AE: 16%
· MPR-
MPR R is
is a new standard
standard treatment option for
elderly patients
18

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We
W Are Grateful to All Patients, Nurses and
Physicians of the Participating Centers
Dimopoulo
Dimopou s
lo
Greece
Gobbi
Italy
Ahlgren
Sweden
Adam
Czech Republic
Dmoszynska
Poland
Masliak
Ukraine
Kropff
Germany
Domnikova
Russia
Kaplan
Ukraine
Foa
Italy
Rossiev
Russia
Keting
Ukraine
Palumbo
Italy
Cagirgan
Turkey
Taylor
Australia
Catalano
Australia
Prince
Australia
Scudla
Czech Republic
Gisslinger
Austria
Horvath
Australia
Jaccard
France
Jedrzejczak
Poland
Spencer
Australia
Morra-Barbarano
Italy
Delforge
Belgium
Gregersen
Denmark
Rukavitsin
Russia
Zodela
Zode va
la
Georgi
Georg a
i
Engelhardt
Germany
German
Capot
Capo e
t
Spain
Weisel
Germany
Terpos
Greece
Zweegman
The Netherlands
Cascavilla
Italy
Rowe
Israel
Pilipenko
Ukraine
Van Droogenbroeck
Belgium
Hellmann
Poland
Lysaya
Ukraine
Iosava
Georgia
Abdulkadyrov
Russia
Tretyak
Ukraine
Cavo
Italy
Greil
Austria
Joshua
Australia
Kloczko
Poland
Maisnar
Czech Republic
Mollee
Australia
Blade Creixenti
Spain
Attal
France
Augustson
Australia
Beksac
Turkey
Knop
Germany
Gastl
Austria
Spicka
Czech Republic
Alegre Amor
Spain
Rossi
France
Plesner
Denmark
Yong
United Kingdom
Goldschmidt
Germany
Naumann-Radke
Germany
Iskrov
Belarus
Crotty
Ireland
Liebisch-Langer
Germany
Fillet
Belgium
Skotnicki
Poland
Ben-Yehuda
Israel
Schots
Belgium
Osmanov
Russia
Corso
Italy
Macro
France
SM
San
i
Miguel
Si
Spain
Ludwig
Austria
Dölken
Germany
Ríos Herranz
Spain
Niederwieser
Germany
Nagler
Israel
Stenner
Switzerland
Caravita
Italy
Shpilberg
Israel
Schey
United Kingdom
Uss
Belarus
19

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Disclosures
Disclosures: Palumbo: Celgene: Honoraria; Janssen Cilag:
Honoraria. Off Label Use: Lenalidomide is not approved for first line
use in multiple myeloma. Dimopoulos: Celgene: Honoraria. Delforge:
Janssen-Cilag: Consultancy, Honoraria; Celgene: Honoraria, Speakers
Bureau. Kf
Krop f
ff: Ot
Or h
tho Bi
Bi t
o ech: Cl
Consu t
ltancy, Honoraria, S
k
pea ers
Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Foa:
Celgene: Membership on an entity's Board of Directors or advisory
committees. Yu: Celgene: Employment. Herbein: Celgene:
Employment. Mei: Celgene: Employment. Jacques: Celgene:
Employment. Catalano: Celgene: Research Funding.
20

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Discontinuation rate
2005-2007
2007
2009
50
40
30
MPT
MPV
20
Meta-analysis1
40%
VISTA2
10
36%
MPR-R MM-015
16%
0
Reduced Risk of Progression
2005-2007
2007
2009
0
-10
MPT
Meta-analysis1
-20
MPV
37%
VISTA2
MPR-R
-30
44%
MM-015
50%
-40
-50
1. Kapoor et al. ASH 2009 Abstract # 0615; 2. San Miguel et al. N Engl J Med 2008;359:906-17 Appendix.

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MPR-R in Elderly NDMM
MPR-R is superior to MP
­ Higher and more rapid responses
­ 50%
d
re
d
uce ri k
s
f
o
i
progress on
MPR induction regimen
­ Hi h
g er ORR
ORR, faster response, Improved Quality f
o Response
­ Low discontinuation due to AE: 16%
­ More patients able to continue initial therapy with better quality of
responses
Efficacy of continuous lenalidomide therapy
­ Unprecedented 75% reduction of risk of progression
MPR-R in comparison to MPT
­ Reduced risk
s of
o pr
p og
o r
g essi
ess on
o 50% ver
e sus
sus 37
3 %
­ Rate of discontinuation 16% versus 40%
22

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