Phase III trial of lenalidomide plus high-dose
dexamethasone versus lenalidomide plus low-
dose dexamethasone in newly diagnosed multiple
myeloma (E4A03): a trial coordinated by the
Eastern Cooperative Oncology Group
S. Vi
V ncent Rajkumar,
Rajkumar Susanna Jacobus, Natalie
Natalie Callander,
Callander
Rafael Fonseca, David Vesole, Michael Williams, Rafat
Abonour, David Siegel, and Philip
gp Greipp
pp
Mayo Clinic, Rochester, MN; Dana Farber Cancer Institute, Boston,
MA; University
University of Wi
W sconsin,
i
Madison,
Madison, WI; Mayo
Mayo Clinic Arizona,
Scottsdale, AZ; St. Vincent's Hospital, New York, NY, University of
Virginia, Charlottesville, VA, Indiana University, Indianapolis, IN,
Hackensack University Medical Center, Hackensack, NJ
Thalidomide/Dex in Newly Diagnosed MM
Study
Type of study
No. of
Response
patients
rate
Rajkumar et al (Mayo
Phase II
50
64%
Clinic)
Weber et al (MDACC)
Phase II
40
72%
Cavo et al
Phase II
71
66%
Rajkumar et al (ECOG)
Phase III
207
63%
Rajkumar et al (MM 003)
Phase III
470
63%
Rajkumar SV. J Clin Oncol 2002;20: 4319-4323; Weber D. J Clin Oncol Jan 2003; Cavo et al. Haematologica
2004:89:826-31; Cavo M. Blood 2005;106:35-39; Rajkumar SV. J Clin Oncol 2006;24:431-6; Rajkumar SV.
ASH 2006
Mayo Phase II Trial
Lenalidomide/Dex (Rev/Dex) in New MM
Endpoint
Response Rate
Rate
Response rate (PR or better)
91%
CR plus VGPR
56%
Grade 3-4 non-hematologic toxicities: 55% patients
Lacy MQ. ASH 2006; Rajkumar et al. Blood 2005;106:4050-4053
Aim
· A phase III trial comparing lenalidomide plus
high-dose
g
dexamethasone versus
lenalidomide plus low-dose dexamethasone
as first line therapy in newly diagnosed
multiple myeloma
Schema
R
445 pts
A
N
@ 4 months
D
Rev + Dex
CR/PR
Pts eligible for
O
4l
x4 cycles
SCT can
M
proceed to SCT*
I
Z
A
Rev + Low
Less
Thal +
T
dose Dex
than
Dex
CR/PR/Stable
I
x 4l
4 cycles
PR
x 4 cycles
O
N
Tt
Treat
t
men S h
c
d
e
l
u e
Days
1
8
15
22
28
Lenalidomide 25 mg PO d1-21
A
Total Dex
A
dose per
Dex
Dex
Dex
Cycle =
d1-4
d9-12
d17-20
480 mg
Lenalidomi
do
de 25 mg PO days
days 1-21
Tot
To a
t l
a Dex
Dex
B
dose per
D
D
D
D
Cycle =
e
e
e
e
160 mg
x
x
x
x
d1
d8
d15
d22
DVT
h
prop
l
y axis
· Prior to Sept 15, 2005: Thromboprophylaxis with ASA
recommended but not mandated
· After Sept
Sept 15, 2005: ASA instituted as mandatory
thromboprophylaxis; warfarin/LMWH strongly
recommended for pts in Arm A
Patient Characteristics
Characteristics
Arm A
Arm B
(n=223)
(n=222)
ISS (%)
Stage I
30 5
.
31 5
.
Stage II
37.8
37.8
Stage III
23.3
23.9
Patient Characteristics
Characteristics
Arm A
Arm B
(n=223)
(n=222)
Male (%)
57.8
54.1
Age (yrs)
(yrs)
66 (36-88)
65 (35-86)
ECOG PS < 1 (%)
89.7
89.6
BMPC (%)
44.5
40.0
Serum M protein (g/dL)
3.2
3.1
Hemoglobin (g/dL)
10.9
11.1
Patient Characteristics
Characteristics
Arm A
Arm B
(n=223)
(n=222)
DS Stage III (%)
79.3
75.2
MM Bone Disease (%)
(%)
65
60
Albumin (g/dL)
3.5
3.6
LDH (U/L)
155
159
B2 Microglobulin (µg/mL)
3.75
3.5
Creatinine (mg/dL)
1.1
1.0
Serious adverse events
Hematologic Toxicity
Toxicity
Arm A
Arm B
P value
(N=433 Ever Reported)
(N=217)
(N=216)
Hemoglobin
7.8%
6.0%
0.12
Neutrophils
9.7%
19%
0.002
Platelets
4.1%
5.1%
0.16
Si
Serious d
a verse events
Non-Hematologic Toxicity
Toxicity
Arm A
Arm B
P value
(N=433 Ever Reported)
(N=217)
(N=216)
DVT/PE (AdEERS*)
23.8%
9.1%
<0.001
Infection/Pneumonia
14.7%
5.1%
<0.001
Hyperglycemia
9.7%
6%
0.05
Cardiac ischemia
2.8%
0.5%
0.05
Atrial fibrillation/flutter
2.3%
0.5%
0.09
Neuropathy
1.4%
0.9%
0.31
DVT/PE
Toxicity
Arm A
Arm B
(N=443 Started Treatment)
N=223 (%)
N=220 (%)
DVT/PE
First 4 months
20
7
Any time
24
9
PE
9
4
DVT/PE
Arm A
Arm B
Before
After
Before
After
mandatory
mandatory
mandatory
mandatory
prophylaxis
prophylaxis
prophylaxis
prophylaxis
N=132 (%)
N=91(%)
N=132 (%)
N=88 (%)
First 4 months
23
14
8
5
All time
26
21
10
8
Serious adverse events
Non-Hematologic Toxicity
Ti
Toxicit
ity
AA
Arm A
AB
Arm B
P value
(N=433 Ever Reported)
(N=217)
(N=216)
Any non Hem toxicity (Grade >=3)
52.1%
34.3%
<0.001
Toxicity of Any Type (Grade >=4)
28.6%
18.1%
0.003
Early Deaths (< 4 months)
4.5%
1.4%
0.034
Pl
Pre iliminary data on t
s em cellll harvest,
transplant
% Reporting
% reporting
% missing
% unsuccessful
successful
data
harvest/SCT
Harvest
26%
94%
34
3. %
4%
26
2. %
6%
Transplant
24%
93.3%
4.8%
1.9%
One-year Si
Survi l
va R t
a e
N
Events
Survival
Probability
(95%CI)
Len-High
223
26
08
0. 7
87 (0.82, 0 92)
.
Dex(RD)
Len-Low
222
8
0.96 (0.94, 0.99)
D(
Dex Rd)
(Rd)
Ol
Overa lll Survival (
t
mon h
ths)
Rd
RD
One-year Si
Survi l
va R t
a e by Age
N
Events
Survival Probability
(95%CI)
()
Age <65
L
Hi
en-
h
g Dex
104
8
09
0. 1
91 (0 85
.
, 0 97)
.
Len-Low Dex
108
2
0.98 (0.96, 1.00)
Age 65
Len-High Dex
119
18
0.83 (0.76, 0.90)
Len-Low Dex
114
6
0.94 (0.89, 0.99)
Ol
Overa lll Survival (
t
mon h
ths): Age <65
<65
Rd
RD
Ol
Overa lll Survival (
t
mon h
ths): Age 65
Rd
RD
One-year S
i
urv
l
va
t
ra e in Ph
Phase III Newly
Diagnosed MM Trials
1-yr
Study
Age
Phase
N
Regimen
Survival
Ref
rate
Rajkumar, E1A00
Median=65
III
103
Thal Dex vs Dex
80%
JCO 2006
Rajkumar, MM003
Median=65
III
470
Thal Dex vs Dex
80%
ASH 06
Palumbo
Median=72
III
255
MPT vs MP
%
87 ~
Lancet 06
Attal, IFM
<65
III
200
Auto vs Chemo
88%~
NEJM 1996
Child, MRC
<65
III
401
Auto vs Chemo
87%~
NEJM 2003
Barlogie, S9321
<=70
III
516
Auto vs Chemo
84%*
JCO 06
Attal, IFM
<60
III
399
Single vs Double Auto
90%~
NEJM 2003
Barlogie, TT II
<75**
III
668
TT2 +/-Thal
92%
NEJM 2006
E4A03 Arm A
Median=65
223
223
Len + high-dose dex
87%
ASCO 2007
E4A03 Arm B
Median=65
222
222
Len + low-dose dex
96%
ASCO 2007
*intent to treat population; **80% age <65
Rajkumar, ASCO 2007
Cl
Concl
i
us ons
· Lenalidomide plus
plus low
low-dose dexamethasone is
associated with significantly superior survival and
lower toxicity compared to lenalidomide plus high-
dose dexamethasone
· High one-year survival rate with lenalidomide plus
low-dd
dose dexameth
thasone
· DVT risk is 5-8% with lenalidomide plus low-dose
dexameth
thasone with
ith
ti
rou ne aspirin proph l
y
i
ax s
· Response, TTP, and PFS assessment is ongoing
· Major implications for use of high-dose
dexamethasone in myeloma