ECOG
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. Vincent Rajkumar, Susanna Jacobus, Natalie Callander,
Rafael Fonseca, David Vesole, Michael Williams, Rafat
Abonour, David Siegel, and Philip Greipp
Mayo Clinic, Rochester, MN; Dana Farber Cancer Institute, Boston,
MA; University of Wisconsin, Madison, WI; 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
Mayo Phase II trial of Len/Dex in New MM
88% OS at
N=34
1
3 years
RR: 91%
surviving.8
CR/VGPR: 56%
tion.6
Transplant
.4
Propor
No Transplant
.2
0
0
5
10 15 20 25 30 35 40 45
Time (months)
Lacy MQ. Mayo Clin Proc. Oct 2007
Aim
· A phase III trial comparing lenalidomide plus
high-dose dexamethasone (RD) versus
lenalidomide plus low-dose dexamethasone
(Rd) as first line therapy in newly diagnosed
multiple myeloma
Schema
R
445 pts
A
N
@ 4 months
D
Len + Dex
Pts can
O
(RD)
go off study
M
x4 cycles
I
Z
A
Len + Low
Less
Thal +
T
dose Dex
than
Dex
CR/PR/Stable
I
(Rd)
PR
x 4 cycles
O
x 4 cycles
N
Treatment Schedule
Days
1
8
15
22
28
Lenalidomide 25 mg PO d1-21
Total Dex
RD
dose per
Dex
Dex
Dex
Cycle =
d1-4
d9-12
d17-20
480 mg
Lenalidomide 25 mg PO days 1-21
Total Dex
Rd
dose per
D
D
D
D
Cycle =
e
e
e
e
160 mg
x
x
x
x
d1
d8
d15
d22
Study Design
· Induction trial; Not designed as a trial
to test efficacy of long-term
lenalidomide/dex
· Primary Endpoint: RR @ 4 months
· Equivalence: overall response rate
in Rd <15%
Eligibility
Status
RD
Rd
Total
(Arm A)
(Arm B)
N=445
N=223
N=222
Eligible
195
188
383
Not eligible
20
22
42
Questionable
1
2
3
eligibility
Missing data for
7
10
17
eligibility
Patient Characteristics
Arm A
Arm B
(n=223)
(n=222)
ISS (%)
Stage I
33.0
33.3
Stage II
41.3
41.4
Stage III
25.7
25.3
Patient Characteristics
Arm A
Arm B
(n=223)
(n=222)
Male (%)
58.3
54.1
Age (yrs)
66 (36-87)
65 (35-85)
ECOG PS < 1 (%)
91.0
90.5
BMPC (%)
40.0
40.0
Serum M protein (g/dL)
3.2
3.1
Hemoglobin (g/dL)
10.9
11.1
Patient Characteristics
Arm A
Arm B
(n=223)
(n=222)
MM Bone Disease (%)
65.3
56.8
Albumin (g/dL)
3.5
3.6
LDH (U/L)
156
158
B2 Microglobulin (µg/mL)
3.8
3.5
Creatinine (mg/dL)
1.1
1.0
Treatment Administered
·245 (55%) patients went off study <6months
·Median duration of therapy
·Arm A: 4 months
·Arm B: 6 months
Arm A
Arm B
%
%
Len dose reduction @ 4 cycles 23%
26%
Dex dose reduction @ 4 cycles 43%
15%
Serious adverse events
Hematologic Toxicity
Toxicity
Arm A (n=222)
Arm B (n=219)
Type (Grade 3+)
%
%
Fishers
Exact
p-value
Hemoglobin
8.1
6.8
0.718
Platelets
5.4
5.5
1.000
Neutrophils
11.7
18.7
0.047
Serious adverse events: Non-Hematologic
Toxicity
Arm A (n=222)
Arm B (n=219)
Type (Grade 3+)
%
%
Fishers
Exact
p-value
DVT/PE
25%
9%
<0.001
Infection/Pneumonia
14%
7%
0.030
Fatigue
13%
10%
0.294
Hyperglycemia
11%
6%
0.126
Nonneuropathic weakness
10%
4%
0.008
Cardiac ischemia
3%
0.5%
0.068
Atrial fib/flutter
3%
0.5%
0.122
Neuropathy
2%
1.5%
1.000
Serious adverse events
Non-Hematologic Toxicity
Toxicity
Arm A
Arm B
P value
(N=441 Ever Reported)
(N=222)
(N=219)
Any non Hem toxicity (Grade >=3)
50%
30%
<0.001
in first 4 cycles
Any non Hem toxicity (Grade >=3)
65%
45%
<0.001
Toxicity of Any Type (Grade >=4)
19%
8%
0.001
Early Deaths (< 4 months) All pts
5%
0.5%
0.01
Early Deaths (< 4 months) Pts <65
1%
0%
Ability to harvest stem cells
No.
% reporting
% missing
% unsuccessful
Reporting
successful
data
harvest
Harvest
149
97%
1%
2%
Response within 4 cycles
Arm A
Arm B
Total
N=196
N=190
N=386
%
%
%
Complete Response
2%
1%
2%
82%
70%
Partial Response
80%
69%
75%
Minimal Response
5%
15%
10%
No Response/Stable
6%
8%
7%
Progressive Disease
3%
2%
3%
Unevaluable
4%
5%
5%
Missing (no. of pts)
5
9
14
Response within 4 cycles
Arm A
Arm B
Total
Fisher's
N=196
N=190
N=386
Exact
p-value
2-sided
%
%
%
> PR
80%
67%
74%
0.004
82%
70%
76%
0.007
CR+VGPR
44%
26%
35%
<0.001
Best Overall Response
Arm A
Arm B
Total
N=196
N=190
N=386
N (%)
N (%)
N (%)
Complete Response
4%
2%
3%
52%
42%
VGPR
48%
40%
44%
Partial Response
30%
29%
29%
Minimal Response
4%
14%
9%
No Response/Stable
7%
8%
7%
Progressive Disease
3%
3%
3%
Unevaluable
4%
5%
4%
Missing (no. of pts)
3
6
9
Best Overall Response
Arm A
Arm B
Total
Fisher's
N=196
N=190
N=386
Exact
p-value
2-sided
%
%
%
> PR
82%
71%
76%
0.01
CR+VGPR
52%
42%
47%
0.06
Response Duration
PFS and TTP
PFS
TTP
Survival Rate
N
12 month Survival
24 month survival
Probability (95%CI)
Probability (95%CI)
Len-High
223
0.88 (0.83-0.92)
0.75 (0.68-0.82)
Dex(RD)
Len-Low
222
0.96 (0.93-0.99)
0.87 (0.81-0.93)
Dex(Rd)
P=0.003
P=0.009
Overall Survival
Survival Rate by Age
N
12 month
24 month
survival
survival
probability
probability
(95%CI)
(95%CI)
Age <65
Len-High Dex
104
0.92 (0.87-0.97)
0.85 (0.78-0.93)
Len-Low Dex
108
0.97 (0.94-1.00)
0.91 (0.84-0.98)
Age 65
P=0.13
P=0.16
Len-High Dex
119
0.84 (0.77-0.91)
0.67 (0.56-0.77)
Len-Low Dex
114
0.95 (0.84-1.00)
0.82 (0.74-0.91)
P=0.01
P=0.009
Overall Survival: Age <65
Overall Survival: Age 65
Survival Rate
12 month Survival
12 month survival
(95%CI)
(95%CI)
Pts off study <6 months
Rx >6months
N=245
N=192
Len-High
0.83 (0.75-0.88)
0.97 (0.90-0.99)
Dex(RD)
Len-Low
0.93 (0.86-0.97)
0.99 (0.94-0.99)
Dex(Rd)
P=0.02
P=0.15
Cause of Death
Median Follow up 21 mos
Arm A
Arm B
N=46
N=25
N
N
Progressive Disease
26
17
Thromboembolic
5
1
Infection
4
3
Cardiac
6
2
Stroke
1
1
Resp Failure
1
0
Second Cancer
1
0
Unknown
2
1
Conclusions
· RD and Rd are highly active in newly diagnosed MM
· Rd had lower response rates than RD, but this was
within the 15% limit that was defined in study design
as clinically equivalent
· Rd is associated with superior OS compared to RD
· Response duration, TTP or PFS with Rd not inferior to
RD
· The excess mortality in the high-dose dex arm was
due to both disease progression (myeloma deaths) as
well as increased toxicity.
· This study has major implications for the use of high-
dose dexamethasone in the treatment of newly
diagnosed MM.