US Cooperative Groups Myeloma Trials
S Lonial, S Giralt, B Durie, B Barlogie, E
Stadtmauer, J Zonder, R Fonseca, M
Dhodapkar, K Anderson
Anderson, V Rajkumar
Sagar Lonial, MD
Associate Professor, Winship Cancer Institute
Director of Translational Research,
B-cell Malignancy Program
Groups
ECOG
SWOG
CALGB
BMT CTN
ECOG
Randomized trial of
of lenalidomide
lenalidomide plus
plus high
high dose
-
dexamethasone versus lenalidomide plus low-dose
dexamethasone in newly diagnosed myeloma (E4A03), a
trial coordinated by the Eastern Cooperative Oncology
Group: Analysis of response, survival, and outcome with
primary therapy
therapy and with stem
stem cell transplantation
transplantation.
S. Vincent Rajkumar, Susanna Jacobus, Natalie Callander, Rafael
Fonseca, David Vesole,
,, Michael Williams, Rafat Abonour, David Siegel
g ,
Michael Katz, and Philip Greipp
Mayo Clinic,
y, 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 and
International Myeloma Foundation, North Hollywood, CA
ECOG E4A03 Schema
R
4 Cycles
A
N
D
Len/Dex
CR or PR
Off study for
O
(RD)
SCT; or continue
M
at MD discretion
I
Z
A
Len/low
Less
T
dose Dex
Dex
Thal/Dex
CR/PR/St b
a l
than
ble
I
(Rd)
(4 cycles)
PR
O
N
Overall Survival
Survival
96%
100
Rd
80
87%
y
RD
bilit
60
oba
Pralivrv 40
Su
20
P<0.001
0
0
6
12
18
24
Time in Months
Numbers at Risk
RD
223
179
103
37
0
Rd
221
192
103
37
0
Median Follow up: 12.5 months
DMC closed study; immediate crossover to Rd was mandated
Response to Therapy
Arm A
Arm B
P value
%%%
Response in 4 cycles (PR)
79%
68%
0.008
VGPR within 4 cycles
42%
24%
<0.008
BO
Best O
l
verall Response (PR)
81%
0%
7
0.009
VGPR
51%
40%
0.040
CR (IF-)*
17%
14%
0.428
Overall Survival
Survival
100
Rd
80
75%
3-yr OS rate
y
RD
yilit 60
robab
lP
vivaur 40
S
20
P=0.46 log-rank;
P=0.01
01 Pepe Fleming
-
0
0
6
12
18
24
30
36
Time in Months
Nu
N mbers
ber at
at Ri
Risk
s
RD
223
208
195
184
173
123
78
Rd
222
217
212
201
192
146
83
Overall Survival:
Survival: Transplant
Transplant following 4
cycles of RD vs. Rd
RD
100
92%
3-yr OS rate
80
Rd
80
ility
60
ab
robPl
rviva
40
Su
20
P=NS
0
0
6
12
18
24
30
36
Time in Month
ths
Numbers at Risk
RD
50
50
49
48
47
35
20
Rd
40
40
40
38
37
32
21
Rl
Resu t
ltsof Pi
Primary Therapy bd
beyond 4 cycles ith
w
RD
"Primary Rd"
Rd"
(n=140)
%
Overall Response Rate
91%
CR* (IF-)
22%
CR + VGPR
57%
Grade 3 non-heme toxicity**
26%
*measured in serum or urine
** 52% with RD
Overall Survival:
Survival: Primary
Primary Therapy beyond
beyond 4
cycles of RD vs. Rd
100
Rd
79%
80
3-yr OS rate
RD
yilit 60
robabPl
rviva
40
Su
20
P=NS
0
0
6
12
18
24
30
36
Ti
Time in
in Months
Numbers at Risk
RD
108
108
103
97
90
67
44
Rd
140
140
139
133
128
95
51
S0232: Dex +/-
+/ Lenalidomide for
for
Previously Untreated Myeloma
Ud
Updated R
l
esu t
lts
d
an Impact f
o
Cytogenetics
yg
Zonder JA, Crowley JJ, Hussein MA,
Bolejack V, Abidi
Abidi MH, Moore Sr
Sr. DF
DF,
Whittenberger BF, Durie BGM, Barlogie B
Abstract #8521, 2008 Annual ASCO meeting, Chicago, IL
SWOG S0232: Study Design
Induction Therapy
Maintenance Therapy
Three 35
35--day
day courses
Repeat q 28 days until PD
Len 25 mg/d x 28 days
Len 25 mg/d x 21 days
Dex 40 mg d 14, 9-12, 17-20
Dex 40 mg d 14, 14-18
(n=100)
Untreated
MM
(n=198**)
PD
PD
n=44
Placebo 25 mg/d x 28 days
Placebo 25 mg/d x 21 days
Dex 40 mg d 14, 9-12, 17-20
Dex 40 mg d 14, 14-18
(n=98)
ASA 325 mg/day required
**Protocol closed after early interim analysis by DSMC.
Patient Status 198 pts
* As of July
LD
D
18th
18 , 2007
D
Ineligible
Ineligible
100 pts
98 pts
19 pts
12 pts
No difference
in Age, Race,
Gender, ISS, PS
73 resp eval
84 resp eval
81 pts
86 pts
44
PD
PD
Study Closure
Responses (IMWG)
LD
Dex
X-over
(n=73)
(n=84)
(n=44)
NA
7%
NR
14%
PR
14%
32%
VGPR
CR
33%
47%
75%
29%
69%
62%
48%
28%
17%
15%
19%
2%
8%
p <
= 0.0001
0.001
S0232: LEN-DEX v PLACEBO-
DEX FOR
FOR UNTREATED
MYELOMA
Overall Survival
Event-free Survival
LEN
LEN--DEX
DEX (19
(19 / 97)
100%
100%
LEN
LEN--DEX
DEX (43
(43 / 97
97)
80%
80%
60%
Placebo
Place -DEX (23 / 95)
60%
95)
40%
40%
CR=22%
CR=4%
20%
20%
PR=63%
PR=48%
Placebo
Placebo--DEX
DEX (61 / 95)
P = 0.47
P = 0.0003
0%
0%
0
12
24
36
48
0
12
24
36
48
Months After Registration
Months After Registration
Cytogenetic abnormalities (CA), available in 109 patients,
f
con err d
e i f
n
i
er or over ll
a
d
an eve t
n -free sur i
v
l
va
on Plac-DEX (p=0.006/0.008) and LEN-DEX arms (p=0.007/0.079)
Slide courtesy of B Barlogie
Zonder et al, ASH 07, ASCO 08
BMT
BMT--CTN
CTN 0102: Schema
age <70
At least 3 months of
Maintenance
systemic therapy
ypy
Thalidomide and
3-9 months from start of
Dexamethasone
therapy
for 1 yr
Autologous PBSC graft
Melphalan 200 mg
pg/m2 Auto
of
HCT
> 4 x 106 CD34 cells/kg
Randomized
Melphalan 200 mg/m2 Auto
HCT
Assigned based on HLA-ID sib
Observation
N=700
TBI 200 cGy
140+ Allos
MMF/CSP
Observation
Accrued in
in 3
Allo HCT
years
Analysis:08-09
Status 0102
Fully accrued 12/03-3/06
700 + pts in 3 years
py
140 auto/allo patients
Data review ongoing
Planned
l
ana
i
ys s 2010 for ASCO
and ASH-possibly earlier
Correlative
FLC CR assessment
PCR for 4,14
CALGB 100104
Revlimid vs Placebo
maintenance
500 pts
To be fully accrued Q2 09
-
Melphalan 200 mg/m2 single
autograft
Modular Concept for ECOG Myeloma
Clinical Trial Development
E1A98 Obs/Sample
E1A00 TD vs. D
S9321 Chemo vs. SCT
S9321
E4A03 RD vs. Rd
E4A98 Auto/mini-allo
JMY 10 Thal/Pred vs. Obs
E2A02 Bortezomib
ib
E1A97 DLI
DLI
Stem Cell
Tr
T ansplant
r
Asymptomatic
Induction
Maintenance
MM
Rx
Non
Tr
T ansplant
r
Consolidation
E3A06 R vs. Obs
S0777- Rd vs VRd
CALGB 100104
E1A08 Bortezomib vs Obs
E1A06 - MPT vs. MPR
E1A05 - VRd vs. Vd
CALGB 100104 R vs. Pl
CTN Ph
Phase III
eastern cooperative oncology group
ECOG: MPT vs MPR
E1A06: Phase III New
New
N
MM, non
non--transplant
non transplant
non--transplant candidates
R
A
CR/PR/
Continue therapy
N
MPT
Stable
till prog. or toxicity
D
O
M
IZ
A
Prog.
TI
MPR
Off Rx
R
anytime
O
N
eastern cooperative oncology group
Initial Therapy of MM
S0777: Phase III New
New
N
MM, transplant candidates
Lenalidomide and low
low--dose
low dose
low--dose Dexamethasone vs.
Bortezomib, Lenalidomide, and low
low--dose
low
low-dose
-dose Dexamethasone (Rd vs. VRd)
()
R
A
CR/PR/
Continue therapy
N
Rd
Stable
till prog. or toxicity
D
O
M
IZ
A
Prog.
TI
VRd
Off Rx
R
Rx
i
anyt me
O
N
* Active
eastern cooperative oncology group
Consolidation Therapy for MM
E1A05: Phase III Novel
Novel
N
non
non--transplant
non transplant
non--transplant consolidation
Bortezomib and low
low--dose
low-dose
-dose Dexamethasone vs.
Bortezomib Lenalidomide,
Lenalidomide and
and low-
low dose Dexamethasone
Dexamethasone (Vd vs
vs. VRd)
V
VRd)
R
A
CR/PR/
Continue therapy
N
Vd
Stable
till prog. or toxicity
D
O
M
IZ
A
Prog.
TI
VRd
Off Rx
R
anytime
O
N
* Active
eastern cooperative oncology group
SCHEMA: BMT CTN
Lenalidomide
No Consolidation
Maintenance
Register
MEL
VRD x 4
Lenalidomide
and Randomize
200mg/m2
Maintenance
MEL
Lenalidomide
200mg/m2
Maintenance
Active Myeloma within 12 months of initial treatment
Age<=70 yrs
Pts with
with progr
pr
essive
ogr
disease will
w
be excluded
All pts will have enough PBPC collected for two
transplants
No contraindication to lenalidomide, bortezomib or
dexamethasone
Stratify by
yy B2M, response
p
to initial therapy
py and
cytogenetics
Intent-to-treat analysis. Randomization prior to first
ASCT
New IWG criteria will be used for response assessment
Status
December 08
Protocol approved by PRC
January 09
Protocol approved by DSMB
March 09-
09 July
-
09
Distribution to Centers
Finalize CELGENE/MILLENIUM contracts
Finalize CTSU/CTEP Drug distribution SOP's
Commence protocol awarement activitivies
Finalize CALGB100104
July 09
Protocol activation in non CALGB100104 sites
August 09
Protocol activation in all sites
August December 09
Protocol awareness activities
Initial Therapy of MM
E3A06/SWOG: Phase III Hi
H gh
High-
g -Risk
h Risk
High--Risk Smoldering Myeloma*
Lenalidomide vs. observation
R
A
CR/PR/
Continue therapy
N
Lenalidomide
Stable
till prog. or toxicity
D
O
M
IZ
A
Prog.
TI
Observation
Off Rx
R
Rx
i
anyt me
O
N
* Review at CTEP
eastern cooperative oncology group
Maintenance Therapy for MM
E1A08: Phase III Pos
o t
Post-
s -transplant
t transplant
Post--transplant Maintenance
Bortezomib versus Observation
R
A
CR/PR/
Continue therapy
N
Obs
Stable
till prog. or toxicity
D
O
M
IZ
A
Prog.
TI
Vl
Ve
V l
e
Off Rx
R
anytime
O
N
* Concept submitted to CTEP
eastern cooperative oncology group
Relapsed MM and Related Plasma Cell Disorders
Relapsed MM
E2A08: Phase II VDDC in high-
high risk
-
relapsed MM
Planned carfilzomib trial (CRd vs Rd)
Waldenström's Macroglobulinemia
SWOG:Trial of Tandem Transplant
Plan for new trial with bortezomib (Bz vs Rit)
AL Amyloidosis
ECOG: MVD vs MD, VRD
SWOG: Mel+
Mel Bortezomib as HDT
eastern cooperative oncology group