CALG
CAL B
B 100104
A Phase III Randomized, DoubleBlind Study of
Maintenance Therapy With Lenalidomide (CC 5013) or
Placebo Following Autologous Stem Cell
Transplantation for Multiple Myeloma
Philip McCarthy, Roswell Park Cancer Institute, representing CALGB, ECOG and BMT CTN
Why
Wh Main
t
Main e
t nance Ther
apy?
Ther
· Induction therap
ther y
ap fo
f llow
o
e
llow d
e by auto
aut log
o
o
log us
stem cell transplant (ASCT) alone will
cytoreduce but not cure most Multiple
Myeloma patients
· Can maintenance therapy:
prevent or delay disease progression?
convert partial responses to complete responses?
improve overall survival?
CALG
CAL B
B 100104
100104 Schema
Reg
Re i
g stra
st t
ra i
t on
Rest
Re a
st gi
g ng
n
Randomiza
Randomiz tion
a
Day
Da s
y
s 90
90100
100
Placebo
SD Stage 13, <70 years
> 2 cycles of induction
Mel
Mel 200
CR
Att
At a
t in
i ed SD or
be
t
be t
t er
t
PR
1 yr from start of therapy
ASCT
SD
Lenalidomide*
2 x 106 CD34 cells/kg
10 mg/d with
(515 mg)
*Revlimid® Celgene
Corp, Summit, NJ
Stratification based on diagnostic 2M and thalidomide and lenalidomide use
during Induction
Objective
Objectiv s
· Primary Objective:
Dete
Det rmine
e
the
eff
i
eff cacy
c of lenalidomide
in
pr
olonging
pr
time
to progression (TTP) in myeloma patients following ASCT
Powered to determine a TTP improvement prolongation
from 24 months to 33.6 months (
9.6 month)
hs)
· Seco
Sec ndar
o
y Objectiv
es
Objectiv :
CR rate postASCT
PFS
PF and
OS
Feasibility of longterm lenalidomide administration
Accrual
· Target Accrual: Register 538 with a goal of 462 randomized based
on 10% drop out rate
· First enrollment in April of 2005
· Accrual increased after BMT CTN 0102 closed in 2007
CALG
CAL B: n=376;
ECO
G : n=133; BMT
CT
N: n=59
· Closed in July of 2009: 568 registered pts from 46 Centers
· Drop out rate before randomization is ~15%
· Patients continued on therapy until progression
· The CALGB DSMB Report in November of 2009 analyzed
outcomes for 418 pts: 210 randomized to lenalidomide and 208
to placebo
· The DSMB report results were released in December of 2009
Mont
Mon hly Accrual
600
500
400
BMT CTN
CTN 0102 Closed
300
200
100
0
Adverse Events during maintenance
for
fo 368
of 418 ra
r ndomiz
a
e
ndomiz d patien
pa
ts
tien
Max Adv Events
3 Severe
4 Life Threat
5Lethal
Total
n
%
n
%
n
%
n
Hematologic
Lenalidomide
61
31
26
13
0
0
194
Placebo
8
5
8
5
0
0
174
Non Hematologic
Lenalidomide
60
31
6
3
3
2
194
Placebo
33
19
5
3
3
2
174
Hematologic events:
p=0.0001
Nonhematologic events:
p=0.0096
Grade 35 Adverse Events during maintenance
for
fo 368
of 418 ra
r ndomiz
a
e
ndomiz d patien
pa
ts
tien
Lenalidomide n=194
Placebo n=174
PValue
N
%
N
%
Thrombocytopenia
23
12
6
3
=0.01
Neutropenia
83
42
13
7
<0.0001
Anemia
10
6
1
1
=0.0028
Fatigue
11
6
5
3
=0.19
Rash
9
5
3
2
=0.12
Diarrhea
8
4
5
3
=0.52
Febrile neutropenia
11
6
3
2
=0.48
Document
Documen ed
t
Inf
In e
f ction
e
13
7
3
2
=0.03
13% (28 of 210) on Lenalidomide and 2% on placebo (4 of 208) came off therapy
due to AEs and 12% (26 of 210) on Lenalidomide and 7% (14 of 208) on placebo
came off therapy for other reasons
Resul
u ts
t
· TTP wa
s de
fined
de
as
disease pr
ogr
pr
e
ogr ssion
e
or
death
dea due to
any cause
· TTP was calculated from day 0 of ASCT
·
f
O 210 ll
lenal d
i
d
omi e pts, 29 have ex
d
perience an event
(progression or death)
· Of 208
placebo pts, 58 hav
ha e
v e
x
e perienced
x
an
event
ev
(p
<
0.0001)
· Estimated hazard ratio of 0.42, thus a 58% reduction in
the risk of
disease
pr
ogr
pr
e
ogr ssion
e
with
lenalidomide
Median TTP: Not yet reached
Median TTP 25.5 mo
CALGB 100104, Nov 2009
Median Follow up from ASCT is 12 months
There is not long enough followup to determine if there is a
diff
dif er
f ence
er
in OS; 11
deat
dea hs
t in lenalidomide arm and
17
deaths in the placebo arm (p<0.2)
CALGB 100104, Nov 2009
Resul
u ts
t
· 28% of the 309 targete
g
d events have occurred
· Stratification by Beta2 microglobulin and previous
thalidomide or lenalidomide exposure during induction
demonstrated a benefit between lenalidomide over
placebo in each stratification
· The study was unblinded in December 2009 allowing
patients (with physician support) to cross over to open
label lenalidomide
· 77 of 89 eligible placebo patients have started
lenalidomide ther
apy
ther
CALGB 100104, Nov 2009
CALGB 100104, Nov 2009
CALGB 100104, Nov 2009
Conclusions
· Maintenance therapy with lenalidomide when compared to
placebo will
signific
an
signific tly
an
pr
olong
pr
time
to
disease
progr
pr
e
ogr ssion
e
· Currently, there is no difference in OS at a median followup of 1
year postASCT
· Lenalid
id
om e prold
longed TTP wih
it i
hin patient stra ifi
t
i
cat on b
y hi h
g
and low 2M, and prior thalidomide or lenalidomide induction
therapy
· Lenalidomide maintenance produced some hematologic toxicity,
but this was not severe with dropouts due to all AEs at 13%
Pa
P rticipa
a
t
rticipa ing
t
Cen
t
Cen er
t s
er
·
CALGB: Dana Farber Cancer Inst, Illinois Onc Res Assoc, Memorial Sloan
Kettering Cancer Ctr, Mt Sinai School of Med, North Shore Univ Hosp, Roswell
Park Cancer Inst, State Univ NY, Upstate Med Univ, Ohio State Univ Med Ctr,
Ui
Univ Calif
i
orn a San Diego, Ui
Univ Calif
i
orn a San Fi
Francisco, Ui
Univ Chicago, Ui
Univ
Illinois Chicago, Univ Minnesota, Univ Nebraska, Univ North Carolina Chapel
Hill, BMT Group Georgia, Virginia Commonwealth Univ, Univ of Vermont,
Wake Forest Univ School Medicine, Walt
l e
t r Reed
R
Army
Arm Med Ctr, Wash
s in
i gt
g o
t n
Univ School Medicine, Weill Med College Cornell Univ, Western Pennyslvania
Hosp
·
ECOG
ECO :
G Cancer
Inst
Ins of Ne
w
Ne Jer
s
Jer ey
s , Case West
s e
t rn
r Metr
Me o
tr Health Med Ctr,
Columbia Presbyterian, St Lukes Hsp, Univ of Florida Gainesville, Fox Chase
Cancer Ctr, Geisinger Med Ctr, Indiana Univ Medical Ctr, Jewish Hospital,
Mars
Mar hfie
s
ld Clinic, Med College
Colleg Georgia,
Geor
Univ Miami, Univ Pe
P nnsylv
nns
a
ylv nia, Univ
Pittsburgh, Scottsdale, Univ Hospital Cleveland, Vanderbilt Univ, Med College
of Wisconscin, Univ of Wisconsin
·
BMT
BMT CTN
CT : City
of
Hope,
LDS Hosp,
MD Ander
s
Ander on,
s
Oregon
Or
Health
Sciences
Univ, Univ of Mississippi Med Ctr
CALG
CAL B
B 100104
100104 Coopera
Cooper t
a iv
t e
iv Ef
f
Ef o
f r
o t
r
CALGB: C Linker, K Anderson, K Owzar, R Larson, R Schilsky, M
Bertagnolli, V Hars, M Kelly, M Seiler, L Bressler, J Postiglione, S
Sutherland, C Hofmeister, H Hassoun, D Hurd, P Richardson, D
Weisdorf, R Vij, T Gentile, K van Besien, T Shea, A Bashey, L Isola, S
Devine
De
ECOG: E Stadtmauer, J Wingard, N Callandar
BMTCTN: S Giralt, M Horowitz, M Pasquini, J Ferrara, J Antin, R
Maziarz, A Krishnan, G Somlo, S Carter, N Poland, A Foley, C Gurgol
This study was supported in part by grants from the NCI to CALGB
(M Bertagnolli,
Bert
MD,
MD Chair),
to the CALG
CAL B St
a
St t
a is
t tic
is a
tic l
a Cent
Cen er
t (S
George, PhD), to ECOG and NHLBI/NCI funding to BMTCTN. The
content of this presentation is solely the responsibility of the
authors
author and does not necessarily re
r presen
pr
t
esen the official
of
views
view of the
NCI
Ongoing Statistical Center Analyses
Evaluating other induction regimens (Bortezomib, other
agents)
Evaluating Detailed AEs
· relationship to lenalidomide or placebo dose
Response dt
data
· prior to ASCT, at randomization, following maintenance
Ability
y to Continue Therapy
py
Dose modification
Other patient risk factors e.g. cytogenetics, LDH
Therapy after progression
Long term Followup
Induction Re
gi
g me
m ns
n : Pr
eliminary
Pr
Re
sul
u ts
Regimen
N
%
Thalidomidebased (No Bortez or Len)
152
27
Lenalidomidebased (No Bortez or Thal)
122
22
Bortezomibbased (No Len or Thal)
109
20
Bortezomib+Thalidomidebased (No Len)
68
12
Bortezomib+Dex+Lenalidomide (No Thal)
52
9
Dex
De a
x methasone
me
based (No Borte
Bort x
e , Len or Thal)
23
4
Thalidomide and Lenalidomide treatment
17
3
Bortezomib, Lenalidomide and Thalidomide treatment
3
1
Other
2
1
Missing
6
1
Total
554
100