Abstract 8023
Impact of
o pri
p or
o thali
a domide (T
( ) th
t er
e apy on th
t e
efficacy of pegylated liposomal doxorubicin (PLD)
and bortezomib (B) in
relapsed/refractory multiple myeloma
P. Sonneveld, R. Hajek, A. Nagler, A. Spencer, J. Blade,
T. Robak, S.H. Zhuang, J-L Harousseau, and
R. Z. O l
r
k
ows i
ki for th
the
DOXIL MMY-3001 study investigators
Therapeutic consideration for patients with
reld
lapse /
d/ f
re ractory
l
mu i
t l
p e
l
mye oma
Multiple therapeutic options
Therapeutic goals
Optimize TTP and survival
Reverse and improve end organ function
Minimize treatment-related toxicities
Factors impacting 2nd line treatment choice
Response and tolerability to prior therapy
Patient comorbidities
Oral vs IV
Rationale for sub group analyses
Report of possible resistance to lenalidomide in patients
previously treated with thalidomide1
Pre-specified subgroup analyses of previously reported study
(MMY 3001:
3
Bortezomib vs. PLD + Bortezomib) to assess:
The difference in efficacy (TTP, OS, response rates) between
t
t
rea ment groups in
ti
pa
t
en s ith
w
i
pr or exposure to
thalidomide/lenalidomide (IMiD) therapy
Whether efficacy differs based upon prior exposure to IMiD
therapy
1Wang, et al. BLOOD 2006. 108(11): p1014a - abstract 3553
DOXIL-MMY-3001 Study Design
Bortezomib 1.3 mg/m2 days 1, 4, 8, 11 every
R
21 days for up to 8 cycles
A
N
646 patients:
D
Relapsed and/or
Pi
Primary
O
refractory myeloma
Up to 8 cycles
endpoint:
M
Stratifications:
or until PD or
TTP
I
1. 2m(2.5, >2.5 but
2m ( 2.5,
2.5
unacceptable
Secondary:
Z
5.5, >5.5)
2. Response vs.
toxicity
OS, ORR,
A
prog
pgression on initial
safety
T
therapy
I
O
N
Bt
Bort
i
ezom b
ib as b
a ove + Pegylated li
liposomal
doxorubicin 30 mg/m2 on day 4
Time to Progression
(MMY 3001-
3001 all patients)*
1.0
PLD + Bortezomib
0.8
9.3 months (n=324)
reeF-no
0.6
ressigro
sP
atient
Bortezomib
P
0.4
of
6.5 months (n=322)
()
cent
Per
0.2
Statistical analysis: HR (95% CI)
1.82 (1.41,
(, 2.35) p = 0.000004
0.0
0
40
4
80
8
120
160
200
20
240
280
320
360
400
440
480
Days
Tr
T ea
r
tm
ea
en
tm
t
en Grou
G
Gro
Gr
p
rou
u
DOXI
DOX L + VE
V L
E C
L A
C
ELC D
A E
D
VELC
V
A
ELC D
A E
D
* Orlowski R, et al. BLOOD 2006. 108(11): p124a - abstract 404
MMY 3001
646 patients
268 IMiD exposed
378 IMiD naïve
(94% Thal, 6%
6% Len)
Len)
130 patients PLD + B 138 patients B
194 patients PLD + B 184 patients B
Baseline Characteristics (IMiD Exposed)
PLD + Bortezomib
Bortezomib
N=130
N=138
Mean Age (y
g( rs
y
)
60.7
62.1
Gender
Male
58%
57%
Months since
Median
46.3 mos.
46.7 mos.
initial diagnosis
Time since first
Median
1.4 mos.
1.6 mos
progression
Albumin (g/dL)
37
3. 5
75
37
3. 0
70
2.5
17%
17%
-microglobulin
2
>2.5 - 5.5
48%
52%
(mg/L)
>5 5
.
35%
31%
Not Done
52%
52%
Cytogenetic
Yes
19%
19%
abnormality
No
28%
28%
Not Evaluable
2%
1%
Baseline Characteristics (IMiD Exposed)
PLD + Bortezomib
Bortezomib
N=130
N=138
0
43%
45%
ECOG Score
1
57%
55%
Number of Prior
1
8%
12%
Therapies
>2
>
92%
88%
Corticosteroid
100%
100%
Alkylating agent
90%
86%
Type of prior therapy
Anthracycline
79%
70%
SCT
72%
58%
Time to progression
PLD + Bortezomib (vs.
PLD + Bortezomib
Bortezomib)
(vs. Bortezomib)
Ht
Heterog
i
ene t
ity
IMiD exposed
IMiD naive
test*
Median Time To
270 days
295 days
Progression
(vs 205 days)
(vs 189 days)
Hazard Ratio
1.62 (1.08, 2.41)
2.01 (1.42, 2.84)
(95% CI, log rank
P = 0.446
log rank p=0.018
log rank p<.0001
p value)
*Treatment by subgrou
yg
p (IMiD
(
exposed
p
, IMiD Naïve) interaction test from the Cox model
Time To Progression (IMiD exposed)
1.0
PLD + Bortezomib
270 days
08
0.
0 8
ee
Fr
Bortezomib
-
on
essi
0.6
essi
205 days
gror
sP
ent
atiP 0.4
of
rcent
Pe
0.2
Statistical analysis: HR (95% CI)
1.62 (1.08, 2.41) p=0.018)
0.0
0
40
4
80
8
120
160
200
20
240
280
320
360
400
440
480
Days
Tt
Trea
T
t
rea me
t
t
n Grou
G
p
rou
OC
DO
D XI
O
L + VE
V L
E
A
OC
CADE
CA
VE
V
CA
L
DE
CA
Time to progression (PLD +
Bortezomib)
1.0
IMiD exposed vs naïve
0.8
IMiD exposed
reeF-
IMiD naive
siones 0.6
ess
ogr
sPr
ient
Pat
0.4
tofn
rce
Pe
0.2
0.0
0
40
4
80
8
120
160
200
20
240
280
320
360
400
440
480
Days
Pr
P i
r o
i r
o IMID Tr
T eat
a m
t e
m nt
n
Pr
P io
i r
o IMID
IM
Na
N i
a v
i e
v
Pri
P o
ri r
o IMID
IM
ex
e p
x o
p s
o ed
e
Response Rates
PLD + Bortezomib
PLD + Bortezomib
(IMiD exposed, N=123)
(IMiD naive, N=180)
OR (CR+PR)
48%
47%
CR
4%
5%
PR
44%
42%
CR
n
9%
9%
CR+VGPR*
31%
27%
Duration of Response
319 days
310 days
(CR+PR)
()
* According to the IMWG criteria
Adverse Events of Clinical Interest
PLD + Bortezomib
PLD + Bortezomib
(IMiD exposed, N=126)
(IMiD naive, N=192)
Tota
t l
a (
l %
( )
Grade 3/4
3/4 (%)
Tota
t l
a (
l %
( )
Grade 3/4
3/4 (%)
Peripheral Neuropathy
40
5
32
4
Neutropenia
33
28
35
31
Febrile Neutropenia
3
3
3
3
Bleeding/hemorrhage1
gg
2
3
16
5
Mucositis/stomatitis
21
3
20
2
Hand foot syndrome
17
6
15
4
Thromboembolic Events
0
0
2
1
Alopecia
2
0
1
0
Symptomatic Cardiac
8
-
7
-
Comparative Results Based on Prior IMiD Exposure
PLD + Bortezomib
Lenalidomide + Dex1,2
(IMiD exposed, N=130)
(Thal exposed, N=126)
EFFICACY
Median TTP (day
(ys)
270
258 (36.9 weeks)
()
OR (%)
48
54
CR/nCR (%)
(%)
13
11.9
.
SAFETY (%)
(n=126)
(n=126)
PE + DVT
DVT
0
14
Neutropenia (> Gr. 3)
28
33
Ne rop
u
ath
ropathy (> Gr. 3)
5
4
1Wang, et al. BLOOD 2006. 108(11): p1014a - abstract 3553; 2Wang, et al. JCO 2006 ASCO Annual Meeting Proceedings
Part I. Vol 24, No. 18S (June 20 Supplement) ­ Oral presentation based on abstract 7522
Conclusions
In patients previously exposed to IMiD therapy, TTP is
significantly longer with PLD + B compared to bortezomib alone
TTP in patients treated with PLD + B is comparable between
patients who rec'd p
pprior IMiD therapy
py to those who did not
Objective response rates, including the rate of CR, and duration
of response were comparable b t
e ween
ti
pa
t
en s t
t
rea d
e
ith
w
PLD
+ B regardless of whether or not they rec'd prior IMiD therapy
Conclusions (cont.)
Proportion of patients experiencing adverse events is
comparable between those previously exposed to IMiD therapy
and those who were
t
no
Low incidence of thrombovascular events (across all sub groups)
which is favorable compared to other second line therapies (e.g.,
Lenalidomide + Dex)
Acknowledgements
All of the patients whose participation made this study
possible
Investigators, research nurses, and study coordinators at
144 sites in 18 countries
Johnson & Johnson Pharmaceutical Research &
Development and Ortho Biotech Products, LP
Disclosures for All Authors
Johnson & Johnson Pharmaceutical Research &
Research Support
Development,
p, LLC; Ortho Biotech Products, LP
Employee
S. H. Zhuang
Consultant
Dr. Sonneveld (Ortho Biotech)
Major Stockholder
None
Speakers Bureau
None
Hi
Honorari
onorar a
None
Scientific Advisory Board
None
Backl
kup s id
lides
Overall Survival (IMiD exposed)
1.0
PLD + Bortezomib
08
0.
0 8
Bortezomib
reeF-no
0.6
gressior
sP
PLD+Bortezomib
Bortezomib
atientP 0.4
of
Censored
87%
83%
ercent
Died
P
13%
17%
0.2
HR (95% CI) 1.42 (0.75, 2.66)
p = 0.278
0.0
0
40
4
80
8
120
16
1 0
6
200
240
28
2 0
8
320
360
400
440
480
520
Days
Tr
T ea
r
tm
ea
en
tm
t
en Gr
G oup
ou
DO
D X
O I
X L + VELC
V
A
ELC D
A E
D
VELC
V
A
ELC D
A E
D