Prolonged therapy improves quality of
response, and CR
CR is
is associated with
superior outcomes, with VMP in the
phase 3 VISTA
VISTA study
Jean-Luc Harousseau,1 Antonio Palumbo,2 Ruben Niesvizky,3 Paul G. Richardson,4 Rudolf Schlag,5
Jean Luc Harousseau, Antonio Palumbo, Ruben Niesvizky, Paul G. Richardson, Rudolf Schlag,
Meletios A. Dimopoulos,6 Ofer Shpilberg,7 Martin Kropff,8 Michel Delforge,9 Rik Schots,9 Michele
Cavo,10 Anatoly Golenkov,11 Mieczyslaw Komarnicki,12 Maria-Victoria Mateos,13 Andrew Cakana,14
Kevin Liu,15 William Deraedt,16 Anthony Boral,17 Helgi van de Velde,16 Jesús F. San Miguel13
1Dt
Depart
t
men f
o H
t
ema l
o ogy, U i
n
i
vers tity H
i
osp tit l
a H t
o l
e -Dieu, N t
an es, F
2
France; U i
n
i
vers tita di
di Ti
Torino, Ti
Torino, ItIt l 3
aly; W ill
e
Medical College of Cornell University, New York, USA; 4Dana-Farber Cancer Institute, Boston, USA; 5Praxisklinik Dr.
Schlag, Würzburg, Germany; 6University of Athens, School of Medicine, Athens, Greece; 7Rabin Medical Center,
Petah-Tiqva, Israel; 8University of Münster, Germany; 9Myeloma Study Group Belgian Hematological Society, Belgium;
10Institute of Hematology and Medical Oncology 'Seràgnoli', University of Bologna, Bologna, Italy; 11Moscow Region
Clinical Institute, Moscow,
,, Russia; 12
; Department of Hematology,
pgy, University of Medical Sciences, Poznan, Poland;
13Hospital Universitario Salamanca. CIC, IBMCC (USAL-CSIC), Salamanca, Spain; 14Johnson & Johnson
Pharmaceutical Research & Development, High Wycombe, UK; 15Johnson & Johnson Pharmaceutical Research &
Development, L.L.C., Raritan, NJ, USA; 16Johnson & Johnson Pharmaceutical Research & Development, Beerse,
Belgium; 17Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
1
Introduction
The goal of treatment for multiple myeloma (MM) is to improve long-term
outcomes, i.e. time to progression (TTP), overall survival
survival (OS)
(OS)
Quality of response, notably complete response (CR), is prognostic for
improved long-term outcomes:
Extensive evidence in previously untreated MM patients receiving high-
dose therapy and stem cell transplant1-8
However, evidence limited in the non-transplant setting9
With novel agents higher CR rates are achieved and the impact can be
assessed more easily
1. Harousseau J-L et al. Blood 2008;112 (abstract 2778).
6. Attal M et al. N Engl J Med 2003;349:2495502.
2. van de Velde H et al. Haematologica 2007;92:1399406.
7. Martinez-Lopez J et al. Haematologica 2007;92:42 (abstract S7b.6).
3. Attal M et al. N Engl J Med 1996;335:917.
8. Harousseau J-L et al. Blood 2006;108:877a (abstract 3077).
4. Child JA et al. N Engl J Med 2003;348:187583.
9. Kyle RA et al. Cancer 2006;106:195866.
2
5. Cavo M et al. J Clin Oncol 2007;25:243441.
Clinical benefit with bortezomib associated with
quality of
of response in
in APEX
APEX study in relapsed MM
VISTA findings are supported by analysis of outcomes with single-agent
b t
ib i th APEX h
III t d i
l
d MM1
bortezomib in the APEX phase III study in relapsed MM
CR with bortezomib associated with significantly longer median TFI
and TNT vs VGPR and PR
However, median TTP was similar with CR, VGPR and PR, possibly
due to the stringent definition of relapse from CR vs progression from
PR in EBMT criteria
Quality of response to bortezomib in APEX
CR (n=27)
VGPR (n=31)
PR (n=77)
Medi
dian TFI, months
24 1
.
69
6.9
64
6.4
Median TNT, months
27.1
13.6
14.0
Median TTP, months
9.7
10.8
8.5
Median OS not reached in any group
1. Niesvizky R et al. Br J Haematol 2008;143:4653.
3
VISTA study
study design
Patients randomized to receive nine 6-week cycles of VMP or MP alone:
Vb t
ib 1 3
/ 2
V: bortezomib 1.3 mg/m
· Cycles 14: twice weekly (days 1, 4, 8, 11, 22, 25, 29, 32)
· Cycles 59: weekly (days 1, 8, 22, 29)
Ml
M: melphalan 9 mg/ 2
/m , d1
days 14l
4, cycles 19
P: prednisone 60 mg/m2, days 14, cycles 19
Stratification: 2-microglobulin, albumin, and region
Primary end point: TTP
Additional efficacy end points: response rate, CR rate, time to
response, duration of response (DOR), time to next therapy (TNT), OS
Response determined by prespecified computer algorithm and progression
determined by investigator assessment using EBMT criteria1
In a post-hoc analysis, response determined using IMWG uniform
2
criteria
1. Bladé J et al. Br J Haematol 1998;102:111523.
4
2. Durie BGM et al. Leukemia 2006;20:146773.
Analyses of
of outcomes by response
TTP, TNT, treatment-free interval (TFI), and OS evaluated according to
response by EBMT and IMWG criteria
Associations examined in intent-to-treat population by multivariate Cox
regression analysis with time-dependent covariates
Adjusted for stratification factors, with age, sex, race, MM type,
baseline KPS, and number of bone lesions as covariates
Outcomes evaluated in patients achieving CR with VMP either early
(l
(cycles 14) or later (
l
cyc es 59)
Response and TTP data from third interim analysis,1 data cut-off June 15,
2007 (median follow-up: 16.3 months)
Formal collection of tumor assessment data stopped
TNT, TFI, and OS data from updated analysis, data cut-off April 25, 2008
(median follow-up: 25.9 months)
1. San Miguel J et al. N Engl J Med 2008;359:90617.
5
VMP shows significantly higher response
rates than
than MP
MP
Responses were more rapid and durable with VMP vs MP
VMP (N=337)
MP (N=331)
p-value
ORR (EBMT criteria), n (%)
238 (71)
115 (35)
<0.001
CR
102 (30)
12 (4)
<0 001
.
PR
136 (40)
103 (31)
<PR
95 (28)
212 (64)
ORR (IMWG criteria), n (%)
251 (74)
128 (39)
<0.001
CR
111 (33)
13 (4)
<0.001
VGPR
28 (8)
13 (4)
PR
112 (33)
102 (31)
<PR
82 (24)
199 (60)
Median time to first / best
1.4 / 2.3 / 4.2
4.2 / 4.9 / 5.3
<0.001
response / CR, months
Median DOR, months
19.9
13.1
CR
24.0
12.8
PR
15.3
13.2
6
Quality of response to VMP improved with
prolonged treatment
treatment
28% (29/102) of CRs occurred after cycles 14
Presented by Dr Palumbo at EHA 2008; Palumbo A et al. Haematologica 2008;93(Suppl 1):83 (abstract 0207).
7
Superior long-term outcomes
with VMP vs
vs MP
MP
VMP, which resulted in significantly higher overall response and CR rates, was
associated with
ith i
s gnifi
ifi
tl
can y b t
e ttter long-tt
term outcomes compared with
ith MP
MP
VMP
MP
HR
p-value
(N=344)
(N=338)
TTP
24.0
16.6
0.48
<0.001
TNT
28.1
19.2
0.53
<0.000001
TFI
16.6
8.4
0.54
<0.000001
3-year OS
72%
59%
0.64
0.0032
San Miguel JF et al. Blood 2008;112:abstract 650.
8
CR (EBMT) is associated with improved
long term
-
outcomes
CR associated with significantly longer TTP, TNT, and TFI vs PR
CR and PR associated with significant
significant benefits for
for all parameters vs
vs <PR
<PR
Hazard ratio, p-value
vs PR
vs <PR
TTP in patients achieving:
CR
0.45, p=0.004
0.31, p=0.0001
PR
0.69, p=0.021
TNT in patients achieving:
CR
0.46, p=0.0004
0.27, p<0.0001
PR
0.59, p<0.0001
TFI in patients achieving:
achieving:
CR
0.38, p<0.0001
0.21, p<0.0001
PR
0.55, p<0.0001
OS in patients achieving:
achieving:
CR
0.82, p=0.50
0.41, p=0.003
PR
0.50, p=0.0002
9
Multivariate Cox regression analysis
TTP in patients achieving CR is longer
vs PR (EBMT) with VMP
10
TFI in patients achieving CR is longer
vs PR (EBMT) with VMP
11
TNT in patients achieving CR is longer
vs PR (EBMT) with VMP
12
OS in patients achieving CR appears
similar vs
vs PR
PR (EBMT)
(EBMT) with
with VMP
VMP
No statistically significant difference
in OS with CR vs PR, likely due to
small number of deaths
13
CR (IMWG) is associated with improved
long term
-
outcomes
Hazard ratio, p-value
vs VGPR
vs PR
vs <PR
TTP in patients achieving:
CR
0.45, p=0.019
0.50, p=0.013
0.29, p<0.0001
VGPR
1.11, p=0.73
0.64, p=0.14
PR
0.58, p=0.001
TNT in patients achieving:
CR
0.51, p=0.015
0.54, p=0.003
0.29, p<0.0001
VGPR
10
1. 5
05, p 08
=0. 5
85
05
0. 6
56, p 00
=0. 18
018
PR
0.53, p<0.0001
TFI in patients achieving:
CR
0.41, p=0.002
0.48, p=0.0005
0.22, p<0.0001
VGPR
1.17, p=0.53
0.54, p=0.016
PR
0.46, p<0.0001
OS in patients achieving:
CR
0.85, p=0.67
0.86, p=0.61
0.45, p=0.005
VGPR
1.01, p=0.98
0.52, p=0.055
PR
0.52, p=0.0007
14
Multivariate Cox regression analysis
Time from CR to subsequent therapy appears
si i
m l
ilar
i
w th
ith early vs later CR
CR (EBMT)
(EBMT) with
ith VMP
15
Timing of CR with VMP does not appear to
have an impact on outcome
Outcomes compared among VMP patients achieving CR during cycles 14
(early) or
or during cycles 59(
9 later)
(later)
No clear difference in clinical benefit associated with achieving CR
early vs later
Time from CR to subsequent therapy appears similar
similar in
in both groups
groups
Time from randomization to subsequent therapy, time from first response to
subsequent therapy, and OS appear slightly longer with later vs early CR
due to inherent:
Longer time taken to achieve CR
Slightly longer duration of therapy (mean 8.4 vs 7.6 cycles)
· However, duration of
of CR
CR appears similar
similar in
in patients receiving
receiving <9
vs all 9 cycles of VMP
Findings should be interpreted with caution due to the small number of
patients who
who had relapsed from CR at data cut-
cut off (26
(26 of 102)
Longer follow-up required before definitive conclusions can be drawn
16
Duration of CR by algorithm appears similar between patients
recei i
v ng <9 cycles vs 9
l
cyc es (EBMT)
ith
w
VMP
VMP
17
CONCLUSIONS
This analysis of VISTA demonstrates the prognostic significance of CR on
long-term outcomes in
in the
the non-transplant setting
By EBMT criteria, CR vs PR and PR vs <PR associated with improved
long-term outcomes
By IMWG criteria, CR vs VGPR associated with improved
improved outcomes;
outcomes similar with VGPR vs PR
Our data also indicate clinical benefit of CR with VMP is similar regardless of
time to achieve CR
CR
Substantial proportion of CR patients achieved CR later (after 24
weeks treatment)
`L t
a er CR
CR '
s appear as prognostically important as early CRs
These results therefore support continuation of VMP therapy to achieve
maximal response
1. Niesvizky R et al. Br J Haematol 2008;143:4653.
18
ACKNOWLEDGMENTS
The authors would like to thank the VISTA investigators
Please add any additional acknowledgments
19
Background slides
20
Time from randomization to subsequent therapy appears
slightly longer in patients achieving later vs early CR (EBMT)
ih
with VMP
VMP
21
Analysis of
of outcomes by
by response (IMWG)
(IMWG)
Analysis of outcomes in patients achieving CR vs (VGPR+PR) vs <PR by
IMWG criteria demonstrated similar findings to CR vs PR vs <PR by EBMT
criteria
Outcomes were also determined for CR vs VGPR vs PR vs <PR
Findings should be interpreted with caution due to the small number
of VGPRs (n=41; 28 VMP, 13 MP)
CR vs VGPR by IMWG criteria was associated with significantly longer TTP
(HR=0.45), TNT (HR=0.51), and TFI (HR=0.41)
VGPR vs PR by IMWG criteria was associated with no significant
differences in outcomes
22
Patient demographics and baseline disease
characteristics in
in the
the VMP and
and MP arms
VMP, N=344
MP, N=338
Ml
Male, %
51
49
White, %
88
87
Median age, years
71
71
Age 75 years, %
31
30
KPS 70% / 80% / 90%, %
35 / 30 / 35
33 / 28 / 40
ISS1 Stage I / II / III, %
19 / 47 / 35
19 / 47 / 34
Lytic bone lesions: 0 / 13 / 410 / >10, %
35 / 21 / 19 / 25
34 / 18 / 20 / 29
Median ß2M, mg/L
4.2
4.3
ß2M <2.5 / 2.55.5 / >5.5 mg/L, %
12 / 55 / 33
12 / 55 / 33
Median albumin, g/dL
3.3
3.3
Albumin <3 5
. g/dL, %
58
59
Region: Europe / N America / Other, %
79 / 9 / 11
78 / 9 / 13
IgG / IgA / Light chain, %
64 / 24 / 8
62 / 26 / 8
Median serum creatinine, mg/dL
1.1
1.1
CrCl 30 / >3060 / >60 mL/min, %
6 / 48 / 46
5 / 50 / 46
23
1.Greipp PR et al. J Clin Oncol 2005;23:341220.
TTP in patients achieving CR is longer vs
VGPR/PR (IMWG)
(IMWG) with
with VMP
VMP
Findings should be interpreted with
caution due to the small number of
patients with VGPR
Similarly, in patients with ISS stage III MM, median TTP with VMP was longer with
CR (24.0 months) vs VGPR (15.6 months) or PR (16.1 months)
24