Superior outcomes with VMP vs MP:
Results of the phase III VISTA trial
JF San Miguel,1 R Schlag,2 N Khuageva,3 O Shpilberg,4 M Dimopoulos,5 M Kropff,6
I Spicka,7 M Petrucci,8 O Samoilova,9 A Dmoszynska,10 K Abdulkadyrov,11
R Schots,12 B Jiang,13 A Palumbo,14 M Mateos,1 K Liu,15 A Cakana,16
H van de Velde,16 PG Richardson17
1Hospital Universitario de Salamanca, Spain; 2Praxisklinik Dr. Schlag, Würzburg, Germany; 3SP Botkin Moscow City Clinical Hospital, Russian
Federation; 4Rabin Medical Center, Petah-Tiqva, Israel; 5University of Athens School of Medicine, Greece; 6University of Münster, Germany;
7University Hospital, Prague Czech Republic; 8University La Sapienza, Rome, Italy; 9Nizhnii Novgorod Region Clinical Hospital, Russian
Federation; 10Medical University of Lublin, Poland; 11St Petersburg Clinical Research Institute of Hematology & Transfusiology, Russian
Federation; 12Myeloma Study Group Belgian Hematological Society, Belgium; 13People's Hospital, Peking University, China; 14Universita di
Torino, Italy; 15Johnson & Johnson PRD, Raritan, United States; 16Johnson & Johnson PRD, Beerse, Belgium; 17Dana-Farber Cancer Institute,
Boston, United States
1
VISTA: VELCADE as Initial Standard Therapy in multiple
myeloma: Assessment with melphalan and prednisone
Randomized, international, phase III trial of VMP vs MP in previously
untreated MM patients who were not candidates for HDT-ASCT
Patients: Symptomatic multiple myeloma/end organ damage with
measurable disease
65 yrs or <65 yrs and not transplant-eligible; KPS 60%
R
VMP
Cycles 1-4
A
Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32
N
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
D
Cycles 5-9
O
Primary Endpoint: TTP
Bortezomib 1.3 mg/m2 IV: days 1,8,22,29
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
M
Secondary Endpoints: CR
I
9 x 6-week cycles (54 weeks) in both arms
rate, ORR, TTR, DOR,
Z
PFS, TNT, OS, QoL (PRO)
MP
E
Cycles 1-9
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
2
Rigorous assessment of efficacy and safety
Independent data monitoring committee (IDMC)
constituted and operating as per regulatory guidelines
Response and progression were assessed q3 weeks
per EBMT1 using central laboratory for M-protein
quantification; results reported in real time to the
investigator for evaluation
Safety assessed using NCI Common Toxicity Criteria
­ IDMC monitored safety data monthly
3
1. Bladé et al. Br J Haematol 1998;102:1115-23.
Results
682 patients randomized from December 2004 to September
2006 from 151 centers in 22 countries worldwide
IDMC recommended study stop in September 2007
­ Based on protocol-specified interim analysis
(data cut-off 15 June 2007)
­ VMP was significantly superior for all efficacy endpoints
Efficacy endpoint
HR
95% CI
p-value
TTP
0.540
0.417-0.699
0.000002
PFS
0.609
0.486-0.763
0.00001
OS
0.607
0.419-0.880
0.00782
TNT
0.522
0.390-0.699
0.000009
CR
11.2*
6.1-20.6
<0.000001
*Odds ratio
4
Patient demographics and
disease characteristics
VMP, N=344
MP, N=338
Male, %
51
49
White, %
88
87
Median age, years
71
71
Aged 75 years, %
31
30
KPS 70%, %
35
33
ISS Stage I / II / III, %
19 / 47 / 35
19 / 47 / 34
ß2M <2.5 / 2.5-5.5 / >5.5 mg/L, % (median ß2M, mg/L)
12 / 55 / 33 (4.2)
12 / 55 / 33 (4.3)
Albumin <3.5 g/dL, % (median albumin, g/dL)
58 (3.3)
59 (3.3)
Region: Europe / N America / Other, %
78 / 9 / 12
78 / 9 / 13
IgG / IgA / Light chain, %
64 / 24 / 8
62 / 26 / 8
Lytic bone lesions, %
65
66
% plasma cells in bone marrow biopsy, median
40
41
Serum creatinine, median (mg/dL)
1.1
1.1
CrCl 30 / >30-60 / >60 ml/min, %
6 / 48 / 46
5 / 50 / 46
History of neurological conditions, %
18
20
History of cardiac conditions, %
35
31
5
Response to Treatment
high CR with VMP
VMP, N=336
MP, N=331
p-value
M-protein*
M-protein
EBMT1
EBMT1
ORR (CR+PR)
82%
71%
50%
35%
<0.000001
CR (IF-)
35%
30%
5%
4%
<0.000001
PR
46%
40%
45%
31%
VGPR (90% M-protein)
10%
N/A
5%
N/A
*measured in serum or urine by centralized laboratory
6
1. Bladé et al. Br J Haematol 1998;102:1115-23.
Time to Response and Duration of Response
rapid and durable responses with VMP
VMP
MP
p-value
Time to response1, mos
All responders
1.4
<10-10
4.2
Time to CR
4.2
<10-10
5.3
Duration of response1, mos
All responders
19.9
13.1
Patients with CR
24.0
12.8
7
Time to progression
~52% reduced risk of progression on VMP
VMP
MP
VMP: 24.0 months (83 events)
MP: 16.6 months (146 events)
HR = 0.483, p < 0.000001
Number of patients at risk
MP: 338
296
241
206
152
86
53
22
5
VMP: 344
295
272
245
185
111
65
31
17
8
Overall survival
~ 40% reduced risk of death on VMP
VMP
MP
Median follow-up 16.3 months
VMP: not reached (45 deaths)
MP: not reached (76 deaths)
HR = 0.607, p = 0.0078
Number of patients at risk
MP: 338
320
301
280
220
157
116
69
29
7
VMP: 344
315
300
290
235
168
115
72
36
4
· OS @ 2-years 82.6% in VMP vs 69.5% in MP
· <75 years OS @ 2-years...... 84% in VMP vs 74% in MP
· 75 years OS @ 2-years...... 79% in VMP vs 60% in MP
· Treatment related deaths on each arm: VMP 1%; MP 2%
9
Relationship between TFI and TNT
Treatment-free interval
Time on therapy
Next Therapy
Time to next therapy
VMP
MP
VMP: not reached (73 events)
TNT not reached for VMP vs
MP: 20.8 months (127 events)
20.8m for MP (p=0.000009)
HR = 0.522, p = 0.000009
· Patients on VMP were 48% less
likely to start second-line therapy
· For VMP vs MP patients, 35% vs
57% at 2-years started second-
line therapy
TFI not reached for VMP vs
9.4m for MP (p=0.0001)
Number of patients at risk
MP:
338
309
261
229
178
119
77
38
15
4
VMP: 344
311
285
266
209
142
89
50
26
2
10
Grade 3/4 adverse events (%)
Serious adverse events were 46% for VMP vs 36% for MP
VMP (n=340)
MP (n=337)
Gr 3
Gr 4
Gr 3
Gr 4
Neutropenia
30
10
23
15
Thrombocytopenia
20
17
16
14
Anemia
16
3
20
8
GI
19
1
5
<1
Peripheral Sensory Neuropathy
13
<1
0
0
Fatigue
7
1
2
0
Asthenia
6
<1
3
0
Pneumonia
5
2
4
1
Herpes Zoster
3
0
2
0
Transfusion (26% vs 35%) and EPO support (34% vs 42%) were somewhat
lower on the VMP arm
PN resolved or improved in 75% of cases in a median of 64 days
DVT was low and the same on both arms (1%)
11
Tolerability and safety
VMP was well tolerated; patients remained on therapy for a
median of 46 weeks (8 cycles) vs 39 weeks with MP (7 cycles)
­ Patients received the same percentage of planned MP
dose intensity in both arms (M=99%, P=100%)
14% of patients discontinued due to AEs in each arm
12
Conclusions
VMP significantly prolongs survival and is superior for all pre-specified efficacy
endpoints in the largest MP-based phase III study
­ Rapid and durable responses with unprecedented CR rate (35%)
­ Prolonged TTP, time to next therapy/treatment-free interval, and OS
Data are robust and consistently superior across all prognostic subgroups
VMP was well tolerated, with patients on therapy for 46 weeks
­ Discontinuations due to AEs were low and identical for both arms
These results establish VMP as a new standard of care for MM patients not
eligible for HDT-ASCT, based on the highest level of evidence
13
Acknowledgments
151 investigators in 22 countries,
and most of all, the patients!
14