Bortezomib plus melphalanprednisone continues to
demonstrate a survival benefit vs melphalanprednisone in
the phase III VISTA trial in previously untreated multiple
myeloma after more than 3 years' follow-up and extensive
subsequent therapy use
Maria-Victoria Mateos,1 Paul G. Richardson,2 Rudolf Schlag,3 Nuriet K. Khuageva,4
Meletios A. Dimopoulos,5 Ofer Shpilberg,6 Martin Kropff,7 Ivan Spicka,8 Maria T.
Petrucci,9 Antonio Palumbo,10 Olga S. Samoilova,11 Anna Dmoszynska,12 Kudrat M.
Abdulkadyrov,13 Rik Schots,14 Bin Jiang,15 Dixie L. Esseltine,16 Kevin Liu,17 Andrew
Cakana,18 Helgi van de Velde,19 Jesús F. San Miguel1
BACKGROUND
Novel-agent-based regimens in previously untreated MM patients
ineligible for high-dose therapy result in improved response rates
and time to progression (TTP) / progression-free survival (PFS)
vs conventional regimens1
However, analysis of overall survival (OS) is complicated by the
impact of novel agents as rescue therapies2
It has been suggested that frontline use of novel agents could
induce more resistant relapses3
These issues were explored in an updated analysis of the phase
III VISTA study of bortezomib plus melphalanprednisone (VMP)
versus MP alone in previously untreated MM patients ineligible
for high-dose therapy
1. Palumbo A, Rajkumar SV. Leukemia 2009;23:449456.
2. Anderson KC, et al. Leukemia 2008;22:231239.
3. San-Miguel J, et al. J Clin Oncol 2008;26:27612766.
VISTA initial analysis: VMP superior to MP for
all efficacy endpoints1
VMP
MP
p-value
Best response by EBMT criteria
N=337
N=331
Overall response rate (CR+PR), %
71
35
<0.001
Complete response (CR), %
30
4
<0.001
Median time to first response*, months
1.4
4.2
<0.001
Median time to CR, months
4.2
5.3
<0.001
Median duration of response (DOR), months
All responders
19.9
13.1
ND
Patients achieving CR
24.0
12.8
ND
Outcomes
N=344
N=338
Median time to progression (TTP), months
24.0
16.6
HR 0.48, p<0.001
Median time to next therapy (TNT), months
NR
20.8
HR 0.52, p<0.001
Median treatment-free internal (TFI), months
NR
9.4
ND
Median overall survival (OS), months
NR
NR
HR 0.61, p=0.008
*Medians shown for responding patients; p-values based on total study population; CR by International Uniform Response Criteria for VMP vs.
MP was 33% vs. 4%, p<0.001; ND: not determined; NR: not reached
Follow-up was limited (median 16.3 months); 12% of patients remained on therapy
1. San Miguel et al. N Engl J Med 2008;359:906-17.
VISTA study design
Response/progression assessed every 3 weeks during treatment
then every 8 weeks until disease progression per EBMT criteria
Patients then followed at least every 12 weeks for survival and subsequent
therapy use
Response and TTP data not updated due to stopping of formal
centralized collection of M-protein data after initial analysis1
1. San Miguel et al. N Engl J Med 2008;359:906-17.
VISTA: updated analysis
Updated analyses of OS, time to next therapy
(TNT), and treatment-free interval (TFI) after
prolonged follow-up and more extensive use of
subsequent therapy
Median follow-up 36.7 months; data cut-off March 2009
All patients had completed VISTA study treatment
Analysis of survival from start of subsequent therapy
and response to rescue therapies, to explore:
whether VMP induced more resistant relapses than MP
whether VMP upfront appeared more beneficial than
conventional treatment upfront with novel agents used at
relapse
Updated OS superior with VMP vs MP
VMP 3-year OS rate: 68.5%
MP 3-year OS rate: 54.0%
There was a 35% reduced risk of death with VMP after median follow-up of
36.7 months
Improved OS with VMP versus MP seen consistently in patient subgroups
predefined by age, sex, race, -microglobulin, albumin, region, ISS stage,
2
and creatinine clearance
Updated TNT and TFI superior with VMP vs MP
178 (52%) VMP and 233 (69%) MP patients have received
subsequent therapy
Median TNT and TFI significantly longer with VMP versus MP
43% and 18% of VMP and MP patients, respectively, had TFI 2
years
Subsequent therapies and investigator-reported best
response to subsequent therapy (2nd line and beyond)
Subsequent therapy and responses achieved
VMP (N=178)
MP (N=233)
Bortezomib-based therapy, n (%)
43 (24)
116 (50)
CR+PR, %
47
59
Bortezomib
retreatment
CR, %
6
8
Thalidomide-based therapy, n (%)
81 (46)
110 (47)
CR+PR, %
41
53
CR, %
3
5
Lenalidomide-based therapy, n (%)
57 (32)
30 (13)
CR+PR, %
59
52
CR, %
9
4
Response rates shown in response-evaluable patients in each arm.
Patients could have received more than one agent, either within the same combination regimen, as part of consecutive
separate regimens within the same line of therapy, or as part of separate regimens within different subsequent lines of
therapy.
Survival among patients receiving
subsequent therapy
VMP 3-year OS rate: 67.9%
MP 3-year OS rate: 55.9%
OS from randomization prolonged with VMP versus MP among
patients who had received subsequent therapy (HR 0.688, p=0.021)
3-year OS rates were 67.9% and 55.9%, respectively
Improved OS with VMP seen despite 50% of MP patients receiving
subsequent bortezomib
Survival from start of subsequent therapy
Median survival from start of subsequent therapy was 30.2 versus 21.9
months in the VMP and MP arms, respectively (HR 0.815, p=0.21)
Survival from start of subsequent therapy similar among VMP and MP patients who
received any novel agents as subsequent therapy (data not shown)
VMP subgroup analyses of OS age
Within the VMP arm, OS longer among patients
aged <75 vs 75 years (HR 1.664, p=0.011; 3-year
OS: 74.1% vs 55.5%)
Reflects expected adverse impact of advanced age
VMP subgroup analyses of OS
renal impairment
By contrast, no statistically significant difference but trend to longer
OS among patients with creatinine clearance 60 versus <60 mL/min (HR
1.291, p=0.238; 3-year OS: 74.5% vs 63.1%)
OS curves similar until 2428 months (median TTP/TNT), with
subsequently greater divergence; trend to shorter OS for patients
with creatinine clearance <60 mL/min
VMP subgroup analyses of OS
renal impairment
Survival from start of subsequent therapy appeared longer in patients
with creatinine clearance 60 versus <60 mL/min who received
subsequent thalidomide/lenalidomide but not bortezomib, panel A
below
By contrast, no survival difference was apparent in the small number of
patients who received subsequent bortezomib but not
thalidomide/lenalidomide, panel B
VMP subgroup analyses of OS cytogenetics
Similarly, no statistically
significant difference but trend to
longer OS among patients with
standard-risk versus high-risk
cytogenetics (HR 1.346, p=0.399; 3-
year OS 71.6% vs 56.1%)
OS curves again similar until
2428 months (median
TTP/TNT), with subsequently
greater divergence; trend to
shorter OS for patients with
high-risk cytogenetics
Survival from start of subsequent
therapy appeared similar between
cytogenetic risk groups among
patients who received any
subsequent novel-agent-based
therapy, as shown, left
Conclusions
Updated analysis after more than 3-years follow-up confirms
that VMP results in significantly longer OS than MP
OS benefit seen both overall and in patients who had received
subsequent therapy
VMP resulted in greater clinical benefit in terms of significantly
longer TNT and TFI vs MP
Salvage therapies similarly effective following VMP or MP
Use of bortezomib upfront does not preclude successful use of novel
agents at relapse
Retreatment with bortezomib-based therapies effective; 47%
response rate
Post-relapse survival appeared longer following VMP
Indicates that frontline bortezomib use does not induce more
resistant relapse