Melphalan and Prednisone (MP) Versus Melphalan,
P d
re
i
n sone
d
an Thalidomide (MPT) as Initi
itial Th
Therapy for
Previously Untreated Elderly and/or Transplant Ineligible
Patients with Multiple Myeloma: A Meta-Analysis
f
o Rd
Randomi d
ze C
t
on
l
ro lll d
e Trials
Prashant Kapoor,
p, S. Vincent Rajkumar
j
, Angela
g
Dispenzieri
p
,
Martha Q. Lacy, David Dingli, Robert A Kyle, Morie A. Gertz,
Philip R. Greipp, Shaji Kumar and Sumithra J. Mandrekar
MC
Mayo li
Cli i
n c, Rochester, MN
MN
Scottsdale, Arizona
Rochester,
Rochester Minnesota
Jacksonville, Florida
Meta-analysis/Overview: Combination
Chemotherapy versus Melphalan and
Prednisone
Years
01
23
4
5
6+
100
90
alive 80
still 70
60
27 randomized trials
50
ercentage 40
p
30
24.4
%
19.4
20
%
1.4% SD 1.4
timated
23.0
t
18.0
(log-rank
Allocated CCT (% ± SD)
0
(g
SD)
10
Es
2P > .1; NS)
Allocated MP (% ± SD)
0
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;12:3832
BACKGROUND
· A
j
ma
it
or y of
t
pa i
tients with myeloma
are older than 65 years of age
· Trials comparing efficacy of standard
melphalan-prednisone (MP) therapy
with MP plus thalidomide (T) in the
transplant ineligible, elderly patients
with multiple myeloma have
have provided
conflicting evidence.
OBJECTIVE
To perform a meta-analysis of RCTs
comparing MP with MPT as
as initial
initial
therapy for previously untreated
elderly and/or
and/or transplant ineligible
patients with multiple myeloma
METHODS
· Comprehensive search strategies used
Pb
Pu M
bMed
Abstracts from Annual Meetings
· All relevant randomized controlled trials
identified through August 1st, 2009
· Data extracted for response rates,
progression-free survival, overall survival
dd
and adverse eff
ffects
METHODS
· All data were pooled using a random effects
model
· Heterogeneity was tested with Cochran's Q
and I2
· Publication bias was assessed with Begg
and Egger funnel plots
MP versus
esus MPT: 5 Phase III RCTs
ORR
CR
PFS
OS
STUDY
N
Reference
(%)
(%)
(Months)
(Months)
MPT
167
76
16
21 8
.
45.0
Pl
Pal
b
um o tl
et al.
Blood 2008;
MP
164
48
4
14.5
47.6
112:3107-3114
MPT
165
66
2
13 0
.
37.0
Wijermans
W
et al.
ASH 2008
MP
168
47
2
10.0
30.0
(Abstract 116)
MPT
196
76
13
27 5
.
51.6
Facon et al.
Lancet 2007;
MP
125
35
2
17.8
33.2
370:12091218
MPT
113
11
62
7
24.0
44.0
Hulin et al.
al
JCO, Aug 2009
MP
116
31
1
19.0
29.0
3664-3670
MPT
182
42
6
15.0
29.0
Gulbrandsen et al.
EHA 2008
MP
181
28
3
14.0
32.0
(Abstract 209)
CR + nCR
Forest Plot of Response Rate
(Odds Ratio: MP vs. MPT)
Odds ratio and 95% CI
STUDY
OR
P-value
IFM 95-06
0.17
<0.05
ITALIAN
0.19
<0.05
IFM 01-01
0.29
<0.05
HOVON
0.47
<0.05
NORDIC
0.54
0.01
01
SUMMARY 0.31
<0.001
0.1
0.2
0.5
1
2
5
MPT is Better
MP is Better
Outcome: Odds of responding to treatment; MP vs. MPT (< 1 implies worse for MP)
Cochran's Q: 16.3 (p: 0.003); I2=75.5%
Forest Plot of Progression-free
g
Survival
(Hazard Ratio: MP vs. MPT)
Hazard ratio and 95% CI
STUDY
HR PV
P al
Va u
l e
u
IFM 95-06 2.0 <0.05
ITALIAN
1.6 <0.05
IFM 01-01 1.6 <0.05
HOVON
1.3
1.3 <0.05
NORDIC
1.1 0.32
OVERALL 1.5 <0.001
01
0.1
02
0.2
05
0.5
1
2
5
10
MP is Better
MPT is Better
Cochran's
Cochran' Q: 12 2
. (p
(p-value: 0 02);
.
I2
I =67%
2
Outcome: HR for death or progression; MP vs. MPT
(> 1 implies worse outcome for MP)
Forest Plot of Overall Survival
(Hazard R ti
a o: MP vs. MPT)
Hazard ratio and 95% CI
STUDY
HR Pl
P value
IFM 95-06 1.7 <0.05
ITALIAN
1.0 0.81
IFM 01-01 1.5 <0.05
HOVON
1.2 0.16
NORDIC
0 9
.
0 40
.
OVERALL 1.2 0.09
0.1
0.2
0.5
1
2
5
10
MP is Better
MPT is Better
Cochran's Q: 12.3 (p-value: 0.02); I2=67%
Outcome: hazard ratio for death; MP versus MPT (> 1 implies worse outcome for MP)
Forest Plot of Grade 3 Peripheral Neuropathy
(Odds Ratio: MP vs. MPT)
Odds ratio and 95% CI
STUDY
OR P Value
IFM 95-
95 06
06
00
0. 4
04 <00
<0. 5
05
ITALIAN
0.05 <0.05
IFM 01-01
0.97 0.98
HOVON
0 12
.
<0 05
.
OVERALL 0.15 0.008
00
0. 1
01
01
0.1
1
10
100
MP is Better
MPT is better
Outcome: Odds of gr
grade
ade 3 or higher event;
ev
MP ve
versus
us MPT (<
(< 1 implies better
better for
for MP)
Cochran's Q: 5.0 (p-value: 0.17); I2=39.8%
Forest Plot of Grade 3 Deep Venous Thrombosis
(Odds Ratio: MP vs. MPT)
Odds ratio and 95% CI
STUDY
OR P-Value
IFM 95-06 0.31 0.01
ITALIAN
IT
0 16
.
0 0
. 2
02
IFM 01-01 0.54 0.34
HOVON
0.03 0.01
OVERALL 0.11 0.002
0.01
0.1
1
10
100
MP is Better
MPT is better
Cochran's Q: 4.5 (p-value: 0.2); I2=33%
Outcome: Odds of grade 3 or higher event; MP versus MPT (< 1 implies better for MP)
Limitations and Advantages
· Only 5 RCTS with cross-trial heterogeneity
· The impact of high-risk genetic features
features
was not addressed in any RCT
· Confirmed the
the benefits of addition of
thalidomide to melphalan-prednisone on
RR and PFS
· Clearly identifies that MPT therapy is more
toxic
· Results of individual patient data analysis
would provide additional answers
Altern
te ativ
at e Effectiv
ect e Reg
egimens in Elde
derly
EFS
MPR
VMP vs. MP
OS
Palumbo, A. et al. J Clin Oncol; 25:4459-4465 2007
San Miguel JF et al. N Engl J Med 2008;359:906-917
CONCLUSIONS
· MPT can be considered an appropriate
front-line regimen in transplant-
ineligible/elderly patients with newly
diagnosed
l
mu ti
lti l
p e myeloma
· Compared with MP, the previous standard
of care, MPT demonstrates
demonstrates
Superior response rates (P<0.001)
Improved progression-free survival
(P<0.001)
Improved overall survival (P=0.09)
With additional toxicit
ity