Ml
Melphl
hal
Pd
an-Predni
Th
sone-
alidomide (MP T)
-
is also superior to Melphalan-Prednisone (MP)
iP
in P t
a i
tients 75 Years of Age with
ith Unt
t
rea d
e
Multiple Myeloma (MM): Preliminary Results
oft
f h
the Randomi d
ze , Doubl
bl bli
e-
d
n ,
Placebo-controlled IFM 01/01 Trial.
C. Hulin, JM. Virion, V. Coiteux, P. Rodon, B. Pegourie,
L. Benboubker, C. Doyen, M. Dib, G. Guillerm, P. Moreau.
on behalf the Intergroupe Francophone du Myelome (IFM)
Introduction
· MP-T is standard treatment in newly diagnosed
MM pts older than 65 years.
Palumbo et al; Lancet 2006;367:825-31,
Faconetal; JCO 2006;24,A1
· Trials enrolling pts >75 years of age are rare,
although these pts represent >20% of MM pts.
pts
Dimopoulos et al; Haematologica 2006;91:252-4
· The trial objective was to evaluate MP-
MP T vs MP in a
double-blind, placebo-controlled trial in pts >75 yrs
of age with de novo MM.
IFM 01/01 Study Protocol:
IN
In Newly Di
Di
d
agnose Pt
Pts 7
> 5
75 yrs i
w th
ith MM
MM
12 cycles MP,
MP every
every 6 weeks
weeks
Melphalan
0.2 mg/kg/d Day 1-4
Prednisone
2m
2 g/kg/d
mg/kg/d Day
Day 1 4
-
Double Blind
Placebo
Thalidomide
2 caps
caps 50 mg/d
2 caps
caps 50 mg/d
72 weeks, continously
72 weeks, continously
Cld
lodronate was given to all pts;
No anticoagulant prophylaxis was planned.
IFM 01/01 Study Protocol:
In Newly Diagnosed
Diagnosed Pts >75 yrs with
with
MM
· The primary
primary end-point was overall
overall survival (OS).
· Secondary end-points were progression-free
survil
ival (PFS)
(PFS), response, and toxicity.
· The first central randomization was performed in
April 2002.
· An interim analysis was
was planned after 200 pts
were enrolled ( April 2007).
· The trial
trial was stopped
stopped after enrollment of 232 pts.
Baseline Demographics
and Disease Characteristics (1)
MP
MP-T
All Pts
Pts
(n=100) (n=100) (n=200)
Male
50%
39%
45%
NS
Median age, yrs
77.9
79.2
78.9
NS
>8
> 0
80 yrs
yrs
29%
38%
33 5%
.
NS
Significant
Comorbidity
60%
64%
6%
62%
6%
NS
WHO Index, 2 4
42%
30%
36%
NS
M-Component
-
, IgG
60%
62%
61%
NS
DS Stage III
70%
67%
69%
NS
Baseline Demographics
and Disease Characteristics (2)
MP
MP-T
All Pts
(n=100) (n=100) (n=200)
Creatinine >177 µm/L
8%
7%
7.5%
NS
2 M >= 3.5 mg/l
66%
67%
67%
NS
ISS Stage II
44%
40%
42%
NS
ISS Stage III
28%
33%
30%
NS
Deletion 13, n (%)
17/42 (40) 9/39 (23)
26/81 (32)
NS
EMG abnormal, n (%) 21/55 (38) 17/51(33) 38/106 (35) NS
Protocol Wi
W thdrawal and Progression
Progression
MP
MP-T
(n=100) (n=100)
Protocol withdrawal
85 pts
85 pts
Progression
60%
30%
p<.001
.001
Toxicity
15%
53%
p<.001
Refusal
9%
10%
NS
Study Withdrawal for Toxicity
di
during Treatment
MP
MP-T
(n=100)
(n=100)
Withdrawn for toxicity (# pts)
13
45
Peripheral neuropathy
3
11
Thrombosis/PE
1
7
Ht
Hemat l
o
i
og
l
ca
5
7
Neurologic (non peripheral)
27
Cardiac
0
3
# Withdrawn < 3 months
1
7
# Withdrawn < 6 months
4
20
# Withdrawn < 12 months
8
35
Toxicity (
y(1)
MP
MP-T
(n=100)
(n=100)
Grade 1
18%
19%
Peripheral
Grade 2
4%
17%
neuropathy
p=.02
Grade 3
2%
2%
Neutropenia
Grade 3-4
9%
21%
p=.01
Depression
Grade 2-4
2%
8%
p=.04
Toxicity (
y(2)
MP
MP-T
(n=100)
(n=100)
Thrombosis
Grade 3-4
4%
7%
NS
Constipation Grade 2-4
3%
7%
NS
Somn
So
ol
o en
e ce Grade 2-4
3%
7%
NS
Nausea/
Vomiting
Grade 2-4
5%
3%
NS
Vomiting
Oedema
Grade 2-4
8%
13%
NS
Deaths
MP
MP-T
(n=100)
(n=100)
Number of deaths
54
39
p=.03
Due to myeloma
37
24
NS
Toxic death
1
1
NS
Other reason
16
14
NS
Death < 1 month
23
Death < 3 months
months
4
5
Response to Treatment:
Best Response at 12 months
MP
MP-T
(n=100)
(n=100)
At least PR (50%)
31%
61%
At least VGPR (90%)
8%
23%
Complete Remission
1%
7%
p < 0.0001
PFS by Treatment: ITT, n=200 Pts
1.00
no
0.75
MP Thalidomide
Functin
PFS = 24.1 months
o
[19.8 29] Y/N=61/39
0.50
stributi
Di
0.25
MP Placebo
al
PFS = 19 months
rviv
[14.1 21.3] Y/N=79/21
0.00
Su
0
10
2030
405060
Time from randomization (months)
()
Temps survie ss Even.
Log-Rank test p=0.001
OS by Treatment: ITT, n=200 Pts
1.00
MP Thalidomide
iont
Median OS = 45
.3 m
0.75
[33.3 Unreached] Y/N=39/100
Func
ion
0.50
MP Placebo
istributD
Median OS = 27
.7 m
02
0. 5
25
al
[24.6 34.9] Y/N=54/100
urviv
0.00
S
0
10
2030
405060
Time from randomization (months)
LogRank test p=0.05
Median followup time = 24 months
Tr
T eatment
r
after Progression
Progression
MP
MP-T
(n=72)
(n=67)
Pts treated with Thalidomide
after Progression
Progression
60%
20%
Pts treated with
t Bor
o tez
te omi
o
b
after Progression
32%
24%
Survival Time after Progression
1.00
n
io
nct
MPThalidomide
u
0.75
F
Md
Me i
dian 93
9.3
th
mon s
on
[4.2Unknown] O/N=26/48
ti
0.50
bui
str
MP Placebo
Di
0.25
l
Median 9.8 months
a
[6.917.4] O/N=39/64
iv
urv
0.00
S
0
102030
4050
Time from progression (months)
Conclusions
· MP-T is effective for pts >75 years with newly diagnosed MM.
· MP-T showed
showed clear superiority vs. MP in prolonging PFS
PFS.
· The superiority of MP-T vs. MP for prolonging OS must be
confirmed with further analysis.
y
· The toxicity associated with MP-T in pts > 75 years was
acceptable.
Shortened thalidomide treatment duration could reduce neurotoxicity.
LMWH or Aspirine prophylaxis could reduce thrombosis.
· MP-T could be the reference treatment for patients
older than 65 years with newly diagnosed MM.