Thalidomide-Interferon-2b versus Interferon -2b as maintenance treatment after Thalidomide-Dexamethasone or Melphalan-Prednisolone
in elderly patients with myeloma: A prospective, multicenter, randomized study
Heinz Ludwig1, Zdenek Adam2, Elena Tóthová3, Roman Hajek2, Boris Labar4, Miklós Egyed5, Ivan Spicka6, Heinz Gisslinger7, Johannes Drach8, Ingrid Kuhn9, Axel Hinke10, Niklas Zojer1
1 Department of Medicine I, Wilhelminenspital, Vienna, Austria; 2 Department of Internal Medicine and Hematooncology, Faculty Hospital Brno, Czech Republic; 3 Department of Hematology and Oncohematology University hospital L. Pasteur, Kosice, Slovakia; 4 Department of Internal Medicine, Clinical Hospital "Rebro", Zagreb, Croatia; 5 Department of Internal Medicine, Kaposi Mór Teaching Hospital, Kaposvar, Hungary;
CEMSG Study Group
6 1st Internal Clinic, Charles University Prague, Czech Republic; 7 Department of Medicine I, Division of Hematology and Hemostaseology, Medical University Vienna, Austria; 8 Department of Medicine I, Division of Oncology, Medical University Vienna, Austria; 9 Schering-Plough Inc, Vienna, Austria; 10 WISP Research Institute, Langenfeld, Germany
Introduction
Table 1A. Patient characteristics
Survival after PD tended to be longer in pts. who received IFN maintenance compared to those started
on Thal-IFN (figure 4A), while OS was similar when analyzed from termination of maintenance therapy
(figure 4B).
Prolonged cytostatic therapy, corticosteroids and interferon have been tested as maintenance
Parameter
IFN
IFN-Thal
treatment in multiple myeloma (MM), but results remained unsatisfactory.
Number of Patients
64
64
Table 1B. Response status at start of maintenance
Thalidomide maintenance treatment has been tested after completion of induction therapy ±
Age, Median
72 (55-85)
71 (54-86)
(range)
ASCT and also after conventional treatment as remission maintenance therapy. These studies
Age 70-79 yrs.
38 (59%)
32 (50%)
IFN
IFN-Thal
revealed conflicting results with some trials showing improvement in overall survival and
Age 80 yrs.
5 (8%)
3 (5%)
others not.
CR
7 (11%)
13 (20%)
Gender (f/m)
30/34
30/34
nCR
21 (33%)
43 (67%)
16 (25%)
42 (66%)
In this study, we evaluated the efficacy of thalidomide plus interferon a-2b (IFN) in comparison
Tumor stage at time of induction
VGPR
15 (23%)
13 (20%)
to IFN alone as maintenance therapy in elderly patients with MM.
Stage I
2 (3%)
4 (6%)
PR
12 (19%)
11 (17%)
For induction therapy, patients had been randomized to either thalidomide-dexamethasone or
Stage II
19 (30%)
18 (28%)
MR
3 (5%)
9 (14%)
to melphalan-prednisolone (MP). This report presents the outcome of maintenance therapy
Stage III
43 (67%)
42 (66%)
SD
6 (9%)
2 (3%)
after a median follow up from randomization to maintenance of 35.7 months.
M-Component IgG
46 (72%)
42 (66%)
IgA
14 (22%)
15 (23%)
Objectives
light chain
3 (5%)
6 (9%)
non-secretor
1 (2%)
1 (2%)
Primary objective: progression-free survival; secondary objectives: response rates, overall
Performance
9 (14%)
5 (9%)*
Status 2
P=.396
survival, quality of life and toxicity
Patients and Treatment
PFS tended to be shorter in patients with adverse FISH findings compared to the standard risk group
(figure 4C). Median of OS was 72.3 months in those with standard risk and 39.6 months in those with
289 previously untreated patients with active MM not eligible for autologous transplantation
Statistical Analysis
cytogenetic high risk features (figure 4D).
had been randomized to thalidomide-dexamethasone (145) or to melphalan-prednisolone
Multivariate analysis (Cox model) showed a significant correlation between Thal-IFN maintenance
(144). The outcome of induction therapy has already been reported [1].
Fisher's exact, Cochran-Armitage trend or Wilcoxon tests were used as appropriate. PFS, OS and time on
therapy and PFS (HR: 0.61, CI: 0.39-0.89, P=.04), while for poor performance status (HR: 2.17, CI
maintenance treatment were estimated by the product limit method. Results are presented by intention-to-treat
137 of the patients enrolled received the planned therapy of nine cycles and achieved stable
0.89-5.32, P=.089), low hemoglobin (HR: 2.31, CI: 0.86-6.24, P=.099), and low albumin (HR: 1.79, CI
analysis. Univariate comparisons were performed using the logrank test. The Cox proportional hazard model
0.93-3.43, P=.079), a statistically non-significant correlation with survival was noted.
disease or better and thereby met the eligibility criteria for the maintenance phase.
was applied for multivariate analyses of event-type data and logistic regression for early non myeloma-related
IF
I N
Thal/
l I
/ FN
F
128 were randomized to either thalidomide + IFN or IFN alone (figure 1A and 1B). The
mortality.
QOL
Toxicity
No
N n-H
- ema
m t
a olo
l gic
i al
a
G1
G -2
G3-
3 4
G1-
1 2
G3-
3 4
P=
P
recommended starting dose for thalidomide was 200mg/d and for IFN 3MegaU TIW.
All P values reported are two-sided. Except for the primary endpoint, all statistical tests are of exploratory
Fa
F ti
t g
i ue
31 (49%
9 )
%
5 (8
( %)
%
43 (70
7 %)
%
5 (8
( %)
%
.06
0 4
QoL data (EORTC QLQ-C30) have been obtained in two thirds of the pts. Baseline mean scores
Ne
N ur
u olo
l g
o ic
i a
c l
24 (38%
8 )
%
-
38 (62
6 %)
%
4 (7
( %)
%
.0
. 015
1
Patient characteristics and response status at randomization for maintenance therapy are
nature and no adjustments for multiplicity were applied. Subgroup analyses of the outcome in different age
Typ
y e/G
/ r
G ade
IF
I N
Thal/
l I
/ FN
F
for overall health (Thal-IFN, mean 56; IFN, mean 59) and for overall quality of life (Thal-IFN, mean
In
I fe
f c
e ti
t o
i n
12 (19%
9 )
%
3 (5
( %)
%
13 (21
2 %)
%
4 (7
( %)
%
shown in table 1A and 1B.
groups were not pre-specified prospectively.
n = 124
2
63
61
4 mis
i si
s n
i g da
d ta
t
Ps
P y
s c
y hol
o o
l gic
i a
c l
10 (16%
6 )
%
3 (5
( %)
%
16 (26
2 %)
%
3 (5
( %)
%
58; IFN, mean 60) were markedly lower compared to an age and gender matched control
He
H ma
m t
a olo
l gic
i al
a
G1
G -2
-
G3-
3 4
G1-
1 2
G3-
3 4
P=
P
Co
C ns
n ti
t p
i at
a io
i n
o
11 (17%
7 )
%
1 (2
( %)
%
27 (44
4 %)
%
-
.0
. 004
0
289 Patients randomized
Figure 1A.
Results and Discussion
population (mean 75.3 and 73.3, respectively). Mean scores of both dimensions were similar in the
An
A e
n mia
i
43 (68%
8 )
%
-
46 (75
7 %)
%
1 (2
( %)
%
Dy
D s
y pn
p ea
12 (19%
9 )
%
-
18 (30
3 %)
%
1 (2
( %)
%
.3
. 2
3
Thal-IFN and the IFN group (overall health, P=.31, overall quality of life, P=.27) and did not vary
Le
L uk
u ope
p ni
n a
i
27 (43%
3 )
%
4 (6
( %)
%
32 (52
5 %)
%
4 (7
( %)
%
Na
N us
u ea
e
8 (13
1 %)
%
2 (3
( %)
%
9 (1
( 5%
5 )
%
2 (3
( %)
%
sign. during the conduct of the maintenance study (overall health, P=.51, overall quality of life,
Th
T rom
o boc
o yt
y o
t pen
e ia
i
10 (16%
6 )
%
-
5 (8
( %)
%
4 (7
( %)
%
Fe
F ve
v r
9 (14
1 %)
%
-
8 (1
( 3%
3 )
%
2 (3
( %)
%
128 of the 137 patients qualifying for maintenance therapy finally have been randomized
Ca
C rd
r io
i va
v sc
s u
c la
l r
9 (14
1 %)
%
-
8 (1
( 3%
3 )
%
1 (2
( %)
%
P=.71) (figure 3A-D).
145 assigned to Thal-Dex
144 assigned to MP
Sk
S i
k n
i
7 (11
1 %)
%
-
17 (28
2 %)
%
3 (5
( %)
%
.0
. 041
4
Median follow up after randomization to maintenance: 35 months
Di
D a
i rr
r hea
e
4 (6%)
%
-
2 (3
( %)
%
-
Median duration of maintenance therapy: 13.2 months in pts. randomized to Thal-IFN and 8.3 months in those
Re
R na
n l Imp
m air
i m
r ent
3 (5%)
%
-
3 (5
( %)
%
5 (8
( %)
%
.02
0 6
randomized to IFN (logrank test P=.20) (figure 2A).
123 evaluable for response
126 evaluable for response
Median daily dose of thalidomide: 75mg (range 25 ­ 200mg), median cumulative dose: 28.400mg (range: 1300 ­
Discussion and Conclusion
235.200 mg).
Thal-IFN maintenance therapy resulted in significantly longer PFS but failed to improve OS compared
137 completed 9 cycles and achieved SD
Median weekly dose of IFN: 9 mega units (range 3 - 9 mega units), median cumulative dose of 258 mega U
or better
to single agent IFN maintenance treatment. Pre-treatment with 9 cycles of Thal-Dex induction therapy
(range 3 - 938).
did not reduce the efficacy of subsequent maintenance with Thal-IFN in prolonging PFS.
128 Patients randomized
Consolidation effect: Thal-IFN resulted in an improvement in the depth of response from PR to VGPR or CR in 5
These findings are similar to results obtained in the MRC IX [2] and the HOVON [3] trials with increase
(8%) and IFN in 2 (3%) patients, respectively.
in PFS but not in OS while in the French [4] and Australian [5] studies significant improvements in
64 Thal-IFN
64 IFN
Figure 2A-2F shows time on maintenance therapy, PFS, PFS by induction regimen, OS, OS by induction regimen
both PFS and OS were noted. Barlogie observed an increase in PFS with Thal treatment during
in both maintenance groups.
induction and maintenance. Improvement in OS was noted only in pts with a cytogenetically defined
Figure 2F shows OS in pts <75 years and in those aged 75 years.
high risk profile and only after prolonged follow up.
Figure 1B. Study design
Survival after progression of disease tended to be shorter in patients randomized to Thal-IFN
Induction Phase
Maintenance Phase
Thal-Dex vs MP
maintenance therapy. This phenomenon had been observed in several other, but not all studies
Thal-IFN vs IFN
analyzing treatment outcome after failure to Thalidomide containing induction therapy.
References:
[1] Ludwig et al., Blood 2009, 113:3435-42
Thal-IFN maintenance therapy was associated with more, mostly grade 1 and grade 2,
Thalidomid: 200mg
polyneuropathy, constipation and skin toxicity, but scores for general health and overall quality of life
IFN-
[2] Morgan et al., Blood (ASH Annual Meeting Abstracts), 2008; 112: 656
2b: 3MIU, TIW
IFN 2b: 3 MIU, TIW
[3] Lokhorst et al., Blood 2009 Oct 30. [Epub ahead of print]
were similar in both maintenance arms.
[4] Attal et al., Blood, 2006; 108:3289-94
Conflict of Interest - Disclosure information pertinent to the abstract:
All patients were scheduled to receive zoledronate 4mg, q 4weeks
[5] Spencer et al., J Clin Oncol. 2009 10;27:1788-93
HL: Honoraria (Amgen, Celgene, Mundipharma, Ortho-Biotech, Roche), Research funding (Celgene, Janssen-Cilag, Mundipharma);
RH: Honoraria (Janssen-Cilag); IK: Employment (Schering-Plough)

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