Double versus Single Autologous Stem-Cell
Transplantation for Multiple
Multiple Myeloma:
Myeloma:
A Region Based Retrospective analysis in 485 patients from the
Nordic Area
Bo Björkstrand1, Klausen TW2, Kari Remes3, Astrid Gruber4, Knudsen LM2,
Bergmann OJ2, Lenhoff S5 and Hans E Johnsen2+6
Departments of Hematology
pgy at 1) Huddinge
g University Hospital, Sweden, 2) Herlev University Hospital, Herlev, Denmark, 3) Department
p
of
Medicine, University Central Hospital, Turku, Finland, 4) Karolinska Hospital, Karolinska Institute, Stockholm, Sweden, 5) Lund University Hospital,
Lund, Sweden, 6) Aalborg Hospital, University of Aarhus Denmark & for the Nordic Myeloma Study Group
http://www.nordic-myeloma.org/
Background I
During 1994-2003 NMSG partners have conducted several registration
pg
trials in the Nordic area, evaluating the treatment outcome and care of
multiple myeloma with high-dose chemotherapy.
Trial NMSG #5/94 (N=348; Lenhoff S et al. Blood 2000;95:7-11 ) and
Trial NMSG #7/98 (N=452; Lenhoff S et al. Br J Haematology
2006;133:389-96).
This strategy has included a regional phase II registration study (Trial
HKTH (N=101)) of double high dose melphalan (200 mg/m2)
supported by
by autologous
autologous stem
stem cell transplantation.
Inclusion and
and Exclusion
Ne l
w y diagnosed
diagnosed patients less
The treatment was divided into 4
than 60 years of age who had
phases:
DurieSalmon stage I with at
least one bone lesion, II, or III
II
I: Ind
i
uct on h
t erapy;
myeloma were eligible.
II: Priming and harvest;
III: High-dose therapy with single
The criteria
criteria for
for exclusion were
were
or double high dose melphalan
prior treatment for myeloma,
200 mg/m2 given as one dose
another cancer, abnormal cardiac
intravenously, followed by stem
function, chronic respiratory
respiratory
ll
ce transplantation.
disease, abnormal liver function
or psychiatric disease.
IV: Follow up.
Huddinge Karolinska Turku and Herlev
Double Transplantation Trial 1995-2000
A phase II registration study of
of double
double high
high dose
dose melphalan
melphalan (200 mg/m2
mg/m )
supported by autologous stem cell transplantation
This trial covered a population of
of 3 million. The number
number of
of new
new cases of
of
myeloma <60 years in this population during the study period was estimated
to 200 patients.
The four institutions included 101 patients.
Exclusion was recorded for 9% of newly diagnosed
yg
patients.
p
Among the patients enrolled, 23 percent could not receive their assigned
second transplantation and has not been included in this analysis.
Aims of this retrospective analysis
analysis
To describe the double transplanted and single
transplanted patient groups*.
and compare the Overall and Event free survival.
This information was important for NMSG #15/5
trial design
Base-Line Characteristics
According to Treatment
Table 1. Base-Line Characteristics of the Patients According to Treatment Group.
Variable
Double transplantation
Single transplantation
P-value
N
101
384
Age
54
54
0.4#
Sex (female, male)
44/57; (44 and 56%)
152/232; (40 and 60%)
0.5§
Beta-2 microglobulin
2.8
3.4
0.1#
Stage
12/23/64; (12, 23 and 65%)
16/109/259; (4, 28 and 67%)
0.015§
#) Mann-Whitney test; §) Fisher's exact test; ¤) Log rank test.
Comparison between double and
single transplantation.
Table 2. Comparison between double and single transplantation.
Variable
Double transplantation
Single transplantation
P-value
N (data/missing)
101 (98/3)
384
CR
56 (57%)
155 (40%)
0.003§
CR + VGPR
59 (60%)
155 (40%)
0.0006§
()
()
OS % censored
67
75
0.9¤
OS median (years)
6.3
6.5
EFS % censored
52
46
0.0014¤
EFS % censored
52
46
14
EFS median
3.8
2.7
#) Mann-Whitney test, §) Fisher's exact test, ¤) Log rank test.
Overall survival (a) and event free survival (b) following
double transplantation in trial HKTH (
p(N=101), compared to
single transplantation in NMSG #5/94 plus #7/98 (N=384).
Figure 1a. Overall Survival
Figure 1b. Event Free Survival
Results I
The estimated overall 5-year survival rate was 50
percent in the single-transplant group and 50
percent in the double-transplant group (P=0.9).
In a multivariate analysis of variables including
single versus double transplantation, beta
beta 2
-
microglobulin level, age, sex and disease stage only
beta-2 microglobulin came out significantly
(p<0.0001) and (p=0.001) for overall and event free
survival respectively.
In accordance with these results a 1:1 case-control matched comparison between double and single
transplantation did not identify significant differences in overall and event free survival.
Statistical analysis of variables
on overall (OS) survival
Tabl
b e 3. Sta
St titstitcal analy
al sis of variabl
b es on overal (OS) and ev
even
ent free sur
su vival
al (EFS
F )
OS
Univariat
Multivariat
Variables
RR (95% CI)
P-value
RR (95% CI)
P-value
STx vs. DTx
1.0 (0.7-1.5)
0.9
0.8 (0.5-1.3)
0.4
B2
Beta 2 (l(log)
18
1.8 (1
(1.5 22
-2. )
2)
< 0 00
. 01
00
18
1.8 (1
(1.4 22
-2. )
2)
<0
< 0 0
. 00
00 1
01
Age
1.02 (0.99-1.05)
0.3
1.02 (0.99-1.05)
0.3
Sex (m vs. f)
1.3 (0.9-1.8)
0.1
1.2 (0.8-1.8)
0.4
Stage
-
03
0.3
NI
NI
Stage (II, III vs. I)
2.0 (0.8-5.6)
0.1
1.5 (0.5-5.0)
0.4
Response
1.3 (0.8-1.8)
0.2
NI
NI
non-CR vs. CR
NI Variable not included in multivariate analysis
Statistical analysis of variables on
event free survival (EFS)
EFS
Univariat
Multivariat (N = 380)
Variables
RR (95% CI)
P-value
RR (95% CI)
P-value
STx vs. DTx
1.7 (1.2-2.3)
0.001
1.3 (0.9-1.9)
0.1
Beta 2 (log)
1.3 (1.1-1.6)
0.001
1.3 (1.1-1.6)
0.001
Age
10
1. 0(
00 0
(0 9
. 8
98 10
-1. 2)
02
09
0.9
10
1. 0(
00 0
(0 9
. 8
98 10
-1. 3)
03
06
0.6
Sex (m vs. f)
1.2 (1.0-1.6)
0.1
1.2 (0.9-1.6)
0.2
Stage
-
0.06
NI
NI
St
Stage (II
(II, III
II vs
vs. I)
2.0 (1.
(1 0-3.9)
3.
0.02
0
1.3 (0.
(0 6-2.8)
2.
0.5
Response
1.8 (1.4-2.4)
< 0.0001
NI
NI
Non-CR vs. CR
NI Variable not included in multivariate analysis
Case Control Analysis comparing double and single transplantation.
Overall survival (a) and event free survival (b) following double
transplantation in
in trial
trial HKTH as
w
compared to 101 case
case controlled
controlled
single transplantation in NMSG #5/94 plus #7/98.
Figure 2a. Ol
Overa lll Survi l
va
Figure 2bE
2b. Event Free Survi l
va
Conclusions
In thi
this retrospectitive analysis "up front"
t" double
transplantation with Melphalan (200 mg/m2) as compared to
single transplantation - did not seem to improve the final
outcome among patients in the Nordic area.
It is still unknown if a second transplant should be
recommended up front or at the time of progression as
standard care.