DOUBLE VS SINGLE AUTOLOGOUS
TRANSPLANTATION AND ROLE OF
ADDED THALIDOMIDE AS PRIMARY
THERAPY FOR MULTIPLE MYELOMA
MICHELE CAVO
on behalf of centers participating in the
"Bologna 96" and "Bologna 2002" clinical trials
CAV05002.PPT - 1
"BOLOGNA 96" CLINICAL TRIAL
PRIMARY STUDY OBJECTIVE
To compare the efficacy of single autologous
transplantation to that of double autologous
transplantation as part of first-line therapy
for patients with multiple myeloma.
CAV05002.PPT - 2
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
DESIGN OF THE TRIAL
R
Tx-1
Tx-2
Remission induction
VADx4
VADx4
PBSC mobilization
CTX+
7 g/m2
CTX+
G-CSF
5 µg/kg
G-CSF
1st course HD therapy
MEL
200 mg/m2
MEL
2nd course HD therapy
120 mg/m2
MEL+
12 mg/kg
BU
Maintenance
IFN-
3 MUx3/w
IFN-
CAV05002.PPT - 3
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
Present analysis: 228 pts
Treatment N°
Dead
Living
Median f-up
arm
pts
pts (%)
pts (%)
(mos)
All pts Living pts
Tx-1
115
65 (57)
50 (43)
53
66
Tx-2
113
56 (50)
57 (50)
57
73
CAV05002.PPT - 4
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
RATE OF RESPONSE
(intent-to-treat)
Tx-1
Tx-2
100
100
90
90
83
78
77
80
80
70
70
62
60
54
60
56
58
%
50
%
50
40
40
30
30
48
20
20
35
33
23
10
20
10
14
14
0
0
VAD
CTX
Tx-1
VAD
CTX
Tx-1
Tx-2
nCR
PR EBMT criteria
CAV05002.PPT - 5
Serągnoli Institute - Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
SINGLE vs. DOUBLE TRANSPLANTATION
(intent-to-treat)
TIME TO PROGRESSION
EVENT-FREE SURVIVAL
1,0
1,0
%
%
,9
,9
,8
,8
,7
,7
,6
,6
Tx-1
Tx-2
Tx-1
Tx-2
,5
(24 mos)
(40 mos)
,5
(22 mos)
(35 mos)
,4
,4
,3
,3
,2
,2
,1
,1
P=0.0001
P=0.002
0,0
0,0
0
12
24
36
48
60
72
84
0
12
24
36
48
60
72
84
months
months
CAV05002.PPT - 6
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
SINGLE vs. DOUBLE TRANSPLANTATION
(intent-to-treat)
OVERALL SURVIVAL
1,0
%
,9
,8
,7
Tx-2
,6
(73 mos)
Tx-1
,5
(59 mos)
,4
,3
,2
,1
P=0.3
0,0
0
12
24
36
48
60
72
84
months
CAV05002.PPT - 7
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
SURVIVAL ACCORDING TO ANY TREATMENT RESPONSE
R Tx-1
R Tx-2
1,0
1,0
%%
,9
,9
,8
,8
Any CR+nCR
Any CR+nCR
,7
(85 mos)
,7
(73 mos)
,6
,6
PR
PR
,5
(50 mos)
,5
(73 mos)
,4
,4
,3
,3
,2
,2
,1
,1
P=0.004
P=0.8
0,0
0,0
0
12
24
36
48
60
72
84
0
12
24
36
48
60
72
84
months
months
CAV05002.PPT - 8
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
FAILURE TO ACHIEVE nCR AFTER 1 Tx
OVERALL SURVIVAL
EVENT-FREE SURVIVAL
1,0
1,0
%%
%
,9
,9
,8
,8
Tx-2
,7
(64%)
,7
,6
,6
Tx-1
Tx-1
Tx-2
,5
(60 mos)
,5 (20 mos)
(46 mos)
,4
,4
,3
,3
,2
,2
,1
,1
P=0.01
P=0.0000
0,0
0,0
0
12
24
36
48
60
72
84
months
0
12
24
36
48
60
72
84
months
CAV05002.PPT - 9
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
SURVIVAL ACCORDING TO FINAL RESPONSE
FAILING nCR
ACHIEVING nCR
1,0
1,0
,9
,9
Tx-2
,8
,8
(67%)
Tx-1
(85 mos)
,7
,7
,6
,6
Tx-1
Tx-2
,5
,5
(59 mos)
(73 mos)
,4
,4
,3
,3
,2
,2
,1
,1
P=0.004
P=0.6
0,0
0,0
0
12
24
36
48
60
72
84
0
12
24
36
48
60
72
84
months
months
CAV05002.PPT - 10
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
CONCLUSIONS (1)
In comparison with a single autologous Tx,
double Tx
significantly prolonged the duration
of remission
significantly prolonged EFS
Longer follow-up is required to assess the
benefits of double Tx on OS
CAV05002.PPT - 11
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" CLINICAL TRIAL
CONCLUSIONS (2)
In comparison with a single autologous Tx,
double Tx was of clinical benefit for
patients who failed nCR after 1 Tx
patients who failed nCR after
completion of assigned therapy
No apparent benefit from Tx-2 for patients
who were in nCR after 1 Tx
CAV05002.PPT - 12
Serągnoli Institute -Bologna, Italy
"BOLOGNA 2002" CLINICAL TRIAL
BACKGROUND and RATIONALE
Double
autologous
transplantation
is
superior to a single transplantation
Thalidomide overcomes chemoresistance
by targeting both the myeloma clone and
the bone marrow microenvironment
Thalidomide
Double Autologous
Transplantation
CAV05002.PPT - 13
Serągnoli Institute -Bologna, Italy
"BOLOGNA 2002" CLINICAL TRIAL
PRIMARY STUDY OBJECTIVE
To evaluate the efficacy and toxicity of
thalidomide and dexamethasone as primary
therapy in preparation for double autologous
transplantation for patients with multiple
myeloma.
CAV05002.PPT - 14
Serągnoli Institute -Bologna, Italy
"BOLOGNA 2002" CLINICAL TRIAL
DESIGN OF THE TRIAL
DRUG(s)
DOSE(s)
MONTH(s)
Remission induction
THAL+
100
200mg/d
1 - 4
DEX
40mg x4/d
PBSC mobilization
CTX+
7g/m2
5
G-CSF
5µg/kg
1st course HD therapy
MEL
200mg/m2
6
2nd course HD therapy
MEL
200mg/m2
9
Maintenance
IFN-
3MU x3/w
10
CAV05002.PPT - 15
Serągnoli Institute -Bologna, Italy
"BOLOGNA 2002" CLINICAL TRIAL
Present analysis: 100 pts
STUDY
N°
MATCHING
N° pts
pt
pts
PERIOD
PERIO
CRITERIA
Jan
Jan
Ja 20
2 0
0 2
THAL-DEX
2002
0
THAL-DEX
THAL-DEX
100
10
· Age ± 2 yrs
Ja
J n
a
Ja 20
2 0
200 4
04
0
· 2-M ± 1mg/L
Ma
March 1996
VAD
100
Nov
Nov 2000
2000
· Stage
CAV05002.PPT - 16
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
BASELINE PATIENT CHARACTERISTICS
THAL-DEX (N=100)
VAD (N=100)
N° pts
Mean±SD
N° pts
Mean±SD
P value
Age (yrs)
54.01±5.75
53.94±5.47
n.s.
Stage I
12
12
Stage II+III
88
88
2-M (mg/L)
3.66±5.41
3.49±5.34
n.s.
IgG (g/dL)
61
4.45±2.06
60
5.02±1.84
n.s.
IgA (g/dL)
26
4.35±1.66
31
3.69±1.38
n.s.
Hb (g/dL)
11.01±2.25
11.19±2.00
n.s.
PLTs (x103)
231.51±79.14
233.30±76.53
n.s.
BM PC (%)
52.39±26.85
49.20±26.25
n.s.
CAV05002.PPT - 17
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" and "BOLOGNA 2002" CLINICAL TRIALS
DESIGN OF THE TRIALS
"BOLOGNA 2002"
"BOLOGNA 96"
Vincristine +
THAL
Doxorubicin
DEX
DEX
1°
2°
3°
4°
1°
2°
3°
4°
months
months
CAV05002.PPT - 18
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
RATES OF RESPONSE
(intent-to-treat)
PARTIAL REMISSION
NO RESPONSE - PROGR.
100
100
P=0.0004
P=0.0004
90
90
76
80
80
70
70
60
60
52
48
% 50
% 50
40
40
30
30
24
20
20
10
10
0
0
VAD
THAL-DEX
VAD
THAL-DEX
VGPR
PR EBMT criteria
CAV05002.PPT - 19
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
MAGNITUDE OF TUMOR REDUCTION
IgG
IgA
5000
5000
4000
4000
3000
3000
2000
2000
1000
1000
Baseline
Baseline
0
0
Post-
VAD
THAL-DEX
Post-
VAD
THAL-DEX
treat.
treat.
P=0.02
P=0.03
CAV05002.PPT - 20
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
GRADE 3-4 TOXICITIES
THAL-DEX (N=100) VAD (N=100)
N° pts
N° pts
DVT
15
2
Granulocytopenia
0
12
Constipation
9
3
Infections
4
5
Neuropathy
4
7
CAV05002.PPT - 21
Serągnoli Institute -Bologna, Italy
"BOLOGNA 2002" CLINICAL TRIAL
THALIDOMIDE-RELATED RISK OF DVT
Incidence/Prophylaxis
Incidence/Time
30
26
47
50
25
40
20
15
30
27
% 15
%
12
20
20
10
10
13
5
0
0
12
3
4
No
With
Overall
Warfarin
Warfarin
months after THAL-DEX
In 13/15 pts THAL was safely continued
CAV05002.PPT - 22
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
PBSC COLLECTION
91% of patients treated with VAD or THAL-DEX
received HD-CTX for PBSC collection
Median CD34+
CD34+ < 4
(x106/kg)
(x106/kg)
%
20
10
8
15
6
10
4
5
2
0
0
VAD
THAL-DEX
VAD
THAL-DEX
CAV05002.PPT - 23
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
CONCLUSIONS
In comparison with VAD, Thalidomide-Dexamethasone
as primary therapy in preparation for autologous
transplantation
increased the rate of response (PR)
effected more profound reduction in tumor cell
mass
did not adversely affect PBSC collection
increased the risk of DVT
need of
prophylaxis
Thalidomide-Dexamethasone is an oral alternative to
VAD
CAV05002.PPT - 24
Serągnoli Institute -Bologna, Italy
"BOLOGNA 96" and "BOLOGNA 2002" CLINICAL TRIALS
PARTICIPATING CENTERS
Ancona
Ascoli Piceno
Modena
Avellino
Napoli
Aviano
Nocera Inferiore
Bari
Pesaro
Bologna
Piacenza
Cagliari
Potenza
Catania
Ravenna
Cattolica
Reggio Emilia
Cesena
Rimini
Chioggia
San Marino
Foggia
Sassari
Forlģ
Siena
Genova
Taranto
Latina
Treviso
Messina
Udine
CAV05002.PPT - 25
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
PRE-TREATMENT AND POST-TREATMENT
COMPARISON OF M PROTEIN LEVELS
Serum IgG
Serum IgA
Baseline
Post-treat.
Baseline
Post-treat.
VAD
5024±1847
1600±533
3694±1387 1222±1067
THAL-DEX 4451±2060
980±713
4357±1668
421±368
CAV05002.PPT - 26
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
RESPONSE RATE (VGPR)
(intent-to-treat)
HD-CTX
MEL-200
100
100
P=0.001
P<0.00000
90
90
80
80
63
70
70
60
60
% 50
38
% 50
40
40
27
30
18
30
20
20
10
10
0
0
HD-CTX +
MEL-200 +
HD-CTX
MEL-200
THAL
THAL
CAV05002.PPT - 27
Serągnoli Institute -Bologna, Italy
"BOLOGNA 2002" CLINICAL TRIAL
DESIGN OF THE TRIAL
CTX 7g/m2
MEL-200
MEL-200
Zoledronic
Acid
IFN
THAL
Warfarin
DEX
1°
2°
3°
4°
5°
6°
7°
8°
9°
10°
months
CAV05002.PPT - 28
Serągnoli Institute -Bologna, Italy
THAL-DEX vs. VAD
PBSC COLLECTION
91% of patients treated with VAD or THAL-DEX
received HD-CTX for PBSC collection
Median CD34+
CD34+ 4
(x106/kg)
(x106/kg)
%
100
10
8
75
6
50
4
25
2
0
0
VAD
THAL-DEX
VAD
THAL-DEX
CAV05002.PPT - 29
Serągnoli Institute -Bologna, Italy
Document Outline