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Superiority of VTD over TD incorporated into ASCT for Superiority of

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Superiority of VTD over TD incorporated into ASCT for Superiority of
Superiority of VTD over TD incorporated into ASCT for
newly diagnosed multiple myeloma
Michele Cavo
Bologna University School of Medicine
Seràgnoli Institute of Hematology and Medical Oncology
CAV07005.PPT - 78
STUDY BACKGROUND
•
Primary goals of novel agents incorporated into induction
regimens in preparation for ASCT are the following:
– to increase the rate of CR/VGPR
– to not interfere with adequate PBSC collection
– to
t be
b low
l
t i (allowing
toxic
( ll i mostt off the
th patients
ti t to
t receive
i ASCT)
•
In 2005 we firstly
y p
provided demonstration of superior
p
rate of
response with Thalidomide-Dexamethasone (TD) in comparison
with VAD as induction therapy before ASCT (Blood 2005)
•
TD has emerged as the most commonly used induction therapy for
MM in US, although the rate of CR has been unsatisfactory (10%)
CAV07005.PPT - 79
STUDY DESIGN
RANDOMIZATION
INDUCTION
• VEL-THAL-DEX
INDUCTION
• THAL-DEX
PBSC COLLECTION
• CTX
TRANSPLANTATION
• MEL 200
• MEL 200
CONSOLIDATION
• VEL-THAL-DEX
CONSOLIDATION
• THAL-DEX
MAINTENANCE
• DEX
CAV07005.PPT - 80
TREATMENT SCHEMA
INDUCTION
CONSOLIDATION
Th
Three
21-d
21 d cycles
l
T
Two
35-d
35 d cycles
l
• Bort
B t1
1.3
3 mg/s.m.
/
d 1, 4, 8, 11/cycle
• Bort 1
1.3
3 mg/s
mg/s.m.
m
d 1, 8, 15, 22/cycle
• Thal 100200 mg/d
through
g d 1 to 63
• Thal 100 mg/d
through
g d 1 to 70
• Dex 320 mg/cycle
• Dex 320 mg/cycle
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STUDY END POINTS
Primary
• CR+nCR with VTD vs TD as induction therapy
py
– 80% power to detect a 10-15% difference in
CR+nCR rate
Secondary
• CR+nCR after ASCTs and consolidation therapy in VTD
and
d TD arms
• Clinical outcomes (PFS, OS)
• Toxicity (adverse events)
RECRUITMENT TARGET: 450 pts (225 per arm)
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VTD vs TD incorporated into double ASCT for MM
STUDY PERIOD:
PERIOD
Ma 2006 – April 2008
May
N° enrolled pts
N° ® to
t VTD
N° ® to TD
474
236
238
INTERIM ANALYSIS:
N° evaluable
l bl pts
t (after 1st ASCT)
N° ® to VTD
N° ® to TD
N
460
226
234
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BASELINE PATIENT CHARACTERISTICS
VTD
(n=226)
TD
(n=234)
P value
567 (34-66)
567 (23-65)
0.425
Males (%)
60
60
0.68
ISS (%)
I
II + III
46
54
44
56
0.91
0.97
2-m (mg/L)
3 82 5 (0
3.82.5
(0.2-15.7)
2-15 7)
3 92 1 (1
3.92.1
(1.2-12.8)
2-12 8)
0 79
0.79
Albumin (g/L)
3.80.6 (1.9-5.4)
3.94.0 (1.3-5.2)
0.81
Creatinine (mg/dL)
1.00.3 (0.3
(0.3-2.1)
2.1)
1.00.3 (0.4
(0.4-2.3)
2.3)
0.75
Genetic abnorm.*
del(13q) pos (%)
t(4;14) pos (%)
del(17p) pos (%)
47
19
7
46
20
8
0.71
0 84
0.84
0.78
Age (years)
* evaluated in 92% of pts
CAV07005.PPT - 84
RESPONSE TO INDUCTION THERAPY
VTD
( 226)
(n=226)
TD
( 234)
(n=234)
P value
CR (%)
21
6
<0.001
CR+nCR (%)
32
12
<0.001
 VGPR (%)
62
29
<0 001
<0.001
 PR (%)
94
79
<0.001
Progression (%)
0
4.7
0.001
EBMT criteria (with added nCR and VGPR categories)
CAV07005.PPT - 85
SUPERIOR  nCR RATE WITH VTD
ACROSS SUBGROUPS
STANDARD POOR PROGNOSTIC VARIABLES
VTD
(n=226)
(n
226)
TD
(n=234)
(n
234)
P value
PC  50%
31
13
<0.001
LDH >190 (U/L)
33
9
<0 001
<0.001
Plts <150 (x109/L)
35
4
0.009
Hb <10
10 (g/dl)
24
4
0.002
23.5
6
0.03
20
10
0.004
ISS 3
CRP  8 ((mg/L)
g )
CAV07005.PPT - 86
SUPERIOR nCR RATE WITH VTD
ACROSS SUBGROUPS
CYTOGENETIC ABNORMALITIES BY FISH
VTD
(n=210)
TD
(n=219)
P value
del(13q) pos
CR + nCR (%)
 VGPR ((%))
39
73
12
25
<0.001
<0.001
t(4;14) pos
CR + nCR (%)
 VGPR (%)
40
81
8.5
2
25.5
<0.001
<0.001
0 001
del(17p) pos
CR + nCR (%)
 VGPR (%)
27
73
0
6
0.03
0
03
<0.001
CAV07005.PPT - 87
RESPONSE TO FIRST ASCT
VTD
(n=226)
TD
(n=234)
P value
CR (%)
43
23
<0 001
<0.001
CR + nCR ((%))
55
32
<0.001
 VGPR (%)
76
58
<0.001
EBMT criteria (with added nCR and VGPR categories)
CAV07005.PPT - 88
SUPERIORITY OF VTD TO TD AFTER
SECOND ASCT AND CONSOLIDATION THERAPY
SECOND ASCT*
ASCT
VTD > TD
P value
CONSOLIDATION*
CONSOLIDATION
VTD > TD
P value
C + nCR
CR
C
0.004
C + nCR
CR
C
0.001
CR
0.03
CR
0.005
 VGPR
0.001
 VGPR
0.001
* Patients who discontinued treatment or went off study due to relapse/
progression,
i
toxicity,
t i it death
d th or any other
th reason were included
i l d d in
i the
th analysis
l i
CAV07005.PPT - 89
GRADE 3-4 NONHEMATOLOGIC ADVERSE EVENTS
(INDUCTION THERAPY)
ADVERSE EVENT (AE)
VTD
(n=226)
TD
(n=234)
P value
SERIOUS AE (%)
15
12
0.21
Peripheral neuropathy (%)
9.1
2.1
<0.001
Skin rash (%)
7.9
1.2
<0.001
DVT (%)
39
3.9
55
5.5
0 42
0.42
Infection(s) [excluding HZ] (%)
2.6
4.2
0.34
Constipation (%)
2.6
2.5
0.95
Liver toxicity (%)
1.7
2.5
0.55
1
0
0 61
0.61
Herpes Zoster infection
CAV07005.PPT - 90
OUTCOME OF PATIENTS WITH GRADE  3 PN
WHILE ON VTD AS INDUCTION THERAPY
Pts who remained on therapy (%)
95
RESPONSE RATE (%)
 nCR
 VGPR
 PR
38
67
91
CAV07005.PPT - 91
DISCONTINUATION OF INDUCTION THERAPY
DISCONTINUED ((%))
Toxicity (%)
Progression (%)
Other (%)
Early
y deaths ((%))
VTD
(n=226)
4.4*
3.1
0
1.3
TD
(n=234)
10.2*
2.1
4.7
3.4
0.4
0.9
* P value = 0.01
CAV07005.PPT - 92
PFS AND OS BY STUDY RANDOMIZATION
(VTD vs TD)
PFS
OS
2-yr rates
VTD (n=226) 90%
TD (n=234) 80%
2-yr rates
VTD (n=226) 96%
TD (n=234) 91%
P=0.009
months
P=0.2
months
Median follow-up for VTD and TD: 15 months
CAV07005.PPT - 93
CONCLUSIONS
• In comparison
p
with TD,, three 21-d cycles
y
((63 days)
y ) of
VTD as induction therapy significantly increased the
≥nCR/VGPR rates up to values previously
y seen with
single or double ASCT preceded by conventional
treatment
• Superiority of VTD to TD was maintained across all
subgroups, as identified according to standard
prognostic variables and cytogenetic abnormalities
CAV07005.PPT - 94
CONCLUSIONS
• Benefit with VTD vs TD as induction therapy
t
translated
l t d into
i t
– significantly higher ≥nCR/VGPR rates after
• 1st ASCT
• 2nd ASCT
• consolidation
– Significantly improved TTP and PFS
• Effective combinations of novel induction agents,
such as VTD, can have a remarkable impact on preand post-ASCT outcomes
CAV07005.PPT - 95
ACKNOWLEDGMENTS
PARTICIPATING CENTERS
Alessandria
Ancona
Ascoli Piceno
Avellino
Bari
Bergamo
Bologna
Bolzano
Brescia
Brindisi
Cagliari
Campobasso
Catania
Cesena
Cosenza
Cremona
Cuneo
Fi
Firenze
Foggia
Forlì
Genova
Lecce
Messina
Milano
Modena
Napoli
Padova
Palermo
Parma
Pavia
Perugia
Pesaro
Pescara
Piacenza
Potenza
Ravenna
Reggio Calabria
Reggio Emilia
Rimini
Roma
Salerno
Sassari
Siena
Torino
Treviso
Trieste
Udine
Varese
Vicenza
CAV07005.PPT - 96
ACKNOWLEDGMENTS
Michele Baccarani
Myeloma Research Unit
Patrizia Tosi
Elena Zamagni
Paola Tacchetti
Giulia Perrone
Michela Ceccolini
Annamaria Brioli
Maria Caterina Pallotti
Lucia Pantani
Alessandro Petrucci
Lab of Molecular Biology
Carolina Terragna
Sandra Durante
Giovanni Martinelli
Lab of Cytogenetics
Nicoletta Testoni
Giulia Marzocchi
Statistical Analysis
Mauro Fiacchini
Antonio de Vivo
Data Management
Katia Vitali
Valeria Andreani
Francesca Miselli
CAV07005.PPT - 97
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