Superiority of
of VTD
VTD over TD incorporated into ASCT for
newly diagnosed multiple myeloma
Michele Cavo
Bologna University School of Medicine
Seràgnoli Institute
Institute of Hematology and Medical Oncology
Oncology
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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 be low ti
toxic (l
(a lll
i
ow ng
t
mos
f
o thep ti
a
t
en s to r
i
ece ve ASCT)
·
In 2005 we firstly provided
p
demonstration of superior 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%)
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STUDY DESIGN
RANDOMIZATION
INDUCTION
INDUCTION
· VEL-THAL-DEX
· THAL-DEX
PBSC COLLECTION
· CTX
TRANSPLANTATION
· MEL 200
· MEL 200
CONSOLIDATION
CONSOLIDATION
· VEL-THAL-DEX
· THAL-DEX
MAINTENANCE
· DEX
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TREATMENT SCHEMA
INDUCTION
CONSOLIDATION
Three 21 dl
-d cycles
T3
Two 5
35 dl
-d cycles
· Bt
Bort 1 3
.
/
mg s.m.
· Bort 1 3
. mg/s m
. .
d 1, 4, 8, 11/cycle
d 1, 8, 15, 22/cycle
· Thal 100200 mg/d
· Thal 100 mg/d
through
g d 1 to 63
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
­ 80% power to detect a 10-15% difference in
CR+nCR rate
Secondary
· CR+nCR after ASCTs and consolidation therapy in VTD
d
an TD arms
· Clinical outcomes (PFS, OS)
· To
T xicity
o
(adverse events)
RECRUITMENT TARGET
T
:
ARGET 450 pts (225
(225 per arm)
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VTD vs TD incorporated into double ASCT for MM
STUDY PERIOD:
May 2006 ­ April 2008
N° enrolled pts
474
N° ® to VTD
236
N° ® to TD
238
INTERIM ANALYSIS:
N° evalb
lua l
bl
t
ep s (after 1stASCT)
460
N° ® to VTD
226
N° ® to TD
234
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BASELINE PATIENT CHARACTERISTICS
VTD
TD
P value
(n=226)
(n=234)
Age (years)
567 (34-66)
567 (23-65)
0.425
Males (%)
60
60
0.68
ISS (%)
(%)
I
46
44
0.91
II + III
54
56
0.97
2-m(
m mg/L)
(mg/L)
38
3.825
2.5 (0
(0 2
. -15 7)
.
39
3.921
2.1 (1
(1 2
. -12 8)
.
07
0. 9
79
Albumin (g/L)
3.80.6 (1.9-5.4)
3.94.0 (1.3-5.2)
0.81
Creatinine (mg/dL)
(mg/dL)
1.00.3 (0.3-2.1)
1.00.3 (0.4-2.3)
0.75
Genetic abnorm.*
del(13q) pos (%)
47
46
0.71
t(4;14) pos (%)
19
20
08
0. 4
84
del(17p) pos (%)
7
8
0.78
* evaluated in 92% of pts
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RESPONSE TO INDUCTION THERAPY
VTD
TD
P value
(n=226)
(n=234)
CR (%)
21
6
<0.001
CR+nCR (%)
32
12
<0.001
VGPR (%)
62
29
<0 001
.
PR (%)
94
79
<0.001
Progression (%)
0
4.7
0.001
EBMT criteria (with added
added nCR
nCR and VGPR
VGPR categories)
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SUPERIOR nCR RATE WITH VTD
ACROSS SUBGROUPS
STANDARD POOR PROGNOSTIC VARIABLES
VTD
TD
P value
(n=
(n 226)
(n=
(n 234)
PC 50%
31
13
<0.001
LDH >190
>
(U/L)
33
9
<0 001
.
Plts <150 (x109/L)
35
4
0.009
Hb <10 (g/dl)
24
4
0.002
ISS 3
23.5
6
0.03
CRP 8 (mg/L)
(g)
20
10
0.004
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SUPERIOR nCR RATE WITH VTD
ACROSS SUBGROUPS
CYTOGENETIC ABNORMALITIES BY FISH
VTD
TD
P value
(n=210)
(n=219)
del(13q) pos
CR + nCR (%)
39
12
<0.001
VGPR (%)
()
73
25
<0.001
t(4;14) pos
CR + nCR (%)
40
8.5
<0.001
VGPR (%)
81
25.5
0
< 001
.
del(17p) pos
CR + nCR
nCR (%)
27
0
00
0. 3
03
VGPR (%)
73
6
<0.001
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RESPONSE TO FIRST ASCT
VTD
TD
P value
(n=226)
(n=234)
CR (%)
43
23
<0 001
.
CR + nCR (%)
()
55
32
<0.001
VGPR (%)
76
58
<0.001
EBMT criteria (with added nCR and VGPR categories)
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SUPERIORITY OF VTD TO TD AFTER
SECOND ASCT AND CONSOLIDATION THERAPY
SECOND ASCT*
ASCT
CONSOLIDAT
CONSOLIDA ION
T
*
ION
VTD > TD
P value
VTD > TD
P value
CC
CR + nCR
0.004
CC
CR + nCR
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, toxicit
ity, death or any th
o er reason were included in th
the analysis
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GRADE 3-4 NONHEMATOLOGIC ADVERSE EVENTS
(INDUCTION THERAPY)
VTD
TD
ADVERSE EVENT (AE)
P value
(n=226)
(n=234)
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
04
0. 2
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
Herpes Zoster infection
infection
1
0
06
0. 1
61
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OUTCOME OF PATIENTS WITH GRADE 3 PN
WHILE ON VTD AS INDUCTION THERAPY
Pts who remained on therapy (%)
95
RESPONSE RATE (%)
nCR
38
VGPR
67
PR
91
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DISCONTINUATION OF INDUCTION THERAPY
VTD
TD
(n=226)
(n=234)
DISCONTINUED (%)
()
4.4*
10.2*
Toxicity (%)
3.1
2.1
Progression (%)
0
4.7
Other (%)
1.3
3.4
Early deaths (%
y( )
0.4
0.9
* P value = 0.01
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PFS AND OS BY STUDY RANDOMIZATION
(VTD vs TD)
PFS
OS
2-yr rates
2-yr rates
VTD (n=226) 90%
VTD (n=226) 96%
TD (n=234) 80%
TD (n=234) 91%
P=0.009
P=0.2
months
months
Median follow-up for VTD and TD: 15 months
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CONCLUSIONS
· In comparison
p
with TD, three 21-d cycles (63
(
days)
y) of
VTD as induction therapy significantly increased the
nCR/VGPR rates up to values previously 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
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CONCLUSIONS
· Benefit with VTD vs TD as induction therapy
tl
transl t
a d
e it
into
­ significantly higher nCR/VGPR rates after
· 1st
1 ASCT
· 2nd ASCT
· consolidation
­ Significantly improved TTP and PFS
· Effective combinations of novel induction agents,
such as VTD, can have a remarkable impact on pre-
and post-ASCT outcomes
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ACKNOWLEDGMENTS
PARTICIP
P
A
ARTICIP T
A ING
T
CENTERS
Alessandria
Napoli
Ancona
Padova
Ascoli Piceno
Palermo
Avellino
Parma
Bari
Pavia
Bergamo
Perugia
Bologna
Pesaro
Bolzano
Pescara
Brescia
Piacenza
Brindisi
Potenza
Cagliari
Ravenna
Campobasso
Reggio Calabria
Catania
Reggio Emilia
Emilia
Cesena
Rimini
Cosenza
Roma
Cremona
Salerno
Cuneo
Sassari
Firenze
Siena
Foggia
Torino
Forlì
Treviso
Genova
Trieste
Lecce
Udine
Messina
Varese
Milano
Vicenza
Modena
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ACKNOWLEDGMENTS
Michele Baccarani
Myeloma Research
Research Unit
Lab of
of Molecular Biology
Biology
Patrizia Tosi
Carolina Terragna
Elena Zamagni
Sandra Durante
Paola Tacchetti
T
Giovanni Martinelli
Giulia Perrone
Michela Ceccolini
Annamaria Brioli
Data Management
Maria Caterina Pallotti
Katia Vitali
Lucia Pantani
Valeria Andreani
Alessandro Petrucci
Francesca Miselli
Lab of Cytogenetics
Statistical Analysis
Nicoletta Testoni
T
Mauro Fiacchini
Fiacchini
Giulia Marzocchi
Antonio de Vivo
CAV07005.PPT - 97

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