12/29/2011
ALMA UNIVERSITAS
TAURINENSIS
UNIVERSITA' DEGLI
STUDI DI TORINO
Cattedra di Ematologia
Marco Ladetto MD, Università di Torino
LONG-TERM RESULTS OF THE GIMEMA VTD CONSOLIDATION TRIAL
IN AUTOGRAFTED MULTIPLE MYELOMA PATIENTS (VEL-03-096):
IMPACT OF MINIMAL RESIDUAL DISEASE DETECTION BY REAL TIME
QUANTITATIVE PCR ON LATE RECURRENCES AND OVERALL
SURVIVAL
Marco Ladetto, Simone Ferrero, Daniela Drandi, Federica Cavallo, Luigia Monitillo, Paola Ghione, Sara Barbiero, Mariella Grasso,
Fausto Rossini, Tommasina Guglielmelli, Clotilde Cangialosi, Anna Marina Liberati, Vincenzo Callea, Tommaso Carovita, Luca De
Rosa, Francesco Pisani, Antonietta Pia Falcone, Patrizia Pregno, Alberto Rocci, Roberto Passera, Mario Boccadoro and Antonio
Palumbo
1 Division of Hematology, University of Torino, AOU San Giovanni Battista, Torino, Italy
2 Italian Multiple Myeloma Network, GIMEMA, Italy
3 Statistical consultant, University of Torino, Torino, Italy
ASH Meeting, San Diego, 12th December 2011
DISCLOSURES
In compliance with ACCME policy, ASH requires the following disclosures to the session audience:
Research Support/P.I.
Roche, Amgen, Celgene, Italfarmaco,
Mundipharma, Cephalon
Employee
No relevant conflicts of interest to declare
Consultant
No relevant conflicts of interest to declare
Major Stockholder
No relevant conflicts of interest to declare
Speakers Bureau
Roche, Celgene, Amgen, Glaxo.
Honoraria
Celgene
Scientific Advisory Board
No relevant conflicts of interest to declare
Off-label use of drugs: Post-treatment Consolidation with Bortezomib, Thalidomide
and Dexamethasone is not standard treatment in MM
1

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12/29/2011
PCR-BASED DETECTION OF MRD: A USEFUL PROGNOSTIC TOOL
Corradini et al., Blood 2003
Bakkus et al., BJH 2004
Fenk et al.,
Korthals et al.,
Haematologica 2004
BBMT 2011
GIMEMA VTD CONSOLIDATION TRIAL (VEL-03-096)
MRD DETECTION IN THE NEW DRUG ERA
VTD CONSOLIDATION AFTER ASCT:
MAJOR FINDINGS
· Almost 20% of patients achieved PCR-
negativity by nested PCR
· PCR-negativity was stable on the
medium period (median follow-up of 42
months).
· VTD ensured an additional shrinkage of
residual tumor burden to most patients
· Achieving a low tumor burden by RQ-PCR
predicted a low risk of clinical relapse
Ladetto et al., JCO 2010
2

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12/29/2011
ADDITIONAL ISSUES TO BE ADDRESSED
Impact on PFS
Long-term
predictive value of
MRD analysis
Impact on OS
Long-term stability of
molecular response
Post-treatment
MRD kinetics
Molecular patterns
predicting relapse
WORKING HYPOTHESIS AND ELEGIBILITY
VTD CONSOLIDATION
PATIENTS WITH AT LEAST VGPR
PATIENTS IN MOLECULAR
AFTER ASCT
REMISSION
PCR-POSITIVE
PCR-NEGATIVE
MM at diagnosis
BM
(Bortezomib thalidomide
IMIDs naïve)
GISMM
Less than VGPR
CR or VGPR
VDJ OK
NO VDJ
STUDY ENTRY
NOT ELIGIBLE
NOT ELIGIBLE
3

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12/29/2011
GIMEMA VEL03096 TREATMENT SCHEDULE
AUTOLOGOUS
AUTOLOGOUS
VELCADE 1,6 mg/mq IV
TRANSPLANTATION
TRANSPLANTATION
1 dd
8
15
22
36
DEXAMETHASONE 20
mg /day PO for 4 days
THALIDOMIDE 50 mg/day
THALIDOMIDE from 50 mg/day
MAX 200 mg
MAX 200 mg
ASCT
II
III
IIV
cycles
1
23
4
5
6 12 18 24 30 36
months
MRD
MRD
MRD
MRD
No.
%
Total
39
100
Mean age, y (range)
59 (42-69)
-
Female
16
41
CLINICAL
Mean BM PCs, % (range)
50 (7-90)
-
M component
IgG
18
46
FEATURES
IgA
12
31
Light chain
821
Nonsecretory
12
ISS stage
1
21
54
2
15
38
INCLUSION CRITERIA
3
38
Del13q*
11
38
·Good clinical response after ASCT
Auto-SCT conditioning
Melphalan 100 mg/m2
14
36
· Available molecular marker (VDJ
Melphalan 200 mg/m2
25
64
rearrangement)
Response after auto-SCT
CR
615
·Thalidomide Lenalidomide and
VGPR
33
85
Bortezomib naive
Response after VTD
CR
19
49
VGPR
19
49
PD
12
4

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12/29/2011
CLINICAL OUTCOME OF THE WHOLE POPULATION
Median follow-up from diagnosis: 65 months
Median follow-up from enrollment: 55 months
OS
PFS
02
4
6
8
10
02
4
6
8
10
years
years
N Deaths: 6 (all due to progressive disease)
N Relapses/progressions: 17
Median OS: not reached
Median PFS: 64 months
5-years projected OS: 84%
5-years projected PFS: 69%
METHODS AND DEFINITIONS
consensus 5' primer
consensus 3' primer
QUALITATIVE NESTED PCR
FR1
CDR1
FR2
CDR2
FR3
CDR3
FR4
pt-specific 5' primer
pt-specific 3' primer
On immunoglobulin heavy chain gene (IGHV) rearrangement
(Voena et al, Leukemia 1997)
REAL TIME QUANTITATIVE PCR
For RQ-PCR interpretation the
ESG-MRD-ALL-NHL guidelines were
employed
(Van der Velden et al, Leukemia 2007)
(Ladetto et al, Biol Blood Marrow Transpl 2000)
Definitions
Nested-MR
molecular remission by nested PCR
Standardized-MR
High tumor burden (HTB)
molecular remission by standardized RQ-PCR
Tumor load above the median by RQ-PCR
Active disease (AD)
Low tumor burden (LTB)
Increase of MRD levels of at least one log or
Tumor load below the median by RQ-PCR
quantifiable molecular relapse by RQ-PCR
5

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12/29/2011
ADDITIONAL ISSUES TO BE ADDRESSED
Impact on PFS
Long-term
predictive value of
MRD analysis
Impact on OS
Long-term stability of
molecular response
Post-treatment
MRD kinetics
Molecular patterns
predicting relapse
LONGTERM PREDICTIVE VALUE OF MRD ANALYSIS
After
After
After
Diagnosis
ASCT
2-VTD
4-VTD
Median tumor
110000/10e6
290/10e6
11/10°6
25/10°6
burden
Nested-MR
NA
1/38 (3%)
4/35 (11%)
7/33 (21%)
Standardized-MR
NA
1/38 (3%)
12/35 (34%)
15/33 (45%)
6

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12/29/2011
Survival by molecular tumor burden shrinkage
(38 evaluable patients)
PFS
OS
After ASCT
p = 0.053
After ASCT
p = 0.829
02
46
8
10
02
46
8
10
years
years
5-years PFS: 72% vs 56%
5-years projected OS: 82% vs 88%
HTB vs LTB
RQ-PCR value < median (LTB)
(median)
RQ-PCR value > median (HTB)
Survival by molecular tumor burden shrinkage
(35 evaluable patients)
PFS
OS
After 2-VTD
p = 0.063
After 2-VTD
p = 0.786
02
46
8
10
02
46
8
10
years
years
5-years projected PFS: 74% vs 58%
5-years projected OS: 87% vs 93%
HTB vs LTB
RQ-PCR value < median (LTB)
(median)
RQ-PCR value > median (HTB)
7

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12/29/2011
Survival by molecular tumor burden shrinkage
(33 evaluable patients)
PFS
OS
After 4-VTD
p = 0.01
After 4-VTD
p < 0.05
02
46
8
10
02
46
8
10
years
years
5-years projected PFS: 82% vs 42%
5-years projected OS: 100% vs 79%
HTB vs LTB
RQ-PCR value < median (LTB)
(median)
RQ-PCR value > median (HTB)
Survival by Standard MR after 2 cycles of VTD consolidation
(35 evaluable patients)
PFS
OS
p = 0.057
p < 0.05
02
4
6
8
10
02
4
6
8
10
years
years
5-years projected PFS: 82% vs 56%
5-years projected OS: 100% vs 79%
RQ-PCR
Standard-MR patients
pos vs neg
No Standard-MR patients
8

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12/29/2011
Survival by Standard MR at the end of VTD consolidation (33
evaluable patients)
PFS
OS
p < 0.01
p < 0.02
02
4
6
8
10
02
4
6
8
10
years
years
5-years projected PFS: 82% vs 44%
5-years projected OS: 100% vs 76%
RQ-PCR
Standard-MR patients
pos vs neg
No Standard-MR patients
ADDITIONAL ISSUES TO BE ADDRESSED
Impact on PFS
Long-term
predictive value of
MRD analysis
Impact on OS
Long-term stability of
molecular response
Post-treatment
MRD kinetics
Molecular patterns
predicting relapse
9

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12/29/2011
LONGTERM STABILITY OF MOLECULAR RESPONSE
TIME-
ASCT
VTD-2
VTD-4
Post-VTD
6 m
12 m
18 m
24 m
30 m
36 m
42 m
48 m
54m
60m
7
POINTS
12
15
33
16
R
22
R
39
R
1
31
32
34
35
36
37
4
6
8
10
11
ENTS
20
TI
21
AP
23
24
25
17
2
R
3
R
5
R
9
13
R
MRD-positive samples
R
14
MRD-negative samples
R
18
R
19
ASCT
R
26
2 VTD courses
R
27
28
R
relapse or progression
R
29
R
R
death
30
R
38
clinical follow-up
R
ADDITIONAL ISSUES TO BE ADDRESSED
Impact on PFS
Long-term
predictive value of
MRD analysis
Impact on OS
Long-term stability of
molecular response
Post-treatment
MRD kinetics
Molecular patterns
predicting relapse
10

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12/29/2011
MOLECULAR PATTERNS PREDICTING RELAPSE
Treatment
High tumor burden (HTB)
Low tumor
burden (LTB)
MOLECULAR PATTERNS PREDICTING RELAPSE
Treatment
High tumor burden (HTB)
Active disease (AD)
Low tumor
burden (LTB)
11

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12/29/2011
ACTIVE DISEASE: WHAT DOES IT MEANS
DEFINITION
40
Increase of MRD levels of at
35
least one log or quantifiable
pse
30
molecular relapse by RQ-PCR
laer 25
(only patients with at least 6 months FU after
re
20
completion of VTD consolidation were
foe
evaluated)
b
15
sh
14/30 evaluable
10
ont
patients in AD
5
M
relapse rate: 9/14 (64%)
0
pt2
pt3
pt5
pt18
pt22
pt26
pt27
pt28
pt39
VTD patients
First sign of AD:
Clinical relapse
median 13 months before
is predicted
clinical relapse (1-36)
by ACTIVE DISEASE
Survival by kinetic RQPCR status: active disease (AD)
(30 evaluable patients)
PFS
OS
p < 0.001
p < 0.05
02
4
6
8
10
02
4
6
8
10
years
years
5-years projected PFS: 92% vs 44%
5-years projected OS: 100% vs 86%
No AD patients
AD vs no AD
AD patients
12

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12/29/2011
Survival by kinetic RQPCR status: subgroup analysis
(38 evaluable patients)
PFS
OS
p < 0.001
p < 0.05
02
4
6
8
10
02
4
6
8
10
years
years
5-years projected PFS: 87% vs 38%
5-years projected OS: 100% vs 76%
Low-risk patients (stable LTB)
Low-risk vs high-risk
High-risk patients (HTB+AD)
CONCLUSIONS
our long-term results indicate that:
The achievement of SMR following VTD consolidation in MM patients is
associated with a better outcome in terms of PFS and OS
A kynetic increase in molecular tumor burden (AD), detectable by RQ-PCR,
predicts late disease relapses often several months before clinical recurrence
Taken together these results suggest
the possibility of developing tailored treatments
for patients with high residual burden or showing increasing levels of MRD
during follow-up, as already pursued in other B-cell tumors
13

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12/29/2011
ACKNOWLEDGEMENTS
UNIVERSITY OF TORINO
GIMEMA-MM
HEMATOLOGY DIVISION
Director: Prof. Mario Boccadoro
Vincenzo Callea
Clotilde Cangialosi
Mario Boccadoro
Tommaso Carovita
Antonio Palumbo
Luca De Rosa
Antonietta Pia Falcone
Sara Bringhen
Mariella Grasso
Federica Cavallo
Tommasina Guglielmelli
Simone Ferrero
Anna Marina Liberati
Francesca Gay
Francesco Pisani
Alessandra Larocca
Patrizia Pregno
Chiara Lobetti Bodoni
Fausto Rossini
Alberto Rocci
Manuela Zanni
MRD LABORATORY
Daniela Drandi
Daniela Barbero
EURO-MRD
Elisa Genuardi
Barbara Mantoan
Jacques van Dongen
Luigia Monitillo
Christiane Pott
DATA MANAGEMENT
Debora Caldarazzo
Antonella Fiorillo
Tiziana Marangon
LONGTERM PREDICTIVE VALUE OF MRD ANALYSIS
106
105
genomes)d
inkage
oipl
shr
dy
104
6
10
den
s/
bur
103
tumor
102
rearrangement
lar
V
u
H
c
G
le
I
o
of
10
Standard-MR
M
(number
Nested-MR
After
After
After
Diagnosis
ASCT
2-VTD
4-VTD
Standard-MR
1/38 (3%)
12/35 (34%)
15/33 (45%)
Nested-MR
1/38 (3%)
4/35 (11%)
7/33 (21%)
14

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12/29/2011
LONGTERM STABILITY OF MOLECULAR RESPONSE
ASCT
2-4 VTD
Increasing MRD levels!!!
Relapse
(17 patients)
No relapse
genomes)d
106
(21 patients)
oipl
dy6
105
0/1s
104
LEVEL
RDM
103
rearrangementVHG 102
I
of
101
(number
BST
PCR NEG
DIA
ASCT
VTD-2
VTD-4
6 m
12 m
18 m
24 m
30 m
36m
42m
48m
54m
60m
n° samples
38
38
35
33
29
22
17
14
84
3
1
1
1
15

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