Microsoft PowerPoint - Paris_IMW_ 2011_How I Treat

How I treat a patient eligible for high-dose
therapy and autotransplantion?
Michele Cavo
Bologna University School of Medicine
Seràgnoli Institute of Hematology
May 4, 2011, Paris
CRITERIA TO
T IDENTIFY A MYELOMA PA
P TIENT
A
WHO IS
ELIGIBLE FOR AUTOTRANSPLANT
AUT
A
OTRANSPLANT T
A ION
T
· Patient's chronological age
- Traditionally, although not appropriately, used
- Variable age cut-off
In EU: up to 65 (70) years of age
In US: up to 75 years of age (and higher) in
selected, medically-fit individuals
Cavo M et al, Blood 2011 Mar 29 [Epub ahead of print]
1

CRITERIA TO
T IDENTIFY A MYELOMA PA
P TIENT
A
WHO IS
ELIGIBLE FOR AUTOTRANSPLANT
AUT
A
OTRANSPLANT T
A ION
T
· Patient's chronological age
· Patient's physiological age
· Absence of comorbidities
· Normal organ function
Renal failure does not preclude ASCT
to support reduced-dose melphalan
Cavo M et al, Blood 2011 Mar 29 [Epub ahead of print]
NEW TREATMENT
TREA
PARADIGM
P
FOR PA
P TIENTS
A
WHO ARE
ELIGIBLE FOR AUTOTRANSPLANT
AUT
A
OTRANSPLANT T
A ION
T
(ASCT)
NOVEL AGENTS
Induction
Autograft
Consolidation
Maintenance
therapy
1 ± 2
2

GOALS OF NOVEL-AGENT-BASED
NOVEL-AGENT
INDUCTION THERAPIES
· To maximize the speedy and degree of tumor
reduction up to the VGPR, nCR and CR level
· To quickly reverse disease-related complications,
such as hypercalcemia, renal failure and anemia
· To ameliorate patient's symptoms
· To enable successful collection of PBSCs
· To minimize toxicities precluding subsequent ASCT
LATER
LA
GOALS OF SUBSEQUENT NOVEL-AGENT-BASED
NOVEL-AGENT
TREATMENT
TREA
PHASES
· To furtherly enhance tumor reduction and increase the
rate of CR
- ASCT, either single or double
- Post-ASCT consolidation therapy
· To reduce the risk of relapse and sustain durable CR
- Post-ASCT maintenance therapy
To extend PFS and OS
3

POST-ASCT
POST
HIGH-QUALITY RESPONSES PROGNOSTICATE
PROGNOSTICA
FOR IMPROVED LONG-TERM OUTCOMES
P=.4
P=.03
P=.00001
P=.00001
CR
CR
nCR+VGPR+PR
SD+PD
nCR+VGPR+PR
SD+PD
years from transplantation
years from transplantation
Harousseau et al, J Clin Oncol 2009;27:5720-5726
Martinez-Lopez et al, Blood 2011 Apr 11 [Epub ahead of print]
PROGNOSTIC RELEVANCE OF DURABLE COMPLETE RESPONSE
Survival by 3-year CR*
100%
80%
SUS-CR: achieved and
sustained
60%
CR status
P-value:
Percent
SUS-CR vs NON-CR <0.0001
NON-CR: never
40%
NON-CR vs LOS-CR <0.0001
achieved
SUS-CR vs LOS-CR <0.0001
Median
CR status
Deaths/N
in years
LOS-CR: attained
20%
SUS-CR
28/256
NR
and lost
NON-CR 63/211
5.6 (4.6)
CR status
LOS-CR
23/39
1.6 (1.2)
0% 02
4
6
Years from 3 years from enrollment
*Total therapy 2 regimen (TT2)
Barlogie et al. Cancer 2008;113:355359
4

MORE SENSITIVE TECHNIQUES ARE REQUIRED TO DETECT
THE DEPTH OF RESPONSE BEYOND THE LEVEL OF CR
· Bone marrow level
- Clonality of PC and k: FLC ratio STRINGENT CR (sCR) 1
- Multiparametric flow cytometry IMMUNOPHENOTYPIC CR 2
- Qualitative and quantitative RT-PCR MOLECULAR CR 3,4
· Outside bone marrow
- MRI 5
- PET-CT 6
1. Durie et al, Leukemia 2006;20:1467-1473
4. Ladetto et al, J Clin Oncol 2010;28:2077-2084
2. Paiva et al, Blood 2008;112:4017-4023
5. Barlogie, Blood 2006; 108:2134
3. Terragna et al, Blood 2010;116(21). Abstract 861
6. Zamagni et al, Blood 2010;116(21). Abstract 369
IMPACT ON CLINICAL OUTCOMES OF POST-ASCT
MRD DETECTED BY FLOW CYTOMETRY
PFS
OS
100
100
87%
80
80
62%
Median:
60
60
71 months
59%
40
40
Medians:
30%
Median:
not reached
37 months
20
20
P<0.001
P=0.009
0
0
0
25
50
75
100
125
0
20
40
60
80
100 120 140
5 years
Months
5 years
Months
MRD negative (n=94)
MRD positive (n=53)
Paiva et al. Blood. 2008;112:40174023
5

IMPACT ON CLINICAL OUTCOMES OF POST-ASCT PET-CT NEGATIVITY
Zamagni et al, Plenary Abstract Session II, May 6
LATER
LA
GOALS OF SUBSEQUENT NOVEL-AGENT-BASED
NOVEL-AGENT
TREATMENT
TREA
PHASES
· To furtherly enhance tumor reduction and increase the
rate of CR
- ASCT, either single or double
- Post-ASCT consolidation therapy
· To achieve the deepest response
- Immunophenotypic CR
- Molecular CR
· To reduce the risk of relapse and substain the duration
of CR
- Post-ASCT maintenance therapy
To extend PFS and OS
6

NEW TREATMENT
TREA
PARADIGM
P
FOR PA
P TIENTS
A
WHO ARE
ELIGIBLE FOR AUTOTRANSPLANT
AUT
A
OTRANSPLANT T
A ION
T
(ASCT)
NOVEL AGENTS
Induction
Autograft
Consolidation
Maintenance
therapy
1 ± 2
NOVEL-AGENT-BASED
NOVEL-AGENT
INDUCTION THERAPIES
THAL-
LEN-
BORT-
BORT-IMiD-
BASED
BASED
BASED
BASED
2-DRUG
· TD
· RD
· VD
· Rd
3-DRUG
· TAD
· RAD
· PAD
· VTD
· CTD
· RCD
· VCD
· RVD
· BiRD
4-DRUG
· VTDC
· RVDC
7

PHASE 3 STUDIES OF NOVEL AGENTS INCORPORAT
INCORPORA ED
T
INTO
INT AUTOTRANSPLANT
AUT
A
OTRANSPLANT TION
A
% INDUCTION
% ASCT
REGIMEN
CR
VGPR
CR
VGPR
PFS
OS
TT2 + Thal vs
NR
NR
59 (3-yr)*
NR
56% (5-yr)*
67% (5-yr)*
TT2 no Thal 1
NR
NR
42 (3-yr)*
NR
45% (5-yr)*
65% (5-yr)*
TAD + Thal vs
3
37*
14
54*
34 mo*
73 mo
VAD + IFN 2
2
18*
12
44*
22 mo*
60 mo
VD+Len±Len vs
6
38*
16*
54*
36
81% (3-yr)
VAD+Len±Len 3
1*
15*
9*
37*
30
77% (3-yr)
PAD+Bort vs
NR
42*
NR
61*
36 mo*
HR = 0.73*
VAD+Thal 4
NR
15*
NR
36*
27 mo*
Not reach.
1.Barlogie et al. N Engl J Med. 2006;354(10):1021-1030.
2.Lokhorst et al. Blood 2010;115(6):1113-1120.
3.Harousseau et al. J Clin Oncol. 2010;28(30):4621-4629.
4.Sonneveld et al. Blood 2010;116(21). Abstract 40
* P value statistically significant
PHASE 3 STUDIES OF NOVEL AGENTS INCORPORAT
INCORPORA ED
T
INTO
INT AUTOTRANSPLANT
AUT
A
OTRANSPLANT TION
A
% INDUCTION
% ASCT
REGIMEN
CR
VGPR
CR
VGPR
PFS
OS
TT2 + Thal vs
NR
NR
59 (3-yr)*
NR
56% (5-yr)*
67% (5-yr)*
TT2 no Thal 1
NR
NR
42 (3-yr)*
NR
45% (5-yr)*
65% (5-yr)*
TAD + Thal vs
3
37*
14
54*
34 mo*
73 mo
VAD + IFN 2
2
18*
12
44*
22 mo*
60 mo
VD+ Len ± Len vs
6
38*
16*
54*
36
81% (3-yr)
VAD+ Len ± Len 3
1*
15*
9*
37*
30
77% (3-yr)
PAD + Bort vs
NR
42*
NR
61*
36 mo*
HR = 0.73*
VAD + Thal 4
NR
15*
NR
36*
27 mo*
Not reach.
VTD + VTD vs
19*
62*
42*
82*
68% (3-yr)*
86% (3-yr)*
TD + TD 5
5*
28*
30*
64*
56% (3-yr)*
84% (3-yr)*
VTD vs
35*
60*
46*
65*
Not reach.*
Not reach.
TD 6
14*
29*
24*
40*
27 mo*
Not reach.
vTD vs
13*
51*
30*
61*
Not reach.
Not reach.
TD 7
12*
35*
33*
54*
Not reach.
Not reach.
1.Barlogie et al. N Engl J Med. 2006;354(10):1021-1030.
5.Cavo et al. Lancet 2010;379(9758):2075-2085.
2.Lokhorst et al. Blood 2010;115(6):1113-1120.
6.Rosiñol et al. Blood 2010;116(21). Abstract 307.
3.Harousseau et al. J Clin Oncol. 2010;28(30):4621-4629.
7. Harousseau et al. Blood 2009;114(22). Abstract 354.
4.Sonneveld et al. Blood 2010;116(21). Abstract 40
* P value statistically significant
8

LENALIDOMIDE-BASED REGIMENS ± AUTOTRANSPLANT
AUT
A
OTRANSPLANT TION
A
4 cycles
Best response
CR
VGPR AEs grade
EARLY
CR
VGPR
REGIMEN
(%)
(%)
3 (%)
DEATH (%)
(%)
(%)
PFS
OS
RD vs
NR
42*
52*
5*
13
46
NR
87% (2-yr)
Rd 1
NR
24*
35*
1*
10
36
NR
75% (2-yr)
1.Rajkumar et al. J Clin Oncol. 2006;24(3):431-436.
2.Richardson et al. Blood 2010;116(5):679-686.
* P value statistically significant
LENALIDOMIDE-BASED REGIMENS ± AUTOTRANSPLANT
AUT
A
OTRANSPLANT TION
A
4 cycles
Best response
CR
VGPR AEs grade
EARLY
CR
VGPR
REGIMEN
(%)
(%)
3 (%)
DEATH (%)
(%)
(%)
PFS
OS
RD vs
NR
42*
52*
5*
13
46
NR
87% (2-yr)
Rd 1
NR
24*
35*
1*
10
36
NR
75% (2-yr)
RVD 2
NR
11
NR
NR
29
67
75% (18 mo) 97% (18 mo)
1.Rajkumar et al. J Clin Oncol. 2006;24(3):431-436.
2.Richardson et al. Blood 2010;116(5):679-686.
* P value statistically significant
9

PA
P TIENTS'
A
TO
T LERANCE TO
T NOVEL-AGENT-BASED
NOVEL-AGENT
INDUCTION THERAPIES
COMPLETED
EARLY
RECEIVED
REGIMEN
INDUCTION (%)
DEATH (%)
ASCT (%)
TAD vs
88
4
82
VAD 1
90
3
82
VD vs
95
0
88
VAD 2
92
3
84
PAD vs
91
NR
85
VAD 3
90
NR
83
VTD vs
96
0
89
TD (GIMEMA) 4
92
0
82
VTD vs
NR
2
85
TD (PETHEMA) 5
NR
2
70
1.Lokhorst et al. Blood 2010;115(6):1113-1120.
4.Cavo et al. Lancet 2010;379(9758):2075-2085.
2.Harousseau et al. J Clin Oncol. 2010;28(30):4621-4629.
5.Rosiñol et al. Blood 2010;116(21). Abstract 307.
3.Sonneveld et al. Blood 2010;116(21). Abstract 40.
EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION
Thalidomide
· Adequate collection of stem cells 1,2
Bortezomib
· Not cytotoxic to bone marrow
· Successful mobilization and adequate collection of PBSC with variety of
induction regimens 3-5
REGIMEN
Priming therapy
Collected CD34+ (x106/kg)
VD4
G-CSF
6.8
VTD5
CTX + G-CSF
9.7
1. Breitkreutz et al. Leukemia 2007;21:12941299
3. Kumar et al. Blood 2009;114:1729-1735
2. Cavo et al. Blood 2005;106:35-39
4. Moreau et al. Leukemia 2010;24:1233-1235
5. Cavo et al. Lancet 2010;376:2075-2085
10

EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION
Lenalidomide
· Cytotoxic effect on bone marrow
· Evidence of decreased stem cell yield after lenalidomide exposure
· Recommendation:
- Collection of PBSC within 4 months of initiation of therapy
- Mobilization with G-CSF + cyclophosphamide after 4 months of
therapy and/or in patients aged 65 years
Kumar et al. Blood 2009;114:1729-1735
NEW TREATMENT
TREA
PARADIGM
P
FOR PA
P TIENTS
A
WHO ARE
ELIGIBLE FOR AUTOTRANSPLANT
AUT
A
OTRANSPLANT T
A ION
T
(ASCT)
NOVEL AGENTS
Induction
Autograft
Consolidation
Maintenance
therapy
1 ± 2
11

NOVEL-AGENT-BASED
NOVEL-AGENT
CONSOLIDAT
CONSOLIDA ION
T
THERAPY
AGENT /
N°
PROBABILITY TO UPGRADE
REGIMEN
CYCLES
RESPONSE (%)
PFS
OS
Bortezomib vs
6
VGPR*: 31
Updated @
Updated @
IMW 2011
IMW 2011
no consolidation 1
/
VGPR*: 19
Updated @
Updated @
IMW 2011
IMW 2011
VTD 2
4
CR: 34
60 mo
89% (3-yr)
(median)
molecular CR: 15
> PFS
> OS
1.Mellqvist et al. Haematologica 2011; 96(suppl 1). Abstract 011
* P value statistically significant
2.Ladetto et al, J Clin Oncol 2010;28:2077-2084.
3.Attal et al. Blood 2009;114(22). Abstract 529.
4.Cavo et al. Blood 2010;116(21). Abstract 42.
4.Terragna et al. Blood 2010;116(21). Abstract 861.
NOVEL-AGENT-BASED
NOVEL-AGENT
CONSOLIDAT
CONSOLIDA ION
T
THERAPY
AGENT /
N°
PROBABILITY TO UPGRADE
REGIMEN
CYCLES
RESPONSE (%)
PFS
OS
Bortezomib vs
6
VGPR*: 31
Updated @
Updated @
IMW 2011
IMW 2011
no consolidation 1
/
VGPR*: 19
Updated @
Updated @
IMW 2011
IMW 2011
VTD 2
4
CR: 34
60 mo
89% (3-yr)
(median)
molecular CR: 15
> PFS
> OS
Lenalidomide 3
2
CR: 6
not eval.
not eval.
VGPR: 10
not eval.
not eval.
VTD 4
2
CR: 11
not eval.
not eval.
molecular CR: 25
> PFS
> OS
1.Mellqvist et al. Haematologica 2011; 96(suppl 1). Abstract 011
* P value statistically significant
2.Ladetto et al, J Clin Oncol 2010;28:2077-2084.
3.Attal et al. Blood 2009;114(22). Abstract 529.
4.Cavo et al. Blood 2010;116(21). Abstract 42.
4.Terragna et al. Blood 2010;116(21). Abstract 861.
12

VTD CONSOLIDATION: PCR (patient-specific) QUALITATIVE AND
QUANTITATIVE ANALYSES OF MOLECULAR REMISSION
Efficacy
VTD
Pre-consolidation (day 0) PCR neg
39%
Post-consolidation (day +70) PCR neg
64%
P-value (McNemar Test)
0.0078
· VTD consolidation following double ASCT significantly increased the rate of
molecular remissions up to the 64% value.
· In comparison with TD, VTD consolidation effected more profound reduction in
residual tumor burden (1 log vs 5 log reduction).
Terragna et al. Blood 2010; 116(21). Abstract 861
NEW TREATMENT
TREA
PARADIGM
P
FOR PA
P TIENTS
A
WHO ARE
ELIGIBLE FOR AUTOTRANSPLANT
AUT
A
OTRANSPLANT T
A ION
T
(ASCT)
NOVEL AGENTS
Induction
Autograft
Consolidation
Maintenance
therapy
1 ± 2
13

PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE
Treatment
Induction
Maintenance
with thal
ASCT
duration
Thal+pamidronate vs
Pamidronate vs
No
Double ASCT
until PD
None 1
Thal + pred vs
No
Single ASCT
12 months
Pred2
Thal vs
Yes
Double ASCT
until PD
No Thal3
Thal vs
Yes
Single or double ASCT
until PD
IFN 4
Thal vs
Single ASCT/
Yes
until PD
Non-intensive Tx
None 5
Thal+pred vs
Yes
Single ASCT
until PD
None 6
1.Attal et al. Blood 2006;108:32893294
2.Spencer et al. J Clin Oncol 2009;27:17881793
3.Barlogie et al. N Engl J Med 2006;354:10211030; Blood 2008;112:31153121; J Clin Oncol 2010;28:12091214
4.Lokhorst et al. Blood 2010;115:111320
5.Morgan et al. Blood 2010; 116(21). Abstract 623
6.Stewart et al. Blood 2010; 116(21). Abstract 39
PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE
Induct
Survival
with
Improved PFS
Improved OS
after
Thal
relapse
Yes @ 39 m,
NO 1
Yes
Similar in all groups
Not @ 5.7 yr
Yes
NO 2
Yes
Similar in all groups
(3 yrs follow up)
Yes
Reduced OS after thal
YES 3
Yes
(7.2 yrs follow-up)
exposure
Reduced OS after thal
YES 4
Yes
No
exposure
Reduced OS after thal
YES 5
Yes
No
exposure
Reduced OS after thal
YES 6
Yes
No
exposure
1.Attal et al. Blood 2006;108:32893294
2.Spencer et al. J Clin Oncol 2009;27:17881793
3.Barlogie et al. N Engl J Med 2006;354:10211030; Blood 2008;112:31153121; J Clin Oncol 2010;28:12091214
4.Lokhorst et al. Blood 2010;115:111320
5.Morgan et al. Blood 2010; 116(21). Abstract 623
6.Stewart et al. Blood 2010; 116(21). Abstract 39
14

THALIDOMIDE MAINTENANCE STUDIES
CAVEATS
In ASCT setting, benefit with thal maintenance seen in
terms of PFS but not always of OS 1
· Toxicity , particularly neurological, leading to
discontinuation rates up to 60% 2
· Shorter survival following relapse in patients with
prior exposure to thal
- Selection of resistant clones?
· No benefit in patients with del(13q) and worse
outcome in patients with del(17p) 2,3
1. Cavo et al. J Clin Oncol 2009; 27(32): e186-187
2. Attal et al. Blood 2006;108:32893294
3. Morgan et al. Blood 2010; 116(21). Abstract 623
PHASE 3 STUDIES OF LENALIDOMIDE MAINTENANCE
Median
OS after
Study
Treatment
follow-up PFS / TTP
OS
relapse
Len
42 mo
Len
No
No
IFM 2005-021
- R
34 mo
consolid
significant significant
Placebo
24 mo
difference difference
(P<10-8)
Len
42.3 mo
No
CALGB 1001042
R
17.5 mo
significant
NR
Placebo
21.8 mo
difference
(P<0.0001)
1.Attal et al. Blood 2010; 116(21). Abstract 310
2.McCarthy et al. Blood 2010; 116(21). Abstract 37
15

PHASE 3 STUDIES OF LENALIDOMIDE MAINTENANCE
Adverse events
grade 3
grade 3 febrile
Secondary
Discontinuation
Study
neutropenia (%) neutropenia (%) malignancies (%)
(%)
IFM 2005-021
43
1
5.5
Due to SAEs, 8
Due to AEs, 12
CALGB 1001042
44
6
6.5
other reasons, 13
1.Attal et al. Blood 2010; 116(21). Abstract 310
2.McCarthy et al. Blood 2010; 116(21). Abstract 37
NEW TREATMENT
TREA
PARADIGM
P
FOR PA
P TIENTS
A
WHO ARE
ELIGIBLE FOR AUTOTRANSPLANT
AUT
A
OTRANSPLANT T
A ION
T
(ASCT)
NOVEL AGENTS
Induction
Autograft
Consolidation
Maintenance
therapy
1 ± 2
· Have novel agents incorporated into ASCT
opened the doors for a risk-adapted strategy?
16

IMPACT OF BORTEZOMIB INCORPORATED INTO ASCT ON
PFS ACCORDING TO CYTOGENETIC ABNORMALITIES
PROGRESSION-FREE SURVIVAL
REGIMEN
overall
del (13q)
t (4;14)
del (17p)
VD+ Len ± Len
36 mos (median)
NR
28 mos (median) 14 mos (median)
vs
VAD+ Len ± Len 1 30 mos (median)
NR
16 mos (median)
NR
PAD + Bort
48% (at 3-yr)
40% (at 3-yr)
28% (at 3-yr)
22% (at 3-yr)
vs
VAD + Thal 2
40% (at 3-yr)
29% (at 3-yr)
20% (at 3-yr)
16% (at 3-yr)
VTD + VTD
68% (at 3-yr)
62% (at 3-yr)
69% (at 3-yr)
NR
vs
TD + TD 3
56% (at 3-yr)
46% (at 3-yr)
37% (at 3-yr)
NR
1.Avet-Loiseau et al. Clin Oncol. 2010;28(30):4630-4634.
2.Sonneveld et al. Blood 2010;116(21). Abstract 40.
3.Cavo et al. Lancet 2010;379(9758):2075-2085.
(PERSONAL) CONCLUSION
· INDUCTION THERAPY
- A triplet bortezomib-based regimen is the standard of care
- 3-4 cycles represent a reasonable balance between efficacy
and toxicity
- BiPN will be significantly reduced by introduction of s.c.
bortezomib into daily clinical practice
· ASCT
- Outside clinical trials comparing early vs late ASCT, the
preferred approach should continue to be ASCT up-front
- High-dose therapy further enhance tumor reduction even in
face of high CR rates affected by novel-agent-based induction
regimens
17

(PERSONAL) CONCLUSION
· CONSOLIDATION THERAPY
- Provides an incremental improvement in the rate of high-quality
responses, up to the deepest level of molecular remission
- Its impact on long-term clinical outcomes needs to be
confirmed in prospective, randomized trials
· MAINTENANCE THERAPY
- Lenalidomide reduces the risk of progression (60% range) and
significantly prolongs TTP/PFS
- Benefits with lenalidomide are seen regardless of 2 m, prior
exposure to any of the novel agents, disease status at
randomization, del (13q)
- Does lenalidomide prolong OS?
18