Terapia del paziente candidato al trapianto

Clinica Ematologica
IRCCS Fondazione Policlinico San Matteo
Università di Pavia
Terapia del paziente
candidato al trapianto
Alessandro Corso
Gammopatie monoclonali
e mieloma multiplo
Varese 14 novembre 2011
CHT convenzionale
Melphalan + Prednisone
Risposte complessive ∼ 60%
Remissioni complete rare (∼ 5%)
Stabilizzazione della malattia (plateau)
Sopravvivenza mediana: 3 anni
Lungo sopravviventi a 10 anni: 10%
La risposta completa dovrebbe essere
l’obiettivo nel mieloma multiplo
• La RC è l’obiettivo in molte patologie
ematologiche
• Il trapianto autologo prima e i nuovi farmaci più
recentemente hanno permesso l’aumento del
numero di risposte complete
• La RC ha un impatto sul TTP, sulla
sopravvivenza e sulla QoL
Impact of CR in transplant setting
Meta-analysis of 21 studies
– 10 prospective
4990 patients
– 11 retrospective
Highly significant association between maximal
response following induction therapy and long-term
outcome (P=0.0027)
Highly significant association between maximal
response (CR/nCR/VGPR) during or after HDT/SCT
and long-term outcome (OS/EFS/PFS) (P<0.00001)
van de Velde et al. Haematologica 2007;92:1399–406
CR and overall outcome in MM
721 previously untreated patients <65 years
Treatment: high-dose dex-based combination (primary therapy) +
high-dose melphalan-based regimen + ASCT (intensive therapy)
Patient group
Median Survival
CR after primary therapy
10-14 years
CR after intensive therapy of PR or NR
10-14 years
PR after primary treatment
4.3 years
PR after intensive therapy
5.9 years
Resistant disease
2 years
CR is important regardless of how it is achieved
Wang et al. Blood 2006; 108: abstract 403
PFS and OS in relation to the type of
response after transplant
(dati REL 2010)
Corso et al. Am.J.Haematol, in press
A better quality of response is
associated with a better quality of life
Progressive disease
Stable disease
Partial response
Complete response
0
20
40
60
Quality of life score
80
100
Achieving the best possible response results in improved quality of life
Ludwig et al. IMW 2007 (Abstract 1103)
CRITERIA TO IDENTIFY A MYELOMA PATIENT WHO
IS ELIGIBLE FOR AUTOTRANSPLANTATION
• 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]
PATIENTS ELIGIBLE FOR
AUTOTRANSPLANTATION (ASCT)
HIGH-DOSE THERAPY
Induction
therapy
Autograft
1±2
Consolidation
Maintenance
CR vs nCR: P = .1
CR vs PR: P = .05
nCR vs PR: P = .9
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
OS (Probability)
EFS (Probability)
Influence of Response After Induction: Superior
Outcome When CR Is Achieved Before ASCT
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
12 24 36 48 60 72 84 96
Mos
CR (n = 101)
nCR (n = 96)
CR vs nCR: P = .1
CR vs PR: P = .07
CR vs SD: P = .02
nCR vs PR vs SD: P = .9
PR (n = 346)
0
12 24 36 48 60 72 84 96
Mos
SD (n = 63)
Lahuerta JJ, et al. J Clin Oncol. 2008;26:5775-5782. Reprinted with permission. © 2008
American Society of Clinical Oncology. All rights reserved.
PD (n = 26)
Comparison between different induction regimen:
post-INDUCTION results
≥VGPR
CR
69%
Induction:
• VTD best combination
• 4 cycles > 3 ?
• 6 courses: no adv., + PN
69%
61%
59%
CR/nCR 51%
CR/nCR n/a
39%
CR/nCR 26%
28%
28%
32%
6 VTD CR 31%
4 VTD CR 27%
16%
3 VTD CR 19%
*CR/nCR
G3/4 PN
3 cicli
VTD 9,7%
4 cicli
4 cicli
6 cicli
VTD 10%
VTD 14%
4 cicli
A Phase 3 Prospective, Randomized, International Study (MMY3021) Comparing Subcutaneous and Intravenous Administration
of Bortezomib in Patients with Relapsed Multiple Myeloma
Response rate, %
Bortezomib IV
± dex (n=73)
Bortezomib SC
± dex (n=145)
ORR (CR + PR)
52
52
CR
12
10
PR
40
42
nCR
10
10
VGPR
3
5
≥VGPR (CR + nCR + VGPR)
25
25
n=39
n=82
PR → CR
2/15 (13%)
4/31 (13%)
<PR → PR
7/23 (30%)
14/47 (30%)
Response improvement (cycle 4 → 8)
in patients who received dex, n/N (%)
Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation
Time to Response / Duration
of Response
Time to first response (response-evaluable population)
Patients with response (%)
100
90
80
70
60
50
40
30
20
IV
10
SC
0
0
No. patients at risk
IV
73
SC
145
60
120
180
240
300
360
420
480
540
600
660
720
780
0
0
0
0
Days from randomization
35
70
22
32
12
19
7
11
In responding patients
4
3
2
1
2
0
2
0
2
0
0
0
Bortezomib IV, n=38
Bortezomib SC, n=76
Median time to first response, months (range)
1.4 (0.7–5.3)
1.4 (0.7–5.9)
Median time to best response, months (range)
1.5 (0.7–6.3)
1.6 (0.7–9.1)
Median duration of response, months (95% CI)
8.8 (7.6, 12.1)
9.7 (8.3, 13.6)
0
0
Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation
Time to Disease Progression
Patients without PD (%)
100
90
80
70
60
50
40
30
20
IV
10
SC
0
0
50
100
150
200
250
300
350
400
450
500
550
600
5
8
4
5
3
2
1
1
Days from randomization
No. patients at risk
IV
74
SC
148
60
126
TTP
Median, days (95% CI)
Hazard ratio (95% CI)
56
109
50
93
36
72
24
51
16
32
10
18
7
13
IV
SC
P-value
287.0 (231.0, 323.0)
9.4 months
316.0 (259.0, 357.0)
10.4 months
0.38657
0.839 (0.564, 1.249)
Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation
Pharmacokinetics
Bortezomib IV
(n=14)
Bortezomib SC
(n=17)
223 (101)
20.4 (8.87)
Tmax (hours), median (range)
0.03 (0.03–0.08)
0.50 (0.08–1.00)
AUClast (ng.h/mL), mean (SD)
151 (42.9)
155 (56.8)
Cmax (ng/mL), mean (SD)
Mean bortezomib
concentration (ng/mL)
1000
Bortezomib exposure following SC
injection was equivalent to that following
IV administration
100
10
1
IV (n=14)
0.1
SC (n=17)
0.01
0
6
12
18
24
30
36
42
Time (hours)
48
54
60
66
72
Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation
Peripheral Neuropathy (PN)
Bortezomib IV
(n=74)
Bortezomib SC
(n=148)
Pvalue*
Any PN event, %
53
38
0.04
Grade ≥2, %
41
24
0.01
Grade ≥3, %
16
6
0.03
Grade 1 PN at baseline
28
23
Diabetes at baseline
11
13
Exposure to prior neurotoxic agents
85
86
Risk factors for PN, %
*P-values based on 2-sided Fisher’s exact test
Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation
Recommendations and discussion
points: induction treatment
Aim of induction: achieve high CR rate prior to transplant
VAD should no longer be used
TD / Rd sono probabilmente trattamenti subottimali
Induction regimens should be bortezomib-based
– 3-agent regimens superior to 2-agent combinations
– 4-agent regimens not superior over 3-agent combinations,
but longer follow-up needed
Number of cycles: short induction (3–4 cycles)
With s.c. administration 4-6 cycles
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
1. Breitkreutz et al. Leukemia 2007;21:1294–1299
2. Cavo et al. Blood 2005;106:35-39
3. Kumar et al. Blood 2009;114:1729-1735
4. Moreau et al. Leukemia 2010;24:1233-1235
5. Cavo et al. Lancet 2010;376:2075-2085
EFFECT OF NOVEL AGENTS ON
STEM CELL COLLECTION
Lenalidomide
•
•
Cytotoxic effect on bone marrow
•
Recommendation:
Evidence of decreased stem cell yield after
lenalidomide exposure
-
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
Comparison between different induction regimen:
post-ASCT results
≥VGPR
CR
88%
87%
85%
VTD
CR/nCR Ludwig 76%
CR/nCR Cavo 70%
78%
72%
68%
64%
VTD
MAX CR 57%
47%
TD o VAD
MAX CR 37%
*
3 cicli
+ 2 ASCT (100%)
+2 consol
*CR/nCR
4 cicli
+ 2 ASCT**
4 cicli
+ ASCT
6 cicli
+ ASCT
** 33% VD
Comparison between different induction regimen:
post-ASCT results
≥VGPR
CR
88%
87%
VTD
MAX
85%
VGPR 88%
78%
72%
TD
68%
64%
47%
MAX VGPR 72%
VAD
MAX VGPR 47%
*
3 cicli
+ 2 ASCT (100%)
+2 consol
*CR/nCR
4 cicli
+ 2 ASCT**
4 cicli
+ ASCT
6 cicli
+ ASCT
** 33% VD
Raccomandazioni e punti aperti: trapianto
nell’era dei nuovi agenti
Il trapianto rimane lo standard per i
pazienti giovani
– Uno o due trapianti?
– In prima linea o alla ricaduta?
– Alcuni studi in corso che confrontano il
trapianto upfront verso i nuovi farmaci
Argomenti a favore del
trapianto singolo
Dati del doppio controversi, TMO migliora la
PFS ma non l’OS
Argomenti a favore del
trapianto singolo
Solo i pazienti che ottengono una risposta
subottimale sembrano beneficiare di una
seconda procedura, ma adesso possibilità di
consolidamento con I nuovi farmaci
Con i nuovi farmaci inseriti nei programmi di
terapia ad alte dosi le risposte ≥VGPR sono
spesso >70-80%
25-35% dei pazienti non completa il programma
con il II trapianto
Pazienti con malattia refrattaria o ad alto rischio
non sembrano beneficiare di due procedure
Argumenti a favore del
trapianto in prima linea
• I pazienti tollerano meglio una terapia
intensiva
• L’esposizione ai nuovi farmaci potrebbe
favorire lo sviluppo di cloni resistenti e
quindi ridurre la possibilità di risposta al
momento della ricaduta
• Al momento comunque il trapianto ha
dato i risultati migliori in prima linea
Treatment options after
transplantation
≥VGPR following SCT?
Yes
No treatment
Consolidation with
Thal?
VTD?
Lenalidomide?
No
Second
transplant?
Consolidation:
Thalidomide
Dose?
Duration?
Other novel agent
combination?
Ludwig et al. Oncologist 2010;15:6–25
Malattia residua: sempre presente!
La malattia residua, principale responsabile
delle ricadute, è sempre presente, dopo CC,
trapianto singolo o doppio con o senza nuovi
farmaci !!
L’entità della massa residua è correlata alla
rapidità della progressione
Phase 3: bortezomib consolidation
versus no consolidation following ASCT
Efficacy, %
Bortezomib Observation
P
Post-ASCT
CR/nCR
23
21
CR/nCR
54
35
Improved from PR to CR/nCR
20
12
0.06
Relapse during initial 6 months
1
6
<0.05
Post-consolidation (6-months postrandomization)
• Median number of bortezomib injections: 19
(of 20); median 90% of total planned dose
• Bortezomib held for ≥1 cycle in 31 patients,
mainly due to neuropathy (n=11) or PD (n=8)
<0.005
Grade 3/4 adverse events with
bortezomib consolidation
•Neutropenia 22%
•Thrombocytopenia 9%
Conclusion
•Consolidation with bortezomib given as a single
agent is feasible and improves response after ASCT
•Neurologic pain 5%
•Sensory neuropathy 3%
Mellqvist et al. ASH 2009 (abstract 530)
Consolidation with VTD
Patients: (n=39
(n= ) with ≥VGPR after ASCT
Treatment:
– 4 cycles VTD, started within 6 months
Bortezomib: 1.6 mg/m2, days 1, 8, 15, 22
Thalidomide: initial dose 50 mg/day, with increments up to 200 mg
Dex: 20 mg/day, days 1-4, 8-11, 15-18
Results: at 32 month median follow up
• Six patients achieved
molecular remission; none
had clinical relapse
• 50 month PFS: 100% for
patients with MR vs 62% for
patients with no MR
Ladetto et al. ASH 2009 (abstract 960)
Post-ASCT maintenance with
thalidomide in multiple myeloma
Better response rate and PFS in all studies but
discordant results on OS
Better results in patients with ≤ VGPR after ASCT
Prolonged exposure to thalidomide can select clones
more resistant to therapy so that successive therapies
are less effective in controlling disease
Thalidomide-related neuropathy is dose dependent
and the possibility of reversibility is related to the
length of exposure
Probably more
maintenance
effective
as
consolidation
than
Prospective, randomized study of
lenalidomide after ASCT (IFM 2005 02)
Results
– 542 patients evaluable (received at least one dose of consolidation
treatment with lenalidomide)
435 patients (80%) could receive the planned 2 cycles of
consolidation
64 patients (12%) could receive the 2 cycles with a reduced dose
43 patients (8%) had to definitively discontinue lenalidomide
Post-ASCT
2 cycles
Len
CR
13%
19%
≥VGPR
58 %
68%
Placebo
Len
CR
22%
25%
≥VGPR
70%
77%
3-yrs PFS
4-yrs @OS
35%
80%
68%
88%
• Median follow up from randomization
24 mos
• PFS benefit observed in all patients
indipendently by induction, type of
post-ASCT response, prognostic
factors at onset, cytogenetic
abnormalities
Attal et al. ASCO 2010
Prospective, randomized study of
lenalidomide after ASCT (IFM 2005 02)
Adverse events
Study
IFM 2005-021
CALGB
1001042
≥ grade 3
≥ grade 3
Secondary
febrile
Discontinuatio
neutropenia
malignancies
neutropenia
n (%)
(%)
(%)
(%)
43
44
1
6
5.5
Due to SAEs, 8
6.5
Due to AEs, 12
other reasons,
13
1.Attal et al. Blood 2010; 116(21). Abstract 310
2.McCarthy et al. Blood 2010; 116(21). Abstract 37
Lessons learned from other
hematological diseases
The better the quality of response, the
longer the survival
Current definition of CR is suboptimal
CR is just the first step… to maintain CR
Mateos, EHA 2010
Depth of response
Progression
Treatment initiation
MR
PR
VGPR
nCR
CR
sCR
Time
Depth of response is related to TTP
Definition of CR
EBMT
Negative immunofixation in serum and urine
Complete
Response1
<5% plasma cells in bone marrow
No increase in number of lytic lesions
Disappearance of soft tissue plasmacytomas
IMWG
Negative immunofixation in serum and urine
Complete
Response2
Disappearance of any soft tissue plasmacytomas and <5% plasma
cells in bone marrow
As above plus: Normal free light chain ratio
Stringent Complete Absence of phenotypically aberrant plasma cells in BM by
multiparametric flow cytometry
Response2
No new bone lesions
1 Maintained
for >6 weeks
2 Requires two consecutive assessments done at any time
Blade et al. Br J Haematol 1998;102:1115–1123
Durie et al. Leukemia 2006;20:1467–1473
Report of the 2008 International Myeloma Workshop consensus panel
Transplant setting: Impact of MRD
assessment on survival
PFS
OS
100
100
87%
80
80
62%
60
40
30%
Median:
71 months
59%
40
Medians:
not reached
Median:
37 months
20
0
60
20
P=0.009
P<0.001
0
0
25
50
75
5 years
100
125
Months
0
20
40
60
80
5 years
100 120 140
Months
MRD negative (n=94) MRD positive (n=53)
MRD assessed by immunophenotyping in BM obtained 3 months
after ASCT in CR patients (negative immunofixation) (n=147)
MRD, minimal residual disease
Paiva et al. Blood. 2008;112:4017–4023
Importance of achieving durable complete
response (Results from TT2*)
Survival by 3 year CR
100%
80%
SUS-CR: achieved and
sustained
CR status
60%
P value: a v b<0.0001, b v c <0.0001,
a v c <0.0001
40%
Deaths/N
SUS-CR 28/256
NON-CR 63/211
LOS-CR
23/39
20%
0%
NON-CR: never
achieved
CR status
0
LOS-CR: attained
and lost
CR status
Median
in years
NR
5.6 (4,6)
1.6 (1,2)
2
4
Years from 3 years from enrollment
*Total therapy 2 regimen: Induction: VAD, DCEP, CAD, DCEP
(TT2)
Double transplantation: MEL 200 x 2
Consolidation: DCEP vs DCEP/CAD
Maintenance: Interferon
6
Randomization: thalidomide throughout vs
no thalidomide
Barlogie et al. Cancer 2008;113:355–359
Se la RC è l’obiettivo principale della
terapia del mieloma multiplo
Probabilmente conviene continuare il
trattamento anche quando si ottiene
una RC
Il consolidamento, il mantenimento o
entrambi potrebbero avere un ruolo
centrale
Conclusioni
Obiettivo principale del trattamento deve essere
l’ottenimento di una remissione completa il più
profonda (diversi livelli di RC) e duratura possibile
La remissione completa è associata con
–
Sopravvivenza prolungata
–
Treatment-free interval prolungato
–
Migliore qualità della vita
E’ vero per tutti i pazienti?
Dati non ancora definitivi sul mantenimento