Transcript Folie 1 - Lymphome

DGHO - KML 06.09.2009
Multiple Myeloma
Hartmut Goldschmidt
Sektion Multiples Myelom
Medizinische Klinik V, Universität Heidelberg
Nationales Centrum für Tumorerkrankungen Heidelberg
Multiple Myeloma - Classification
Definitions
MGUS
SMM (AMM)
• <3 g M spike AND • 3 g M spike
OR 10% PC
<10% PC
AND
No
Calcium
Renal Insufficiency
Anemia
Bone disease
MM
•10% PC
•M spike +
AND
YES
Calcium
Renal Insufficiency
Anemia
Bone disease
Multiple Myeloma – ISS-Staging
International Staging System for MM
Stage
I
II
Criteria
Median survival
(months)
Serum 2-microglobulin < 3.5 mg/L
Serum albumin ≥ 35 g/L
Serum 2-microglobulin < 3.5 mg/L
62
44
Serum albumin < 35 g/L
OR
Serum 2-microglobulin 3.5 to
< 5.5 mg/L*
III
Serum 2-microglobulin ≥ 5.5 mg/L
29
* Irrespective of serum albumin level.
Greipp PR, et al. J Clin Oncol. 2005;23:3412
Therapy in MM
Progress in MM Treatment over 40 Years
1990s
Single
ASCT
From 1980s
Myeloablation
+ BMT
1970
1962
Melphalan
1969
Melphalan
+ Prednisone
1980
2000s
Tandem
ASCT?
1990
1984
VAD
2000
1999
Thalidomide
1990s
Supportive
Care
2004
Lenalidomide
2002
Bortezomib
Upfront Therapy
Patient with
‘active disease’
Transplantation
No Transplantation
Age up to 60/65/70/75
‘Normal’ organ function
Stem cells
Patient’s preference
High age
Multimorbidity
Inadequate stem cells
Patient’s preference
H. Ludwig 2009, Post ASH-Slides
VAD in 2005 - 2009
Cavo et. al., Blood July 2005
Comment: Rajkumar Blood Juli 2005
Matched Case-Control Study 200 pts.
100 pts. VAD
100 pts. Thal.-Dex.
ORR 52%
ORR 76%
ORR= Overall Response Rate (at least PR)
It is time to say goodbye to VAD!
ASCT: the Induction Regimen
The goals of the Induction Regimen
 Rapid reduction of tumor mass:
Dexamethasone based (DEX or VAD) !
 Adequate stem cell collection:
No Alkylating (excl. CY) agents !
Q : Could New Drugs improve DEX or VAD ?
Attal 2008, ASH Education MM
ASCT and New Drugs:
induction
Author
Cavo
Rajkumar
Regimen
N
RR
CR/VGPR
VAD
100
52%
14%
Dex-Thal
100
76%
Dex
104
41%
Dex-Thal
103
63%
VAD
200
63%
19%
p
0.001
0.002
CR= 3%
Goldschmidt
0.001
TAD
200
80%
CR=7%
Harousseau
Dex-Vel
48
67%
31%
Rajkumar
Dex-Rev
34
91%
38%
Attal 2007, ASH Education MM
Phase 3: PAD vs VAD as induction treatment
HOVON 65 MM / GMMG-HD4 study
MM Stage II or III, Age 18–65
Randomization
3 x VAD
3 x PAD
CAD + GCSF
CAD + GCSF
MEL 200 + PBSCT
Depending on local
policy for patients PR
MEL 200 + PBSCT
Thalidomide
50 mg/day for
2 years
maintenance
MEL 200 + PBSCT
Allogeneic
Tx
Depending on local
policy for patients PR
MEL 200 + PBSCT
Bortezomib
1.3 mg/m2 / 2 weeks
for 2 years
maintenance
Sonneveld et al. ASH 2008 (abstract 653)
Phase 3: PAD vs VAD as induction treatment
Response data
PAD
(n=150)
VAD
(n=150)
P
Response after induction
CR/nCR
5%
1%
≥ VGPR
42%
15%
≥ PR
83%
59%
Responses after first ASCT
CR/nCR
23%
9%
0.0015
≥ VGPR
80%
50%
0.0019
≥ PR
93%
80%
0.0021
Sonneveld et al. ASH 2008 (abstract 653)
Phase 3: PAD vs VAD as induction treatment
Improvement in CR rate over course of treatment
Induction
HDM
Best (maintenance)
5%
23%
37%
CR/nCR
Adverse events
•
•
VAD
PAD
Fatigue
26%
29%
PN gr 2
17%
13%
PN gr 3/4
6%
16%
DVT
3%
4%
Infections
gr. 2-4
42%
54%
P
0.003
No difference in hematological toxicities
80% of patients able to receive 100% of assigned dose during induction
Sonneveld et al. ASH 2008 (abstract 653)
Protocol for newly diagnosed MM < 60 yrs. - DSMM XI
optional Dex
VelCyDex
VelCyDex
VelCyDex
IEV
1. HD-Mel
200 mg/m²
High risk
Standard risk
HLA identical sibling/MUD
yes
no
2. HD-Mel
200 mg/m²
Allo-SCT
2. HD-Mel 200 mg/m²
R
R
Nil
R
Vel weekly
Nil
Vel weekly
Nil
Vel weekly
Response to VCD treatment with respect to
cytogenetic aberrations (n=160)
%
Best response to VCD treatment (> PR)
100
90
80
70
60
50
40
30
20
10
0
no
13q-
t(4;14)
17p-
Knop et al. ASCO 2009
Study Design
Primary analysis: post-induction CR+nCR in VAD (A1+A2) vs Vel-Dex (B1+B2)
Randomization
stratified by β2-microglobulin level (>3mg/L vs ≤3mg/L) and presence of chromosome 13
abnormalities (by FISH analysis)
A1
A2
VAD x 4
VAD x 4
Induction
DCEP x 2
Consolidation
Melphalan
200mg/m2
+ ASCT
Melphalan
200mg/m2
+ ASCT
Transplant 1
B1
B2
Vel-Dex x 4
Vel-Dex x 4
DCEP x 2
Melphalan
200mg/m2
+ ASCT
Melphalan
200mg/m2
+ ASCT
Second ASCT or RIC allo if <VGPR
Harousseau ASH 2008
Progression-Free Survival
2-yr Median Follow-up
Kaplan-Meier estimate
100
Vel-Dex: 71 events
Median NR; 2-yr PFS 69%
80
60
VAD: 101 events
Median: 28 months; 2-yr PFS 60%
40
20
Vel-Dex (B1+B2)
VAD (A1+A2)
P-value (log-rank) = 0.0115
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Harousseau ASH 2008
© 2009 OptumHealth Education
Treatment options for patients eligible
for transplantation
Induction
Bortezomib-based:
‘Traditional’
VAD
CyDex
VelDex
VTD
PAD
VCD
Stem cell harvest
High-dose melphalan
Stem cell infusion
IMiD-based:
Thal/Dex
TAD
CTD
Rd
VRD
High-doseTherapy in MM
Association between Max. Response and OS in
Patients with MM Treated with ASCT
Maximal Response
Prospective Study
Comparison
P Value
IFM90
CR/VGPR vs. PR vs. other
<0.00001
MRC VII
CR vs. PR vs. MR
0.00002
TT1
CR vs. PR
0.2496
TT2
CR vs. PR/NR
<0.05
IFM94-02
Maximal response
<0.001
IFM99C
CR/VGPR vs. PR
<0.0000
NMSG 5/94
CR vs. PR/NR
0.38
Bologna
≥ VGPR vs. other
0.002
GMA
CR/MRD vs. other
0.22
Meta-analysis
CR/VGPR vs. PR vs. other
<0.00001
Adapted from Van de Velde H et al. Complete response correlates with long-term survival and progression-free survival in
high-dose therapy in multiple myeloma. Haematologica 2007; 92:1399-1406
PAD Induction, MEL-100, Len/Prednisone Consolidation, and Len
Maintenance in Elderly Patients with Newly Diagnosed MM
PAD→MEL-100→LP→L
PBSC Mobilization
PAD
(Cyclophosphamide + G-CSF)
4 cycles
2 cycles
MEL-100
ASCT
LP
2 cycles
4 cycles
L
PAD = bortezomib + pegylated doxorubicin + dexamethasone; MEL-100 = melphalan100 mg/m2;
LP = lenalidomide + prednisone; L= lenalidomide
21-day cycle
1
B
4
B
PLD
Dex*
28-day cycle
PAD
8
B
11
B
21
B = bortezomib 1.3 mg/m2; PLD = pegylated doxorubicin 30 mg/m2;
Dex = dexamethasone 40 mg/d *Dex days 1–4, 8–11, 15–18 on cycle 1
LP: Consolidation
1
21
28
21
28
Lenalidomide 25 mg/d
Prednisone 50 mg/every other day
28-day cycle
L: Maintenance
1
Lenalidomide 10 mg/d
Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at:
50th ASH Annual Meeting; December 6–9, 2008; San Francisco, CA
PAD vs PAD→MEL-100 vs PAD→MEL-100→LP vs PAD→MEL100→LP→L: Response Rate*
100
100
100
90
90
90
90
80
80
80
80
70
70
70
% of Patients
100
60
60%
60
50
47
50
36
40
87%
60
44
50
43
89%
60
50
40
30
30
30
30
20
20
20
20
10
3
1
0
12
10
1
0
0
CR VGPR PR
SD
PD
PAD 4 Cycles
(n=102)
40
30
9
10
2
0
0
CR VGPR PR
SD
PD
PAD→MEL-100
(n=77)
73
70
59
40
13
95%
10
22
5
0
0
SD
PD
0
CR VGPR PR
SD
PAD→MEL100→LP
(n=56)
*Per protocol
Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at:
50th ASH Annual Meeting; December 6–9, 2008; San Francisco, CA
PD
CR VGPR PR
PAD→MEL100→LP→L
(n=40)
GMMG-HD5
Randomization8)
Inclusion
3 x PAd2)
3 x VCD3)
A1 + B1
A2 + B2
1)
1)
CAD4) + leukapheresis
HDM + TPL5)
2. HDM + TPL5) (if no CR)
2 x R6)
A1
Lenalidomide7)
for 2 years
1)
2)
3)
4)
5)
6)
7)
8)
B1
Lenalidomide7)
if no CR
A2
Lenalidomide7)
B2
Lenalidomide7)
if no CR
for 2 years
Risk assessm. within first 4 weeks; high risk patients may go off protocol with participation in an experimental phase II trial (e.g. allogeneic transplantation)
PAd = Bortezomib (PS-341, Velcade) 1,3mg/m² d1,4,8,11; Adriamycin 9mg/m², d1-4; Dexamethasone 20mg, d1-4, d9-12, d17-20
VCD = Bortezomib (PS-341, Velcade) 1,3mg/m² d1,4,8,11; Cyclophosphamid 900mg/m², d1, Dexamethasone 40mg, d1-2, d4-5, d8-9, d11-12
CAD = Cyclophosphamide 1g/m² d1; Adriamycin 15mg/m², d1-4; Dexamethasone 40mg, d1-4;
HDM + TPL = High Dose Melphalan 200mg/m² and autologous stem cell transplantation
R = Lenalidomide (Revlimid) 25mg/d, d1-21;
Lenalidomide 10mg/d, increase to 15mg/d after 3 months
randomization to one of four treatment strategies A1, B1, A2, B2: A1= PAd induction, lenalidomide maintenance for 2 years; B1= PAd induction, lenalidomide maintenance if
no CR; A2= VCD induction, lenalidomide maintenance for 2 years; B2 = VCD induction, lenalidomide maintenance if no CR
Flowsheet 31.08.09
RAD als Induktion bei Patienten mit neu diagnostiziertem Myelom
Phase II - DSMM XII – Studie
Professor Einsele
Allo-SCT
Treo/Flu
RAD RAD RAD RAD
Restaging
CE
Mel 200
mg/m²
R-Maint.
* Bei Zustimmung des Pat. und HLAidentischem Spender
Mel 200
mg/m²
R-Maint.
Maint.
56 – 112 Tage
12 Mo
PBSCT
d 29
d1
d 85
d 57
d 135
d 120
28 – 56 Tage
56 – 84 Tage
Multiples Myelom Stadium II/III
Alter ≤ 55 (60)Jahre
Induktionstherapie (freigestellt)
CR/ PR / MR or PD, maximal 8 Zyklen
Professor
Kröger
Studieneinschluss
Stammzellmobilisierung und Start Spendersuche
Melphalan (200 mg/m²) plus autologous PBSCT
Spender gefunden
(HLA-ident oder MUD (9 oder10/10)
2 Monate nach 1. HDT
allogene PBSCT (Mel 140 mg/m²/Flu/ATG)
kein Spender gefunden
2 Monate nach 1.HDT
2. autologous PBSCT (Mel 200 mg/m²)
Tag 120 nach allogener PBSCT:
Thalidomide 100 mg (2 Jahre)
Tag 120 nach autologer PBSCT:
Thalidomide 100 mg (für 2 Jahre)
weitere DLI eskalierend : Tag 180, 250
und 320 mit MRD Messung
Bei allen Patienten : zentrale Zytogenetik, MRDMessung mittels FACS und patientenspez. Primer
Impact of novel agents on outcome – newly
diagnosed disease
Median overall survival (mos)
70
60
50
40
30
20
10
1971–1976 1977–1982 1983–1988 1989–1994 1995–2000 2000–2006
Year of Diagnosis
Abstract 3594, Kumar et al.
Poster session, Monday December 10