Folie 1

1
DGHO - KML 06.09.2009
Multiple Myeloma Hartmut Goldschmidt Sektion
Multiples Myelom Medizinische Klinik V,
Universität Heidelberg Nationales Centrum für
Tumorerkrankungen Heidelberg
2
Definitions
Multiple Myeloma - Classification

• MGUS
• lt3 g M spike AND
• lt10 PC
• AND

• SMM (AMM)
• ?3 g M spike OR ?10 PC

• MM
• ?10 PC
• M spike
• AND
• YES
• Calcium
• Renal Insufficiency
• Anemia
• Bone disease

No Calcium Renal Insufficiency Anemia Bone
disease
3
International Staging System for MM
Multiple Myeloma ISS-Staging
Stage Criteria Median survival (months)
I Serum ?2-microglobulin lt 3.5 mg/L Serum albumin 35 g/L 62
II Serum ?2-microglobulin lt 3.5 mg/L Serum albumin lt 35 g/L OR Serum ?2-microglobulin 3.5 tolt 5.5 mg/L 44
III Serum ?2-microglobulin 5.5 mg/L 29
Irrespective of serum albumin level.
Greipp PR, et al. J Clin Oncol. 2005233412
4
Therapy in MM
Progress in MM Treatment over 40 Years
1990s Single ASCT
From 1980s Myeloablation BMT
2000s Tandem ASCT?
1970
1980
1990
2000
1969 Melphalan Prednisone
1962 Melphalan
1999 Thalidomide
2004 Lenalidomide
1984 VAD
2002 Bortezomib
1990s Supportive Care
5
Upfront Therapy
Patient with active disease
Transplantation
No Transplantation
Age up to 60/65/70/75 Normal organ
function Stem cells Patients preference
High age Multimorbidity Inadequate stem cells
Patients preference
H. Ludwig 2009, Post ASH-Slides
6
VAD in 2005 - 2009
Cavo et. al., Blood July 2005 Comment Rajkumar
Blood Juli 2005 Matched Case-Control Study 200
pts. 100 pts. VAD ORR 52 100 pts.
Thal.-Dex. ORR 76 ORR Overall Response Rate
(at least PR) It is time to say goodbye to VAD!
7
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
8
ASCT and New Drugs induction
Author Regimen N RR CR/VGPR p
Cavo VAD 100 52 14 0.001
Cavo Dex-Thal 100 76 19 0.001
Rajkumar Dex 104 41 0.002
Rajkumar Dex-Thal 103 63 0.002
Goldschmidt VAD 200 63 CR 3 0.001
Goldschmidt TAD 200 80 CR7 0.001
Harousseau Dex-Vel 48 67 31
Rajkumar Dex-Rev 34 91 38

Attal 2007, ASH Education MM
9
Phase 3 PAD vs VAD as induction treatment HOVON
65 MM / GMMG-HD4 study
MM Stage II or III, Age 1865
Randomization
3 x VAD
3 x PAD
CAD GCSF
CAD GCSF
MEL 200 PBSCT
MEL 200 PBSCT
Depending on localpolicy for patients ?PR MEL
200 PBSCT
Depending on local policy for patients ?PR MEL
200 PBSCT
Allogeneic Tx
Thalidomide 50 mg/day for 2 years maintenance
Bortezomib 1.3 mg/m2 / 2 weeks for 2 years
maintenance
Sonneveld et al. ASH 2008 (abstract 653)
10
Phase 3 PAD vs VAD as induction treatment
Response data
PAD (n150) VAD (n150) P
Response after induction Response after induction Response after induction
CR/nCR 5 1
VGPR 42 15
PR 83 59
Responses after first ASCT Responses after first ASCT 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)
11
Phase 3 PAD vs VAD as induction treatment
Improvement in CR rate over course of treatment
Induction HDM Best (maintenance)
CR/nCR 5 23 37
Adverse events
VAD PAD P
Fatigue 26 29
PN gr 2 17 13
PN gr 3/4 6 16 0.003
DVT 3 4
Infections gr. 2-4 42 54

• No difference in hematological toxicities
• 80 of patients able to receive 100 of assigned
  dose during induction

Sonneveld et al. ASH 2008 (abstract 653)
12
Protocol for newly diagnosed MM lt 60 yrs. - DSMM
XI
IEV
1. HD-Mel200 mg/m²
Standard risk
High risk
HLA identical sibling/MUD
2. HD-Mel 200 mg/m²
yes
no
Allo-SCT
2. HD-Mel 200 mg/m²
13
Response to VCD treatment with respect
tocytogenetic aberrations (n160)

Best response to VCD treatment (gt PR)
Knop et al. ASCO 2009
14
Study Design

• Primary analysis post-induction CRnCR in VAD
  (A1A2) vs Vel-Dex (B1B2)
• Randomization
• stratified by ß2-microglobulin level (gt3mg/L vs
  3mg/L) and presence of chromosome 13
  abnormalities (by FISH analysis)

A1
A2
B1
B2
Induction
VAD x 4
VAD x 4
Vel-Dex x 4
Vel-Dex x 4
Consolidation
DCEP x 2
DCEP x 2
Melphalan 200mg/m2 ASCT
Melphalan 200mg/m2 ASCT
Melphalan 200mg/m2 ASCT
Melphalan 200mg/m2 ASCT
Transplant 1
Second ASCT or RIC allo if ltVGPR
Harousseau ASH 2008
15
Progression-Free Survival 2-yr Median Follow-up
100 80 60 40 20 0
Vel-Dex 71 eventsMedian NR 2-yr PFS 69
Kaplan-Meier estimate
VAD 101 eventsMedian 28 months 2-yr PFS 60
Vel-Dex (B1B2) VAD (A1A2)
P-value (log-rank) 0.0115
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
36
38 40
Harousseau ASH 2008
16
Treatment options for patients eligible for
transplantation
Induction
Bortezomib-based VelDex VTD PAD VCD
IMiD-based Thal/Dex TAD CTD Rd VRD
Traditional VAD CyDex
Stem cell harvest High-dose melphalan Stem cell
infusion
17
High-doseTherapy in MM
Association between Max. Response and OS in
Patients with MM Treated with ASCT
Maximal Response Maximal Response
Prospective Study Comparison P Value
IFM90 CR/VGPR vs. PR vs. other lt0.00001
MRC VII CR vs. PR vs. MR 0.00002
TT1 CR vs. PR 0.2496
TT2 CR vs. PR/NR lt0.05
IFM94-02 Maximal response lt0.001
IFM99C CR/VGPR vs. PR lt0.0000
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 lt0.00001
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 921399-1406
18
PAD Induction, MEL-100, Len/Prednisone
Consolidation, and Len Maintenance in Elderly
Patients with Newly Diagnosed MM
PAD?MEL-100?LP?L
L
PBSC Mobilization (Cyclophosphamide G-CSF)
MEL-100 ASCT
LP
PAD
4 cycles
2 cycles
2 cycles
4 cycles
PAD bortezomib pegylated doxorubicin
dexamethasone MEL-100 melphalan100 mg/m2 LP
lenalidomide prednisone L lenalidomide
21-day cycle
PAD
1 4 8
11 21
B
B
B
B
PLD
B bortezomib 1.3 mg/m2 PLD pegylated
doxorubicin 30 mg/m2 Dex dexamethasone 40 mg/d
Dex days 14, 811, 1518 on cycle 1
Dex
28-day cycle
LP Consolidation
1
21 28
Lenalidomide 25 mg/d
Prednisone 50 mg/every other day
28-day cycle
L Maintenance
1
21 28
Lenalidomide 10 mg/d
Palumbo A et al. Blood. 200811265 abstract
159 updated results presented at 50th ASH
Annual Meeting December 69, 2008 San
Francisco, CA
19
PAD vs PAD?MEL-100 vs PAD?MEL-100?LP vs
PAD?MEL-100?LP?L Response Rate
Per protocol
Palumbo A et al. Blood. 200811265 abstract
159 updated results presented at 50th ASH
Annual Meeting December 69, 2008 San
Francisco, CA
20
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
B1
A2
B2
Lenalidomide7) for 2 years
Lenalidomide7) for 2 years
Lenalidomide7) if no CR
Lenalidomide7) if no CR
1) 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) 2) 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 3) 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 4) CAD Cyclophosphamide 1g/m² d1
Adriamycin 15mg/m², d1-4 Dexamethasone 40mg,
d1-4 5) HDM TPL High Dose Melphalan
200mg/m² and autologous stem cell transplantation
6) R Lenalidomide (Revlimid) 25mg/d, d1-21
7) Lenalidomide 10mg/d, increase to 15mg/d after
3 months 8) 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
21
RAD als Induktion bei Patienten mit neu
diagnostiziertem MyelomPhase II - DSMM XII
Studie Professor Einsele

Allo
-
SCT
R
R
-
-
Maint
Maint
.
.
Treo
/
Flu
Less favourable
Bei Zustimmung des Pat. und HLA-
identischem Spender
Mel 200
Re- staging
CE
RAD
RAD
RAD
RAD
mg/m
²
Very Favourable
Mel 200
R
-
Maint
.
R
-
Maint
.
mg/m
²
PBSCT
d 29
d 85
d 135
d 1
d 57
d 120
12 Mo
56 84 Tage
56 112 Tage
28 56 Tage
22
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
kein Spender gefunden 2 Monate nach 1.HDT 2.
autologous PBSCT (Mel 200 mg/m²)
Spender gefunden (HLA-ident oder MUD (9
oder10/10) 2 Monate nach 1. HDT allogene PBSCT
(Mel 140 mg/m²/Flu/ATG)
Tag 120 nach autologer PBSCT Thalidomide 100 mg
(für 2 Jahre)
Tag 120 nach allogener PBSCT Thalidomide 100 mg
(2 Jahre)
weitere DLI eskalierend Tag 180, 250 und 320
mit MRD Messung
Bei allen Patienten zentrale Zytogenetik, MRD-
Messung mittels FACS und patientenspez. Primer
23
Impact of novel agents on outcome newly
diagnosed disease
Abstract 3594, Kumar et al. Poster session,
Monday December 10