Transcript Slide 1

MULTIPLE MYELOMA
ASH 2006 UPDATE
Jeffrey Wolf, MD
Director, Myeloma Program
UCSF
Myeloma ASH Review
Abstracts to be covered







Abstract 795: Thal/Dex vs Dex frontline
Abstract 57: Thal/Dex vs VAD frontline
Abstract 796: Velcade/Dex frontline
Abstract 56: Velcade/Dex vs VAD
Abstract 798: Revlimid/Dex frontline
Abstract 800: R-MP frontline
Abstract 799: Revlimid/Dex (high dose) vs Revlimid/Dex
(lower dose) frontline
 Abstract 407: VMPT for relapse
 Abstract 404: Velcade/Doxil for relapse
WHAT SHOULD WE BE
LEARNING?
•
•
•
•
Does the type of induction matter?
Does CR matter?
Does transplant matter?
What do we do for the non-transplant patient?
Thalidomide/Dex vs. Dex
Abstract #795
A Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study Thalidomide Plus
Dexamethasone Versus Dexamethasone
Alone As Initial Therapy For Newly
Diagnosed Multiple Myeloma (MM 003)
S. Vincent Rajkumar, Mohamad Hussein, John Catalano,
Wieslaw Jedrzejczak, Svetlana Sirkovich, Marta Olesnyckyj,
Zhinuan Yu, Robert Knight, Jerry Zeldis, and Joan Bladé
Mayo Clinic, Rochester, MN; Cleveland Clinic, Cleveland, Ohio; Frankston
Hospital, Frankston, Australia; Medical Academy of Warsaw, Warsaw,
Poland; Kiev Institution of Oncology of the UAMS, Kiev, Ukraine; Celgene
Corporation, Summit, NJ, and Hospital Clinic, Barcelona, Spain.
Rajkumar et al. ASH 2006, abstract # 795
Trial Design
Thalidomide 50→200* mg d 1-28
Dex 40 mg, d 1-4, 9-12, 17-20
X 4 COURSES
Same except
Dex d 1-4
TTP
OS
RR
Continue until PD
Placebo d 1-28
Dex 40 mg, d 1-4, 9-12, 17-20
Safety
* Thalidomide dose escalated in all patients, over 4 weeks, to improve tolerability
Rajkumar et al. ASH 2006, abstract # 795
Response (RRC/IMWG)
Response Rate (%)
80
PR+VGPR+CR
PR
VGPR
69.4%*
CR
60
25.5%
40
20
0
51.1%*
35.3%
Thalidomide/
Dex
* CR+VGPR
p<0.0001
35.7% *
8.1% *
* p=0.001
12.8% *
3.0% *
Placebo/
Dex
Rajkumar et al. ASH 2006, abstract # 795
Common Non-Hematological Toxicities
Grade 1-2
Grade 3-4
Thal/Dex
Dex
Grade 1-2
Grade 3-4
Constipation
Edema
Insomnia
Asthenia
Tremor
Neuropathy
0.0
10.0
20.0
30.0 40.0
Percent
50.0
60.0
70.0
Rajkumar et al. ASH 2006, abstract # 795
Major Grade 3/4 Toxicities
Thal/Dex (n=234)
Dex (n=232)
DVT/PE
Pneumonia
Hyperglycemia
Atrial Fibrillation
Myocardial Ischemia
Cerebrovascular
Ischemia
Any Grade 4
0
10
20
30
Percent
40
50
Rajkumar et al. ASH 2006, abstract # 795
Time to Progression
HR (95% CI)
0.43 (0.32, 0.58)
Thalidomide/dex median time to progression: 22.4 months
Placebo/dex median time to progression: 6.5 months
P<0.0001
Rajkumar et al. ASH 2006, abstract # 795
Overall Survival
HR (95% CI)
0.82 (0.57, 1.16)
Thalidomide/Dex median overall survival: Not reached
Placebo/Dex median overall survival: 32 months
Rajkumar et al. ASH 2006, abstract # 795
Thalidomide/Dex vs. VAD
Abstract #57
A randomized study of Thalidomide + Dexamethasone
(Thal/Dex) compared with Vincristine, Adriamycine and
Dexamethasone (VAD) as a pre-transplant treatment in newly
diagnosed Multiple Myeloma (MM)
M. Macro, M.Diviné, S.Chevret, J.P.Fermand
& all members of the “Myélome-autogreffe” group
Paris, Amiens, Caen, Créteil, Limoges, Strasbourg
FRANCE
Macro et al. ASH 2006, abstract # 57
Stage II-III MM, <65 years
HD steroids
Randomization
Infusional VAD
Oral Thal/Dex
VAD
3 mthly courses
Thal + Dex
3 mths
Cytoxan (4g/m2) + G-CSF
PBSC Collection
MLP 200 mg/m2
+ autologous PBSC transplantation
Macro et al. ASH 2006, abstract # 57
Thal/Dex vs VAD as Induction: Response
R
Thal/Dex
3 mths
VAD
3 mthly courses
Before PBSC mobilization
CTX + G-CSF
CTX + G-CSF
Before high-dose MLP
MLP 200
mg/m2
MLP 200
At 6 mths post-transplant
mg/m2
VGPR
RR (≥50%)
VAD 7.3%
TD 24.7%
VAD 47%
TD 65%
(p=.0027)
VGPR
RR (≥50%)
VAD 12.6%
TD 34.7%
VAD 52%
TD 66%
(p=.002)
(p=.04)
VGPR
RR (≥50%)
VAD 41.7%
TD 44.4%
VAD 62%
TD 68%
(p=.87)
Macro et al. ASH 2006, abstract # 57
(p=.01 )
(p=.38)
Thal/Dex vs VAD as a pre-transplant treatment in MM
Toxicity
VAD
3 mthly courses
Thal/Dex
3 mths
27%
(p=.07)
39%
7.5%
(p=.004)
22.8%
12.9%
(p=.42)
17.4 %
Any grade ≥ 2 side effect
Venous thrombosis and
pulmonary embolism (no
proph)
Symptomatic peripheral
neuropathy
Macro et al. ASH 2006, abstract # 57
Velcade +/- Dex
Abstract #796
Long-term follow-up of a phase 2
trial of bortezomib alone and in
combination with dexamethasone
for the frontline treatment of
multiple myeloma
S. Jagannath1, B. Durie1, J. Wolf1, E. Camacho1,
D. Irwin1, J. Lutzky1, M. McKinley,1 E. Gabayan1,
A. Mazumder1, J. Crowley2, R. Vescio1
1Aptium
Oncology Research Network, CA;
2Cancer Research and Biostatistics, WA
Jagannath et al. ASH 2006, abstract # 796
Cumulative Best Response (N = 49)
100
100%
Bortezomib
Bortezomib 
dexamethasone
88
90
78
80
60%
40%
20%
Bortezomib(Velcade)
0%
0
1
2
3
4
Months After Registration
Median
Events / N in Months
40 / 49
2
5
6
Response rate (%)
80%
70
60
50
49
49
57
40
30
37
20
10
0
PR
VGPR
CR/nCR
20
6
2
10
14
18
2
4
6
Cycles

Median time to response: 1.9 months

Responses assessed by EBMTR criteria with the addition of VGPR
Jagannath et al. ASH 2006, abstract # 796
OS In All Patients (N = 49)
100%
80%
60%
40%
12-month
Deaths/N estimate
Bortezomib (Velcade) 7/49
92% (83,100)
20%
0%
0
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
12
24
Months after registration
36
48
Median follow-up 26.7 months
Estimated 1- and 2-year survival rates: 92% and 85%
Jagannath et al. ASH 2006, abstract # 796
Velcade/Dex vs VAD
Abstract #56
56
VELCADE/Dexamethasone (Vel/Dex) Versus VAD as
Induction Treatment Prior to Autologous Stem
Cell Transplantation (ASCT) in Newly Diagnosed
Multiple Myeloma (MM): An Interim Analysis of
the IFM 2005-01 Randomized Multicenter Phase III Trial.
Jean-Luc Harousseau,1 Gerald Marit,2 Denis Caillot,3 Philippe
Casassus,4 Thierry Facon,5 Mohamad Mohty,6 Frederic Maloisel,7
Herve Maisonneuve,8 Carine Chaleteix,9 Lofti Benboubker,10 DixieLee Esseltine,11 Michel Attal.12
1Hematology,
Hôpital Hotel-Dieu, Nantes, France; 2CHU Bordeaux, Pessac,
Bordeaux, France; 3Hematology Unit, Hôpital Bocage, Dijon, France; 4Hôpital
Avicenne, Bobigny, Paris, France; 5Hôpital Claude-Huriez, Lille, France; 6Institute
Paoli-Calmettes, Marseille, France; 7Hôpital Civil, Strasbourg, France; 8CHD La
Roche Sur Yon, La Roche Sur Yon, Vendee, France; 9CHU Clermont-Ferrand,
Clermont-Ferrand, Auvergne, France; 10Hematology and Cell Therapy Unit,
CHRU Tours, Tours, France; 11Millennium Pharmaceuticals Inc, Cambridge, MA,
USA; 12Hôpital Purpan, Toulouse, France.
Vel/Dex vs. VAD Induction in Newly Diagnosed
MM: Preliminary Analysis of IFM 2005-01 Trial

Treatment Scheme:
Randomization
Stratification for β2 microglobulin and Ch 13 abnormalities
A
B
Arm A1: VAD
Arm A2: VAD + DCEP
Induction ±
Consolidation
Arm B1: Vel/Dex
Arm B2: Vel/Dex + DCEP
ASCT
Transplant 1
ASCT
Second ASCT or RIC allo if <VGPR
Harousseau et al. ASH 2006, abstract # 56
Vel/Dex vs. VAD Induction in Newly Diagnosed
MM: Preliminary Analysis of IFM 2005-01 Trial
 Response: by investigator assessment; evaluated by modified
EBMT criteria
By Induction Therapy
By Consolidation Therapy
VAD
(A1+A2)
N=82
Vel/Dex
(B1+B2)
N=79
No DCEP
(A1+B1)
N=78
DCEP
(A2+B2)
N=64
9%
20%
11%
28%
VGPR
4%
17%
9%
23%
3%
26%
14%
13%
CR+VGPR
26%
43%
37%
41%
PR (incl VGPR)
59%
62%
68%
61%
CR+PR
67%
82%
79%
89%
CR/nCR
CR
Harousseau et al. ASH 2006, abstract # 56
Vel/Dex vs. VAD Induction in Newly Diagnosed
MM: Preliminary Analysis of IFM 2005-01 Trial
 Efficacy: Impact of baseline characteristics on post-induction
response (preliminary analysis)
Characteristic
CR/nCR rate
VAD (A1+A2)
Vel/Dex (B1+B2)
β2M level
>3 mg/L
4/43 (9%)
8/41 (20%)
4/37 (11%)
9/36 (25%)
Del(13)
Yes
β2M, beta-2-microglobulin; Del(13), chromosome 13 deletion
Harousseau et al. ASH 2006, abstract # 56
Vel/Dex vs. VAD Induction in Newly Diagnosed
MM: Preliminary Analysis of IFM 2005-01 Trial
 Stem Cell Transplant: Preliminary data
Median CD34+ cells collected (x106/kg)
ITT pop receiving 1st ASCT, n (%)
Median time to ANC ≥ 0.5 x 109/L, days
Median time to platelet count ≥ 20 x
109/L, days
Patients not requiring 2nd ASCT
n (%)
VAD
(A1+A2)
N=70
Vel/Dex
(B1+B2)
N=68
TOTAL
N=138
8.7
6.3
7.5
58 (71%)
58 (73%) 116 (72%)
7
7
7
1
1
1
32 (55)
45 (78)
77 (66)
Harousseau et al. ASH 2006, abstract # 56
Vel/Dex vs. VAD Induction in Newly Diagnosed
MM: Preliminary Analysis of IFM 2005-01 Trial
 Safety: No sig difference between 2 arms
VAD (A1+A2)
N=81
Vel/Dex (B1+B2)
N=81
29 (36%)
8 (10%)
14 (17%)
1 (1%)
24 (30%)
7 (9%)
12 (15%)
1 (1%)
7%
17%
10%
Gr 1/2: 7%
Gr 3/4: 0
4%
4%
14%
1%
Gr 1/2: 23%
Gr 3/4: 4%
2%
Overall:
Gr ≥ 3 AE, n (%)
Gr ≥ 4 AE, n (%)
SAE, n (%)
Death, n (%)
By Event:
Neutropenia (Gr 3/4)
Fever/infection (all grades)
Mucositis (Gr 3/4)
Neurologic toxicity (including PN,
paraesthesias, and dysaesthesias)
Thrombosis (all grades)
Harousseau et al. ASH 2006, abstract # 56
What have We Learned?


The use of Vel/Dex over
VAD results in fewer
patients needing a 2nd
transplant
The use of TD is more
toxic than VAD (DVT’s
and VTE’s) and results in
similar outcomes post
transplant
Percent of Patients
who Achieved
VGPR
Vel/Dex
78%
VAD
55%
TD
44%
VAD
42%
Revlimid/Decadron
Frontline
Abstract # 798
Results: Response to Therapy
All 34 pts assessed prior to transplant or any other therapy
All Patients
No Transplant
Objective
Response Rate
91%
CR
18%
24%
VGPR
38%
43%
PR
35%
Lacy et al. ASH 2006, abstract # 798
Toxicity > Grade 3




fatigue (21%)
neutropenia (21%)
anxiety (6%)
pneumonitis (6%)



muscle weakness (6%)
rash (6%)
pulmonary embolism
(3%) with ASA
prophylaxis
Lacy et al. ASH 2006, abstract # 798
1.0
Progression Free Survival
0.8
0.6
0.4
59%
2 yr PFS rate
0.2
N o Trans plant
Trans plant
0.0
Proportion Progression-free and Alive
83%
0
5
10
15
20
25
Time in Months
Lacy et al. ASH 2006, abstract # 798
1.0
Overall Survival
0.4
0.6
90%
2 yr OS rate
0.2
N o Trans plant
Trans plant
0.0
Proportion Alive
0.8
92%
0
5
10
15
20
25
Time in Months
Lacy et al. ASH 2006, abstract # 798
OS for 2 Novel agents in Newly Diagnosed
MM in Combo with Dex: No Transplant
Rev/Dex: Lacy et al
Vel/Dex: Jagannath et al
Revlimid/Melphalan/Prednisone
Newly Diagnosed
Abstract #800
RMP: Treatment Schedule
day
1
2
3
4
21
Mel 0.18–0.25 mg/Kg
Prednisone 2 mg/Kg
Revlimid® 5–10 mg daily
Every 4–6 weeks for a maximum of 9 cycles
Melphalan mg/Kg/d
Revlimid® mg/d
Patients
Cohort 1
0.18
5
6
Cohort 2
0.25
5
6
Cohort 3
0.18
10
6+15
Cohort 4
0.25
10
6+15
6 patients in each cohort with additional 15 pts in cohort 3 and 4
Palumbo et al. ASH 2006, abstract # 800
Dose Limiting Toxicity
DLT at Cycle 1
Cohort 1
0.18–5
Cohort 2
0.25–5
Severe Neutropenia
Cohort 3
0.18–10
Cohort 4
0.25–10
1/6
Neutropenic fever
1/6
Delay at cycle 2
2/6
Cutaneous GR 3
1/6
Thrombosis GR 4
1/6
Metabolic GR 3
Pts with DLT
1/6
0/6
0/6
1/6
3/6
Palumbo et al. ASH 2006, abstract # 800
R-MP vs MPT: Response Rates
R-MP
Cohort 3 (0.18-10)
Best Response
n=21
70
70
60
48%
40
30
Proportion of patients
Proportion of patients
60
50
MPT
Best Response
n=129*
33
24
24
19
20
10
50
37%
40
40
30
21
20
16
10
0
0
SD
PD
0
CR
VGPR
PR
MR
*Historical control – Palumbo et al, Lancet 2006
5.4% of response not available
5
5
MR
SD
8
0
CR
VGPR
PR
PD
Palumbo et al. ASH 2006, abstract # 800
R-MP vs MPT: EFS and OS
R-MP: median follow-up 14.6 months (10.8-21.8) [N=53]
MPT: median follow-up 17.6 months (0.23-44.3) [N=129]*
OS
EFS
p=0.053
Palumbo et al. ASH 2006, abstract # 800
p=0.046
*Historical control – Palumbo et al, Lancet 2006
MPT Superior to MP
Previous Studies
Melphalan/Velcade/Prednisone
(MVP)
Previous Study
Newly Diagnosed
Melphalan + Velcade + Prednisone
(MVP)
Response to Therapy
Response*
(n = 53)
Bortezomib + Melphalan +
Prednisone
CR
32%
nCR
11%
PR
45%
CR + PR
89%
* Modified EBMT criteria

12 of 16 CR patients tested for minimal residual disease; 6/12 (50%) achieved an
immunophenotypic remission

Historical response with MP: 42% nCR + PR Hernandez, BJH, 2004

No DLTs observed in Phase I Phase II: 20% G4 myelosuppression

Phase II trial accruing, goal of 60 pts, dose will be 1.3 mg/m2
Mateos et al. Blood, June, 2006
Revlimid/High Dose Dex vs
Revlimid/Lower Dose Dex
Abstract #799
A Randomized Phase III Trial of Lenalidomide
Plus High-Dose Dexamethasone Versus
Lenalidomide Plus Low-Dose Dexamethasone in
Newly Diagnosed Multiple Myeloma (E4A03): A
Trial Coordinated by the Eastern Cooperative
Oncology Group
S. Vincent Rajkumar, Susanna Jacobus, Natalie
Callander, Rafael Fonseca,
David Vesole, Philip Greipp
Mayo Clinic, Rochester, MN;
Dana Farber Cancer Institute, Boston, MA;
University of Wisconsin, Madison, WI; Mayo Clinic
Arizona, Scottsdale, AZ; St. Vincents Hospital, New
York, NY
Schema
R
A
N
D
O
M
I
Z
A
T
I
O
N
445 pts
Len + Dex
x4 cycles
(40 mg d1-4,
9-12, 17-20)
Len + Low
dose Dex
x 4 cycles
(40 mg wkly
D1,8,15,22)
CR/PR
Less
than
PR
Thal +
Dex
x 4 cycles
@ 4 months
Pts eligible for
SCT
proceed to SCT*
CR/PR/Stable
Rajkumar et al. ASH 2006, abstract # 799
Serious adverse events
Arm A
(N=223)
Arm B
(N=222)
P value
Infection/Pneumonia (Grade
>=3)
16.1%
9.0%
0.031
Fatigue (Grade >=3)
11.7%
4.1%
0.004
Hyperglycemia (Grade >=3)
5.8%
2.3%
0.090
DVT/PE (Grade >=3)
18.4%
6.3%
<0.001
Atrial fibrillation/flutter
(Grade>=3)
3.1%
0.0%
0.015
Neuropathy (Grade >=3)
0.4%
1.4%
0.372
Any non Hem toxicity (Grade
>=3)
54.3%
39.6%
0.002
Toxicity of Any Type (Grade >=4)
19.3%
11.3%
0.025
Death (Grade 5)
4.9%
0.5%
0.006
Toxicity
Rajkumar et al. ASH 2006, abstract # 799
Bortezomib (Velcade®), Melphalan,
Prednisone and Thalidomide (VMPT) in
Advanced Multiple Myeloma
Results of a Multicenter Phase I/II
Study
Abstract 407
Antonio Palumbo
Div. Hematology, University of Torino
V-MPT at 1° Relapse
MPT at Diagnosis
V-MPT (N=14)
1° Relapse
50
45 57%
40 36%
35
30
%25
21% 21% 21%
20
15
10
5
0%
0
CR- VGPR PR
MR SD-PD
^Palumbo et al,Lancet 2006;367:825
MPT (N=129)^
Diagnosis
45
39%
40
35
30
25
%
20
15
36%
21%
15%
13%
10
5%
5
0
CR- VGPR
PR
MR SD-PD
Study design: VMPT vs VMP
At diagnosis
VMPT
9 courses
Maintenance
Velcade
Thalidomide
VMP
9 courses
None
R
End points: PFS, OS, RR, Safety
Retrospective Analysis of ReTreatment
With Bortezomib
Initial Bortezomib Treatment
Bortezomib Re-treatment
VGPR (n=16)
VGPR (n=2)
PR (n=5)
<PR (n=9)
ORR 44%
PR (n=22)
VGPR (n=1)
PR (n=4)
<PR (n=17)
ORR 23%
<PR (n=24)
VGPR (n=1)
PR (n=2)
<PR (n=21)
ORR 13%
Conner T et al. Blood 2006;108:1007a [abstract 3531]
Potpouri
New Agents for Myeloma
Clinical (1)
Abstract Category
#
Compound
Phase
Institution
Investigator
Biopharm
Kosan
Result
406
Hsp 90
Inh (17
AAG)
Tanespimycin
(KOS-953)
+ BZ
I
Richardson
et.al.
3574
AntiCD56
BB-10901
I
Chanan Khan
3575
AntiCD40
HCD122
(formerly
Chir-12.12)
I
Bensinger
Novartis
active
3576
AntiCD40
SGN-40
I
Hussein
SeattleGenetics
+/active
Immunogen active
New Agents For Myeloma
Clinical (2)
Abstract
#
Category Compound Phase
Institution Biopharm
Investigator
Results
3579
Hsp90
Inh
IPI-504
I
Siegel
Hackensack
etc
Infinity
Too
Early
3580
P38
MAPKinase
Inh
Scio-469
II
Siegel etc
Scios
Requires
BZ
3582
Akt Inh
Perifosine
(KRX-0401
II
Richardson,
etc
Keryx
Requires
Dex or
BZ
3583
HDAC
Inh
PXD 101
II
Moffitt, etc
Curagen
Requires
Dex
New Agents for Myeloma
Pre-Clinical (1)
Abstract #
Category
Compound
Institution
Investigator
Biotech
244
AntiangioPI-3 kinase
inhibitor
SF 1126
Lonial
Semafore
Indianapolis
841
Notch Sig.
Inhibitor
Gamma
Secretase Inh.
(GSI)
Moffitt
-
2604
HDAC
Inhibitor
UCL 67022
St. Bart’s
-
3483
HDAC
Inhibitor
PXD 101
Berenson
Curagen
3427
CD40
Ligand
CD40L,
CD154
Baylor
-
New Agents for Myeloma
Pre-Clinical (2)
Abstract #
Category
Compound
Institution
Investigator
Biotech
3452
B-cell Act
Factor Inh
(BAFF)
AMG 523
Farber
Amgen
3460
ERK ½ Inh
AZD 6244
Farber
-
3461
Irreversible
Proteasome
Inh
PR-171
UNC
Proteolix
3462
Organic
Arsenic
Z10-101
Gale
Berenson
Ziopharm
3481
Proteasome
Inh.( Oral)
Multiple
-
Proteolix