The Role of High-
High dose Therapy
in AL-Amyloidosis
Raymond L. Comenzo, M.D.
XIth International Workshop on Multiple Myeloma &
IVth International Workshop on Waldenstrom's
Macroglobulinemia
June 28, 2007
42 year-old man with autonomic and
it
sensorimotor
t
neuropa h
thy
Rapid onset of disease
20kg weight loss in 8 months
Orthostasis,
thostasis nausea and vo
v miting
Total parenteral nutrition
Poor venous access
Amyloidosis by multiple biopsies
Normal left ventricular function
Minimal proteinuria
IgA lambda gammopathy
15% plasma cells in marrow
Gastric emptying scan
1994
Melphalan, Prednisone & Colchicine
Am J Med 1996;100:290-8
MEL 200 SCT on a Clinical Trial:
ll
Complete Hematologic Response
1 year post-SCT
1 year post-SCT
10 years post-SCT
Blood 1996;88:2301-6
CR and Resorption of Amyloid Post-SCT
With Loss of Hepatosplenic RBC Change
Chang s
e
Pre-SCT
Post-SCT
Targets of Therapy:
FLC
FL & the Plasma Cell
lls Producing FLC
FL
1000.0
100.0
erum
)
70.00
s
Ct
- 2 60.00
l(ev 50.00
eLn 40.00
ios
res
30.00
10.0
p
ex
20.00
e
tchain
mg/dL)
ivat 10.00
elR
(
0.00
2
9
59
68
74
76
07
11
30
57
61
67
71
12
ol
14
95
00
M
2
16
16
16
16
17
17
17
17
17
17
17
18
po
17
17
18
OP
H9
ligh
AL
Ctl
MM
MM
Cell
1.0
lines
reeF
0.1
0.1
1.0
10.0
100.0
1000.0
Free light chain serum k (mg/dL)
High-dose Melphalan and SCT:
The Early Experience
Pi
Peri
l
-transp ant mortali
lity
Advanced organ involvement
100
Age
d
an melphalan d i
os ng
CR (n
( =4
= 1)
1
75
)
Patient selection
p<<0.001
(%S 50
PD (n
((n=4
=
=43)
3
Ri k
s -add
dapted melphal
3)
O
lan
25
200/140/100
0
Hl
Hematol i
0
5
10 15 20 25 30 35 40 45 50 55 60
ogic response
Months
Survival and organ responses
L k
eu
i
em a
d
an L
h
ymp oma 2000;37:245 58
-
Blood 2002;99:4276-82
High-dose MEL + SCT:
The Mayo Clinic Experience
Current Opinion in Oncology 2007;19:136
2007;19:136 141
1998
Randomized Phase II SCT Trial
MEL SCT +/- initial therapy
Untreated and < 12 months of diagnosis
Stratified
< 3 or > 3 months from diagnosis
Cardiac
Cardiac, renal or other
Randomized
Arm 1 = Immedi
diate SCT (MEL 200 or
140)
Arm 2 = Two cycles MP
MP, then SCT
Bone Marrow Transplantation 2004;33:381-8
1998
Randomized Phase II SCT Trial
50 patients in each arm
Two cycles MP ineffective
Adequate SC collections
Significant TRM
> 2 organ systems involved
Cardiac amyloid
Ri k
s -adt
dapt d
e
l
me h
p alan
MEL 100 clinical trial*
Bone Marrow Transplantation 2004;33:381-8
p;
*Br J Haematol 1999;104: 553-9
The Role of High-
High dose Therapy
ECOG phase II trial: TRM 10%
IFM Phase III trial: SCT = MelDex
Case-cohort Analysis: SCT > oral therapy
Consensus criteria on diagnosis & response
Series from BUMC
BUMC, UK
UK, ABMTR
SCT & Quality of life
Solid organ transplant + SCT
BMT 2004; 34:149; Blood 2005;106:421a; Blood 2004;103:3960; Blood. 2004;104:1888;
Am J Hematol 2005;79:319; Annals Int Med 2004;140:85; Br J Haematol 2006;134:417;
Mayo Clinic Proc 2006;81:880; Blood 2004;104:1881; Blood 2004;104:1888; Transpl 2007
Risk-adapted Melphalan
& Adjuvant Thal/Dex: MSKCC #02-031
Who? Good risk
1 or 2 symptomatic organ systems
No advanced cardiac involvement
How? With risk-adapted dosing
pg
Mel 100, 140 or 200mg/m2
G-CSF 6ug/kg bid for mobilization
When? Usuall
lly early in th
the di
disease
OS, PFS, Hematologic & Organ Responses
47 ye
y ar-
ar old
-
Wo
W man
o
with Cardiac Amyloid
Am
MEL 140 SCT: CR
Free Kappa
Free Kappa (mg/dl)
50
40
30
mg/dl 20
10
H
0
L
Oct
Jan 2005
Apr
Jul
Oct
Jan 2006
2004
DELANEY TANGLEY L
Brain Natriuretic Peptide
Brain Natriuretic Peptide (pg/ml)
1000
750
500
pg/ml
250
H
L
0
Oct
Jan 2005
Apr
Jul
Oct
Jan 2006
2004
DELANEY TANGLEY L
49 e
y ar old
-
M n
a
ith
w
C d
ar i
di c
a Amyloid
MEL 140 SCT: NR
Free Kappa
Free Kappa (mg/dl)
90
80
70
60
50
40
mg/dl
30
20
10
H
0
L
Brain Natriuretic Peptide
Brain Natriuretic Peptide (pg/ml)
2250
2000
1750
1500
1250
1000
pg/ml
750
500
250
H
0
L
Nov
Dec
Jan 2006
Feb
MSKCC
MSK
#02 031
-
(n=45)
Sept 2002 to June 2005
5000
Sept 2002 to June 2005
4000
l)
170 patients with AL
m
g/ 3000
(pP 2000
57 eligible (34%)
BN
1000
Median age
ag 58 (34 72)
0
-72)
MelDex
02-031
Median 1.5 months
N3345
f
di
i
Age
68 (45 -82)
58 (34 -72)
from diagnosis
# Organs
3 (1 -4)
1 (1 -2)
MSKCC
MSK
#02 031
-
(n=45)
Organ involvement
n (%)
Renal
31 (69%)
Cardiac
11 (24%)
()
Liver/GI
10 (22%)
PNS
8 (18%)
8%)
# of organs
org
inv
in o
v lved
lv
1
30 (67%)
2
15 (33%)
MSKCC
MSK
#02 031
-
(n=45)
Tr
T eatment-related mortality = 4.4% (2/45)
Hematologic responses post-SCT
At 3 months
At 12 months
MEL
N
CR (%)
PR
ORR (%)
N
CR (%)
PR
ORR (%)
100
5
1 (20%)
3
4 (80%)
5
2 (40%)
3
5 (100%)
140
23
5 (22%)
()
7
12 (52%)
()
21
9 (43%)
(%)
8
17 (81%)
(%)
200
15
3 (20%)
8
11 (73%)
15
5 (33%)
5
10 (67%)
43
9 (21%)
18
27 (63%)
41
16 (38%)
16
32 (77%)
Organ responses at 12 months post-SCT
Improved
46% (19/41)
Stable
34% (14/41)
Worse
20% (8/41)
Improved Hematologic Responses with
Adjuvant Dex or Thal/Dex
No
SD PR SD CR
C
PR CR
C
Dex
6
2
2
Th
T al
h /Dex
/D
11
3
3
4
TOTA
TO
LS
17
5
3
6
Hematologic response improved in
45% (14/31)
()
Responses at One Ye
Year
ar in Renal Patients
SD
W
I
CR
PR
S
Hematologic
Renal
IRB #02-031, renal patients = 31
Response in a Renal Patient
TP, Urine (Calc)
TP, Urine (Calc) (mg/TV)
22500
20000
17500
15000
12500
10000
mg/TV
7500
5000
2500
0
Jan 2004
Apr
Jul
Oct
Jan 2005
Apr
Jul
Oct
Jan 2006
Apr
Jul
Creatinine Clearance (Calc)
Creatinine Clearance (Calc) (ml/min)
55
50
45
in 40
m
ml/ 35
30
25
Jan 2004
Apr
Jul
Oct
Jan 2005
Apr
Jul
Oct
Jan 2006
Apr
Proteinuria and Creatinine Clearance
in Renal Patients at Baseline & 1 year Post-SCT
Daily Proteinuria
Creatinine clearance
30000
150
25000
125
y 20000
100
a
in
/d 15000
l/m
75
mg
m
10000
50
5000
25
0
0
Baseline
One Year
Baseline
One Year
Time
Time
p = 0.02, paired t-test
p < 0.01, paired t-test
Overall Survival on #02-031
Cardiac patients
100
100
l 80
80
a
la
rviva 60
rviv 60
u
u
tsn
ts
40
n 40
rce
rce
Pe 20
Pe 20
0
0
0
12
24
36
48
0
12
24
36
48
Months
Months
Br J Haematol 2007 (pub pending)
Predictors of Overall and
Progression-free Survival
84% two-year sur il
vival
63% two-year survival in cardiac patients
Median PFS 40 months
Baseline Predictors
Number of involved organs
Troponin I
Post-treatment Predictors
Normal -to- FLC ratio at 3 months
Hematologic response at 12 months
Br J Haematol 2007 (pub pending)
The Role of High-
High dose Therapy
Pi
Patient
l
se ection
AL-amyloidosis not hereditary amyloid
Usually early in the disease course
1 or 2 symptomatic organ systems
Preserved left-ventricular function
Risk-adapted melphalan dosing
Age, cardiac status and renal function
Adjuvant Therapy & Hematologic response
Second Tr
T ansplant
Free Kappa
Free Kappa (mg/dl)
45
40
35
30
25
g/dl 20
m 15
10
5
H
H
0
L
L
2002
2003
2004
2005
2006
2007
Brain Natriuretic Peptide
Brain Natriuretic Peptide (pg/ml)
400
350
300
250
ml 200
pg/ 150
H
100
50
L
0
2004
2005
2006
2007
MURPHY JAMES
The Future of High dose
-
Therapy
Therap
SCT+TD
Mel/Dex and the risk of myelodysplasia
New regimens for AL-
AL amyloidosis
-
Bortezomib, lenalidomide
High CR and PR rates
Manageable side-effects
Improved patient selection for SCT
New Agents as adjuvant therapy post-SCT
New Agents
g
as first- or second-line therapy
Improved Patient Selection:
Call
lreticulin and h
t e Response to
l
Me phalan
SD
CR
PR
p = 0.03
f
5
onio 4
s
1.00
150
p = 0.02
l)
es
lin
tro
pr
u 3
n
tic
n 0.75
o
ex
e
io
c 100
e
lr
ct
e
a
(%
v
2
0.50
ti
ca
Fr
ityc
la
leba
xi 50
to
1
Re
0.25
Vi
toyC
0.00
0
0
0
10
20
30
40
50
60
NR
PR
CR
0
5
10
15
Melphalan (uM)
Melphalan (uM)
Response categor
pg ies
KOS IMW 2007 PO914; Blood 2007 (in revision)
CD32B is expressed
p
on the
plasma cells of patients with AL
32BDC
CD138
KOS IMW 2007 PO225
CD138+/CD32B+ plasma cells
100
B+
75
2
)%
/CD3
(
+
s 50
8
ll
8
e
3
c
25
CD1
CD32B
CD138
0
merge
Di
D agnosi
i
s
agnosi
Rel
Re a
l ps
a
e
ps
light chain
Conclusions
High-dose therapy for selected patients
Risk-adapted Melphalan
Low Treatment-related mortality
FLC ratio and Hematologic responses
Adjuvant therapy
jpy post-SCT
Upcoming Clinical trials
Hu2B6 MoAb (anti-
(anti CD32B)
New agents as initial & adjuvant therapy
SCT as a platform & a second-line therapy
Acknowledgments
MSKCC
Amyloid Patients & Families
Hani Hassoun
Ping Zhou
MacroGenics, Inc.
Ping Lu
Ezio Bonvini
Adam Cohen
Scott Koenig
Adam Boruchov
Adam Olshen
M Scully/P Napoda/Fred's Team
Richard Steingart
Amyloid Research Fund
Julie Feldstein
The Lymphoma Foundation
Martin Fleisher
Food and Drug Administration
Stephen Nimer
Celgene
Celg
Clinical Trials Office Millenium, Ortho, J&J
Columbia
Mathew
Mathe Maurer