AL AMYLOIDOSIS: DIAGNOSIS
& PROGNOSIS
Morie Gertz
Mayo Clinic
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Monoclonal Gammopathies
Mayo Clinic
1960-2006
n=36,392
Ly
L mphoproliferative
SMM 4% (1,359)
3% (1,157)
Solitary or extramedullary
Amyloidosis
2% (740)
()
(AL) 9% (3,389)
Macro 2% (824)
Other 3.5% (1,259)
Multiple
myeloma
18% (6,408)
MGUS
58.5% (21,256)
CP1102576-1
Amyloidosis
Mayo Clinic
1960-2006
n=4,666Familial 4% (193)
Senile 4% (206)
Secondary (AA)
3% (148
(
)
()
Localized
2 M (11) 0.5%
2 M (11)
15% (707)
Amyloidoma (12)
05
0.
0 %
055%
Primary (AL)
(AL)
73% (3,389)
CP1102576-5
Serum M Proteins in AL &
Ml
Myeloma
30
:=36
3.6
20
amyloid
%
myeloma
10
0
0
GL Fre G
D
M
B
e
K
A
free
ic
L
K
lonal
Does Tumor Mass Reduction
Mt
Ma t
tter: Wh
Why does cyt t
o oxic
chemotherapy work ?
· Myeloma causes of Death relate to Tumor
Mass
· In AL death is driven by organ
Failure/dysfunction
· If the M protein falls does this translate to
improved survival ?
· How much of a reduction is sufficient to
impact outcomes ?
· Should M protein be used as a trial
endpoint?
AL TRANSPLANT
POPULATION
· Median 24-
24 hour
-
urine protein
protein loss was
3.4 g/day
· One-, 2-, and 3 organ
-
involvement
involvement
occurred in 48%, 38%, and 14% of
patients, respectively
· D+100 mortality 11%
· CR IF- S&U & NL FLC ratio
· PR 50% S&U M component & involved
FLC
AL TRANSPLANT
POPULATION
· 69% of patients had renal involvement,
51% had cardiac involvement, 11% had
peripheral nerve involvement, and
and 16%
had hepatic involvement.
· Echocardiographic analysis
analysis showed
showed a
median septal thickness of 12 mm and
a median
median ejection
ejection fraction
fraction of
of 65%.
· Median % of bone marrow plasma cells
was 7f
7, range from 1 - 78
Overall Survival of 282 Transplanted
Amyloid Patients Stratified by
yy
Hematologic Response
1.0
0.8
CR (n=93)
g 0.6
PR (n=108)
rvivinu 04
0.4
S
0.2
NR (n=81)
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120
Months
CP1245979-1
INTERPRETING AL
RESPONSE/SURVIVAL
· Skew in the data
data since with an
an 11
11
% mortality rate a substantial
bf
number of pati
tients become
inevaluable for response
· Landmark analysis at 6 months to
exclude early deaths from
advanced organ failure gives a
better assessment of
of responses
responses
impact on outcome
Landmark Analysis of Amyloidosis Patients
that Survived 6 Months Stratified Based on
Hematologic Response
1.0
0.8
CR (n=86)
g 0.6
PR (n=91)
rvivinu 04
0.4
S
NR (n=36)
0.2
P=0.001
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120
Months
CP1245979-2
Response Translates to
Survival
· Do patients with
echocardiographic evidence of
Cd
Car i
diac AL
AL also benefit
fit from
transplant?
· Recognizing that patients with
cardiac AL are a highly
highly selected
group (milder)...
Overall Survival of 151 Transplanted
Cardiac Amyloid Patients Stratified by
yy
Hematologic Response
1.0
0.8
g
CR n=42
0.6
n=56
rvivinu 04
0.4
S
0.2
NR n=53
P<0.001
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120
Months
CP1245979-3
Landmark Analysis of Cardiac Amyloid
Pts that Survived 6 Months Stratified Based
on Hematologic Response
1.0
0.8
g
n=38
0.6
n=39
rvivinu 04
0.4
n=18
S
0.2
P<0.001
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120
Months
CP1245979-4
DETERMINANTS OF
RESPONSE
· There was a difference in response rate
based on conditioning intensity
(p<0 01)
.
and age
age (p=0 046)
.
. However,
since this was not a prospective study,
patients who received higher intensity
intensity
therapy tended to be younger and have
less extensive organ involvement
involvement
particularly cardiac
What this study does tell
tell us
· In Amyloidosis response is an
it
appropriate
t
surroga e for
i
surv
l
va
· Response is a legitimate endpoint for
Clinical Studies of Therapy including
cardiac AL
· Complete Responders live longer than
partial resp
pponders
· Partial responders live longer than non
responders even correcting for
for early
death by landmark
AMYLOID TRANSPLANT
N=270 SURVIVAL ORGAN #
1.0
1
0.9
1
0.8
2
.8
la
0.7
iv .6
Cum. Survival (1)
3
rvu
Cum. Survival (2)
.S
0.6
m .4
Cum. Survival (3)
Cu
ving 05
.2
0.5
0
Survi 0.4
55 months
0
20
40
60
80
100
Time
0.3
25.5 months
0.2
0.1
00
0.0
0
10
20
30
40
50
60
70
80
90 100 110 120
survival months
Baseline FLC predicts for overall survival.
Median for 119 patients is 152 mg/L
100
80
60
%
urvival,S
40
Baseline FLC
N
Deaths
Overall
20
<152 mg/L
60
7
p = 0.03
152 mg/L
59
15
0
0
20
406080
100
120
Time, months
IMPACT
IMP
OF SERUM TROPONIN
ON SURVIVAL OF AL
1
.8
OS,
N
Deaths months
cTnT <0.035 mcg/ml 136
122
17.0
.6
cTnT 0.035 mcg/ml 106
100
3.7
.Survivalm .4
Cu
P < 0.0001
.2
0
0
20
40
60
80
100
120
Time
Time, months
Impact of serum BNP on
Survival Of AL-2005
1
.8
OS,
l
N
Deaths months
NTproBNP <332 pg/ml
97
84
20.0
.6
NTproBNP 332 pg/ml 145
138
5.8
.Survivam .4
Cu
P < 0.0001
.2
0
0
20
40
60
80
100
120
Time, months
A STAGING SYSTEM FOR AL
USING BNP
BNP & TROPONIN
TROPONIN-
2005
1
OS,
N
Deaths months
Stage I
80
69
26.4
.8
Stage II
73
68
10.5
ving
Stage III
89
85
3.5
.6
survi
tion
.4
P < 0.0001
Propor
.2
0
0
20
40
60
80
100
120
Time, months
CONCLUSIONS
· Conventional Hematologic Response
Endpoints used in Myeloma are valid in
trials of AL
· Response is limited by ability to measure
quantity but not "quality" of presursor
protein i.e. amyloidogenicity. Some
patients progress
progress despite 90% light chain
reductions. Many stabilize even with <50%
declines.
CONCLUSIONS
· Intergroup comparisons are facilitated
facilitated by
reporting cardiac biomarkers, baseline free
light chain levels & number of organs
involved by clinical parameters