Modified High Dose
Dose Melphalan
Melphalan and Autologous
Stem Cell Transplantation in the Treatment of AL
Amyloidosis and High-Risk
yg
Myeloma: Analysis
yy
of a Southwest Oncology Group Trial
SWOG 0115
Vaishali Sanchorawala, Vanessa Bolejack, John Crowley,
Antje Hoering
Hoering, Kathleen
Kathleen Finn, Salli Fennessey, David
David C. Seldin
Seldin,
Bart Barlogie
Prospective Trial of 2 cycles of Modified
HDM/SCT in AL Amyloidosis and High
High-
Risk Myeloma:
SWOG 0115
Objectives:
· Determine the feasibility and tolerability of 2 cycles of
mHDM/SCT in a multi-center study.
· Determine overall and event-free survival after 2
cycles of mHDM/SCT.
· Determine hematologic responses to mHDM/SCT.
Eligibility
gy Criteria
AL Amyloidosis
High-Risk Myeloma
·
Tissue diagnosis
diagnosis of
·
St
Sympt
t
oma i
tic
l
mye oma
amyloidosis
·
Age > 70 years
·
Evidence of an underlying
clonal plasma cell dyscrasia
·
Serum creatinine
creatinine > 2 mg/dL
mg/dL
or calculated CrCl < 50
·
Adequate measures of
ml/kg/min
­ Performance status: SWOG 0-2
­ Cardiac function:
function: LVEF >45%
­ Pulmonary function: DLCO
>50%
­ Hemodynamic function: systolic
BP >90 mm Hg
·
Patients in renal failure on
dialysis, not excluded
·
Prior oral melphalan:
p
cumulative dose < 200 mg
Treatment Protocol
First Registration
·
G-CSF or cyclophosphamide
mobilization and stem cell
l
co lllecti
tion,
ii
minimum yil
ie d
ld >
Stem cell mobilization/collection
7.0 x 106 CD 34+ cells/kg.
Second Registration
·
Modified high-dose melphalan
on D -2 and stem cells infused
1st cycle
48 hours later.
100 mg/m2 HDM/SCT
·
Second cycle of modified
HDM/SCT within 3-6 months
2nd cycle
after first cycle.
100 mg/m2 HDM/SCT
·
Follow-up for hematologic
pg
(3-6 months
months after first)
first)
response at 3, 6, 12 mos and
annually thereafter until death,
Follow-up
5 years after registration or
progression, whichever occurs
first.
Patient Characteristics:
AL Amyloidosis
· 71 patients enrolled from 1/2004 to 3/2010
­ 15 institutions in the US
­ 66 patients eligible
eligible
­ Median age 60 (range 33-78)
­ M/F ratio
ratio = 4/3
4/3
­ Organ system involvement:
· Median number of organs involved 2 (
g(range
g , 1-8)
· Isolated renal involvement
18% (12/66)
· Cardiac involvement
32% (21/66)
· >2 organ systems involved
involved
27% (18/66)
Patient Characteristics:
Characteristics:
High-Risk Myeloma
· 30 patients enrolled from 1/2004 to 3/2010
­ 7 institutions
institutions in the US
US
­ 27 patients eligible
­ Median age 70 (range 41
41 79)
-
­ M/F ratio =3.5/1.0
­ Md
Me i
dian serum creatii
tinine l
l
eve 1 7
.
/
mg dL
/dL (0
(0 9
. 10)
-
Treatment Experience:
AL Amyloidosis
· 5 patients (7%) ineligible for the protocol
· 15 patients (23%) removed from
from the
the protocol because of:
of:
­ Inadequate stem cell collection (n=6)
­ Complications during stem cell mobilization/collection (n=6)
­ Death (n=2)
­ Progression of disease (n=1)
· 51 patients (77%) received an initial cycle of HDM/SCT (100
mg/m2)
· 27 patients (53%) received a 2nd cycle of HDM/SCT (100
mg/m2)
· 24
ti
pa ents (47%)
(47%) did
t
no
i
rece ve a 2nd
2
cyclb
le because of:
­ Toxicities (n=7)
­ Death (n=3)
­ Progression of disease (n
(n=2)
­ Patient choice (n=5)
Treatment Experience:
High-Risk Myeloma
· 3 patients
patients (10%)
(10%) ineligible for the
the protocol
· 10 patients (40%) removed from the protocol because of:
­ Complications during stem cell mobilization/collection (n=3)
­ Progression of disease (n=1)
(n=1)
­ Other reasons (n=6)
· 15 patients (60%) received an initial cycle of HDM/SCT
(100 mg/m2
mg/m )
· 11 patients (44%) received a 2nd cycle of HDM/SCT (100
mg/m2)
· 4 patients (16%) did not receive a 2nd cycle
Treatment
T
-
reatment Related
-
Morbidity
Morbidity and Mortality
Mortality
· Treatment-related mortality:
(d
(
f
e i
fi
d
ne as d
t
ea h
ths
i
w thi
ithin 100 days f
o
i
reg st ti
ra on
d
an
i
w thi
ithin 100
days of SCT)
­ Overall - after registration:
13% (n=12/91)
­ During stem cell mobilization and collection: 4% (n=4/91)
­ Within 100 days of 1st SCT:
12% (n=8/66)
­ No deaths within 100 days of
of 2nd
2
SCT
· Grade 3 and 4 non-hematologic adverse events by
CTCAEv3.0:
­ 47 patients with AL and 25 patients with hMM eligible for
adverse event analysis
­ 85% (
40/47)
n=
f
o AL
AL and 80% (
20/25)
n=
for hMM
hMM
AL Amyloidosis
Overall Survival
Event-Free Survival
100%
Median
100%
Median
Median
Deaths / N in Months
Events / N in Months
AL
25 / 65
54
AL
31 / 65
38
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
0
24
48
72
0
24
48
72
Months After Registration
Months After Registration
High-Risk Myeloma
Overall Survival
Event-Free Survival
100%
Median
100%
Median
Dt
Dea h
ths / N iM
in Month
ths
Et
Events / N iM
in Month
ths
High Risk MM
7 / 25
NR
High Risk MM
10 / 25
31
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
Months After Registration
Months After Registration
Hematologic Responses
· Defined by standard consensus criteria in AL
and IMWG criteria for hMM
· Overall hematologic responses after 2 cycles
of mHDM/SCT
­ 41% (n=11/27) in AL
­ 43% (n=3/7) in hMM
Gertz et al, Am J Hematol, 2005
Conclusions
Careful selection of patients as well as using
difi
mo
ed hi
high-dl
dose mel h
p alan fS
for
CT
SCT in
patients with AL amyloidosis and high-risk
myeloma, even
even in
in the
the setting of
of a multi-center
study, can lead to prolonged overall survival with
acceptable TRM
TRM and morbidity.
Acknowledgements
· Clinical trials office at Boston University
·Myeloma committee of SWOG
· Operations office personnel at SWOG
· Cancer research and biostatistics
· Participating patients, centers and data
managers