M. A. Gertz, M. Q. Lacy, A. Dispenzieri, S. R.
Hayman, S. K. Kumar, D. A. Gastineau,
Mayo Clinic College of Medicine
Extent of Hematologic Response is Important in
Determining Outcome in Transplanted Patients
with Primary Systemic Amyloidosis. Importance
of Achieving a Complete Response
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
DISCLOSURES
· Gertz: Advisory Board Millenium Pharm., Consultant
Novartis
· Lacy: research support Pfizer
· Dispenzieri Research support from Celgene,
Neurochem, and Cytogen.
· Hayman none
· Kumar Research support:Genzyme, Zymogenetics,
ASCO, Amgen oncology Institute
· Gastineau none
Monoclonal Gammopathies
Mayo Clinic
n=34,633
SMM 4% (1,300)
Lymphoproliferative
3% (1,089)
Solitary or extramedullary
2% (705)
Amyloidosis
Macro 2% (785)
(AL) 9% (3,185)
Other 3% (877)
Multiple
myeloma
18% (6,112)
MGUS
59% (20,580)
CP1102576-1
Therapy Of AL
· Therapy has evolved to include Mel
Dex; Ctx Thal Dex; Lenalid dex; & SCT
· End Points of these trials have included
hematologic response
· Is an M protein response very
important in the ultimate endpoints of
renal cardiac & hepatic amyloidosis
· Unlike Myeloma tumor mass does not
determine outcome
Therapy of AL
· 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 age 57 years (range, 31-75
years)
· Gender Male 59%
· Median time to transplantation after
histologic diagnosis of amyloidosis was
4.2 months (lead time bias) 75%< 7mo.
· Serum creatinine levels were greater
than 1.8 mg/dL for 10% of patients but
less than 1.3 mg/dL for 75% of patients
AL TRANSPLANT
POPULATION
· Median 24-hour urine protein loss was
3.4 g/day
· One-, 2-, and 3-organ 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 16%
had hepatic involvement.
· Echocardiographic analysis showed a
median septal thickness of 12 mm and
a median ejection fraction of 65%.
· Median % of bone marrow plasma cells
was 7, range from 1 - 78
Overall Survival of 282 Transplanted
Amyloid Patients Stratified by Hematologic
Response
1.0
0.8
CR (n=93)
0.6
PR (n=108)
0.4
Surviving
0.2
NR (n=81)
0.0
0
1020
30405060
708090 100 110 120
Months
CP1245979-1
INTERPRETING AL
RESPONSE/SURVIVAL
· Skew in the data since with an 11 %
mortality rate a substantial number of
patients become inevaluable for response
· Landmark analysis at 6 months to exclude
early deaths from advanced organ failure
gives a better assessment of 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)
0.6
PR (n=91)
0.4
Surviving
NR (n=36)
0.2
P=0.001
0.0
0
1020
30405060
708090 100 110 120
Months
CP1245979-2
Response Translates to
Survival
· Do patients with echocardiographic
evidence of Cardiac AL also benefit
form transplant?
· Recognizing that patients with cardiac
AL are a highly selected group
(milder)...
Overall Survival of 151 Transplanted
Cardiac Amyloid Patients Stratified by
Hematologic Response
1.0
0.8
n=42
0.6
n=56
0.4
Surviving
0.2
n=53
P<0.001
0.0
0
1020
30405060
708090 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
n=38
0.6
n=39
0.4
Surviving
n=18
0.2
P<0.001
0.0
0
1020
30405060
708090 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 (p=0.046). However,
since this was not a prospective study,
patients who received higher intensity
therapy tended to be younger and have
less extensive organ involvement
particularly cardiac
What this study does not tell
us
· Is Transplant any better than
Chemotherapy ± Novel Agents?
· What role does patient selection have
in determining response?
· Should patients who fail to achieve CR
receive post transplant consolidation to
move them to CR
What this study does tell us
· In Amyloidosis response is an
appropriate surrogate for survival
· Response is a legitimate endpoint for
Clinical Studies of Therapy including
cardiac AL
· Complete Responders live longer than
partial responders
· Partial responders live longer than non
responders even correcting for early
death by landmark
Disclosures: Gertz: Advisory Board Millenium Pharm., Consultant Novartis
Lacy: Pfizer research support
Dispenzieri research swupport from Celgene, Neurochem, and Cytogen.
Hayman none
Kumar Research support:Genzyme, Zymogenetics, ASCO, Amgen oncology Institute
Gastineau none
No discussion of off label medications in this poster