Myeloma International Staging System
Measurement of
of Serum
Serum Albumin
Albumin
Philip R. Greipp, M.D.
Professor of Medicine
Mayo Clinic
Scottsdale, Arizona
Rochester,
Rochester Minnesota
Jacksonville, Florida
XIth International Myeloma Workshop - Kos June 25-30, 2007
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
International Staging
Staging System (ISS)
International Myeloma Working Group
Estimates prognosis by levels of 2-microglobulin and albumin
· Stage 1: S
62 mo.
2M < 3.5 mg/L and albumin 35 g/L
· Stage 2: Either S
S M 3 5 mg/L and albumin 35 g/L
2M 3.5 mg/L and albumin 35
44 mo.
or S2M < 3.5 mg/L and albumin < 35g/l
St
3 S M 55
/L
29 mo
· Stage 3: S2M 5.5 mg/L
29
.
Greipp et al., J Clin Oncol 23(15): 3412-20, 2005
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Background
· ISS well validated in published series
· Chemistry or PEL accepted in the ISS
ISS dataset
· Similar survival distribution by Stage whether
PEL or Chem albumin used
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ISS Stage by Method of Albumin
Median
Median
Deaths / N in Months
Deaths / N in Months
Stage 1
497 / 598 56 (51 60)
,
Stage 1
223 / 441 64 (58 73)
,
Stage 2
890 / 992 39 (37,42)
Stage 2
304 / 511 43 (40,47)
Stage 3
847 / 902 25 (23,28)
Stage 3
352 / 499 27 (23,32)
Logrank P-value < .0001
Logrank P-value < .0001
100%
100%
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
0 24 48 72 96 120144168192216
0 24 48 72 96 120144168192216
Months from initial chemo treatment
Months from initial chemo treatment
Electrophoresis
Chemistry
lh
Electrophoresis: NCIC, Royal
d
Mars en, ECOG, SWOG
h
C
i
em stry: Leeds, Italy, Turkey, Japan MM
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Questions Addressed
· PEL or chemistry albumin best?
PEL albumin levels increased by higher M-spikes
Chem albumin measures albumin + other proteins
· Depending on which method is chosen:
Hi
How many patients h
c ange
?
stage
· Is one method best for the ISS?
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How is Albumin Measured?
· Protein dyes
dyes (Chem)
(Chem)
Bromcresol green
Bromcresol purple
· Protein electrophoresis (PEL)
· Immunonephelometry
py
Albumin
1
2
· Chromatography
· Capillary zone electrophoresis
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Part 1
· Chem higher
g
than PEL albumin
How much higher and in which cases?
· PEL albumin higher with higher M-spike
What is the cutoff
cutoff and how much higher?
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Methods
· 252 samples collected
~1/2 with M-spike, ~1/2 without
· BCG, PEL, nephelometry assayed
Analyzed differences in results according to
M-spike level
Mayo Clinic College of Medicine
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Increase in PEL albumin by M-spike
C Chem albumin compares with nephelometry with no effect from the M-spike;
B PEL albumin higher with M-spike greater than 25 g/L
Note the Chem is about 6g/L higher than the PEL albumin at low M-spike
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· Sl
Same overa lll
t
pa tttern; I G
g > I A
g
f
e fffect
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Part 2. Does the choice of
assay affect albumin
albumin as a
prog
pgnostic marker?
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698 myeloma patient samples
BCG
PEL
· No difference in prognostic impact of 2 albumin assays
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Conclusions - Part 1 and 2
· Chem albumin averages 6 g/L higher than PEL due to non-
specificity of
of dye
dye methods
down-
down staging 2
1
· PEL albumin - M-spike > 25g/L (IgG > IgA)
underestimates M-protein
overestimating albumin up to
5g/L
down-staging 2
1
· Minimal effect on prognostic utility
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Mayo Clinic Comprehensive Cancer Center
Part 3 Impact of Method of Albumin
on International Stage (ISS)
· What is the survival of ISS Stages by
method of albumin?
· How many patients
yp
are down-staged by
gy
each method?
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Methods
· 696 Mayo Clinic patients studied
studied by both
the chemistry (BCG) and PEL albumin at
diagnosis of myeloma
· Stage determined by the ISS
· St ti
a sti l
ca comparisons using K l
ap an
Meier curves and Cox model log rank
l
ana yses
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Survival by ISS Stage
Stage
Chem vs PEL Albumin
P<.001
P<.001
BCG
PEL
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Commonest Scenarios
Albumin PEL
Albumin
PEL
Chem
Scenario A
<35 g/L
>35 g/L
(40 pts)
Stage 2
Stage 1
Scenario B
>35 g/L
<35 g/L
(29 pts)
Stage 1
Stage 2
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PEL Stage 2 but Chem Stage 1
BCG and PEL true Stage
g 1
PEL Stage 2 but BCG Stage 1
Chem downstaged group
N=40
BCG and PEL true Stage 2
P=.03
·Survival curve of 40 Chem down-staged patients trends to true Stage 2
·Survival curve of 29 PEL down-staged patients no trend to true Stages
·PEL the best choice because pts down-staged by Chem misleading
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Conclusion: Part 3
· Commonest cause of down-staging 2
1 is the Chem
method giving higher values than the PEL (40 pts)
· Next commonest cause of down-staging 2
1 is the
PEL
th
me
d
o
i
g i
v ng hi
hi h
g er
l
va ues th
than th
the Ch
Chem
method due to higher M-spike (29 pts)
· Survival by Stage
yg similar whether the BCG or PEL
albumin is used
· Those who are Stage 2 by PEL albumin only behave
like true Stage 2
t
pa iti t
en s
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Recommendations
ISS Alb
Alb
i
um n M
t
easuremen
· Use either the PEL or BCG albumin for the ISS
· We favor the use of the PEL albumin:
Eliminates the need for performance of albumin by an additional
method (the chemistry
(y method)
Avoids the larger proportion of Chem falsely down-staged patients
who behave more like true Stage 2
Available on
on PEL without the need to perform an additional test
Avoid missing data in clinical trials and population studies
· Mayo consensus: Continue to measure and analyze both
methods but use PEL fS
for Stage and assess capillary zone
electrophoresis (CZE) as soon as possible
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Acknowledgements
Jerry Katzmann
Christine Snozek
Snozek
Amy Saenger
Sandy Bryant
Prashant Kapoor
Robert Kyle
Vincent Rajkumar
International Myeloma Foundation
International Myeloma
M
Myeloma Working
W
Wor
Wo ki
k n
i g
n Group
Mayo Immunology labs
Mayo Myeloma Group
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
698 myeloma p
ypatient samples
· 35 g/L is ISS cutoff for stage I
· Results mirror
mirror PEL vs. BCG pattern
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Retrospective review
· 5777 samples
p
over 1-year period
yp
All had PEL and BCG performed on same accession
· Dt
Data
td
sorted by M
ik
-sp e l
l
eve
Zero/low: 0 <15 g/L
Low-intermediate: 15 <25 g/L
High-intermediate: 25 <40 g/L
High: 40 g/L
Mayo Clinic College of Medicine
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· PEL BCG relationship changes
BCG higher when M-spike small
PEL higher when M-spike larg
pge
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Snozek et al., Clin Chem 2007
PEL Stage 1 but BCG Stage 2
BCG and PEL Stage 1
PEL Stage 1 but BCG Stage 2
BCG and PEL Stage 2
P=.03
Numbers are few but PEL Stage 1 who are BCG Stage 2
most like true Stage 2 in the first 2 years and they
resemble true stage 1 in longer follow-up
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Differences in albumin assays
·Dye-bindin
y
g
Non-specific; kinetic assays preferable
BCG > BCP, typically 1 - 5 g/L
· Electrophoresis
Results vary, gel vs. capillary zone
· Nephelometry
Commonly accepted
accepted as gold standard
standard
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