International Staging System (ISS)
for Myeloma: An Update
PR Greipp, J San Miguel, BGM Durie, JJ Crowley, Bart Barlogie, J
Blade, M Boccadoro, JA Child, JL Harousseau, RA Kyle, JJ
Lahuerta, H Ludwig, G Morgan, R Powles, K Shimizu, C Shustik, P
Sonneveld, P Tosi, I Turesson, J Westin
For the International Myeloma Working Group
Supported by a Grant from the International Myeloma Foundation
Analysis by Cancer Research and Biostatistics (CRAB)
Institutions and Groups
Submitting Data
Asia
North America
· Japan (JMSG)
· ECOG
· NCIC
Europe
· SWOG
· Austria
· Mayo Clinic
· Italy (AOSGB)
· University of Arkansas
· France (IFM)
· Spain (Pethema and GEM)
· UK (Leeds - MRC)
· Netherlands (HOVON)
· Nordic (NMSG)
· Turkey (Ankara University)
International Staging System (ISS)
Goals
· Simple, objective, validated and confirmed
Staging for Myeloma
· Using universally available data
· For comparisons among groups
· For stratification in clinical trials
Methods: Eligibility
· Diagnosis of Myeloma*
· Inclusion:
· Patients about to begin chemoRx
· Prior radiation therapy allowed
· Standard and high dose therapy
· Data within 1 month prior to Rx
· Exclusion:
· IgM disorders and primary
amyloidosis
· Asymptomatic Myeloma
* International Myeloma Working Group, Brit J Haem, June 2003
Methods: Factor Selection
Validation and Confirmation
· Univariate and multivariate analysis
· Non-tree and tree models used to develop
a staging system
· Training set including one half the patients
· Validation using the remaining half
· Confirmation in subsets
· Confirmation in the S9321 Clinical Trial
Methods: Staging System Models
· Non-tree models
· Model 1 - 3 groups (weighted
continuous variables)
· Model 2 - Number of risk factors: (IPI)
· Tree model
· Model 3 - Regression tree (risk factors
present and each branch point sequentially
reassessed)
Results
· Period of study 1981-2002
· 10,750 cases with all data
· 66% of patients died
· Standard therapy
7942 (74.0%)
· High dose therapy
2808 (26.0%)
· Test set 5,383; Validation set 5,367
Results: Patient Characteristics
Median
Age
60
Hb (g/dl)
10.5
Plt (# per mcl)
221 x103
Creatinine (mg/dl)
1.1
M-protein
3.9
B2M
3.8
Albumin (g/dl)
3.6
Plasma Cells (%)
40
Results: Hazard Ratios
Variable
Univariate HR
Multivariate HR
· B2M >=3.5
1.81
1.81 1
· platelets <130
1.73
1.63 2
· age >=65
1.67
· creatinine >=2
1.66
1.28 5
· LDH above normal
1.50
· hemoglobin <10
1.49
· albumin <3.5
1.40
1.28 3
· calcium >=10
1.32
1.28 4
· BMPC >=33%
1.29
* Sequence of entry: B2M, Platelets, Albumin, Calcium, Creatinine
Results: Using the Three Models
· Model 1 (Continous Variables)
· B2M, albumin and platelets
· Model 2 (Number of factors)
· B2M, albumin, calcium, and platelets
· Model 3 (Regression Tree)
· B2M and albumin
Results: International Staging
System (ISS)
Stage 1
(B2M <3.5 and albumin 3.5+)
- 62 mos
Stage 2
(Neither Stage 1 or 3*)
- 44 mos
Stage 3 (B2M 5.5+)
- 29 mos
* Stage 2 - B2M <3.5 and albumin <3.5, or B2M 3.5-5.5
Results: Validation
Overall Survival by ISS- Training Set
Overall Survival by ISS- Validation Set
100%
Median
100%
Median
Deaths / N in Months
Deaths / N in Months
80%
Stage I
655 / 1196 62 (58,67)
Stage I
606 / 1111 62 (58,65)
Stage II
1029 / 1551 45 (42,47)
80%
Stage III
1050 / 1388 29 (26,31)
Stage II
1054 / 1606 44 (42,48)
Stage III
968 / 1305 29 (26,32)
60%
60%
40%
40%
20%
20%
0%
0
24
48
72
96
120 144 168 192 216
0%
Months from initial chemo treatment
0
24
48
72
96 120 144 168 192 216
Months from initial chemo treatment
Survival by ISS
For Age < 65 or 65+
Median
Median
Deaths / N in Months
Deaths / N in Months
Stage 1 888 / 1775 68 (64,73)
Stage 1
429 / 622 46 (41,49)
Stage 2 1254 / 2101 49 (46,53)
Stage 2
915 / 1172 37 (34,40)
Stage 3 1156 / 1663 33 (30,35)
Stage 3
919 / 1099 24 (23,27)
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
Less than 65
65+
Survival by ISS
Different Geographic Regions
Median
Deaths / N in Months
Median
Median
Stage 1
132 / 256 58 (47,64)
Deaths / N in Months
Stage 2
161 / 242 38 (31,42)
Stage 1 565 / 1345 71 (64,74)
Deaths / N in Months
Stage 3
182 / 248 24 (19,30)
Stage 2 940 / 1810 51 (48,54)
Stage 1
623 / 800 54 (50,59)
Logrank P-value < .0001
Stage 3 925 / 1462 32 (30,36)
Stage 2 1071 / 1226 40 (37,42)
100%
100%
Logrank P-value < .0001
Stage 3 976 / 1060 25 (24,28)
100%
Logrank P-value < .0001
80%
80%
80%
60%
60%
60%
40%
40%
40%
20%
20%
20%
0%
0%
0 24 48 72 96 120144168192216
0 24 48 72 96 120144168192216
Months from initial chemo treatment
0%
Months from initial chemo treatment
0 24 48 72 96 120144168192216
Months from initial chemo treatment
Asia
Europe
North America
Survival by ISS
For Individual Institutions or Cooperative Groups
Median
Median
Deaths / N in Months
Deaths / N in Months
Stage 1
341 / 674 73 (64,80)
Stage 1
979 / 1727 59 (56,62)
Stage 2
550 / 925 49 (44,54)
Stage 2 1622 / 2353 43 (41,45)
Stage 3
451 / 691 33 (29,38)
Stage 3 1632 / 2079 28 (26,30)
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
Individual Institutions
Cooperative Groups
Survival by ISS
For Standard or Transplant Therapy
Median
Median
Deaths / N in Months
Deaths / N in Months
Stage 1
775 / 1010 51 (48,54)
Stage 1
134 / 570
NR
Stage 2 1413 / 1662 38 (36,40)
Stage 2
194 / 615 73 (62,86)
Stage 3 1362 / 1492 23 (21,24)
Stage 3
214 / 426 42 (39,47)
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
Transplant
Standard
*Higher proportion of older patients and Stage 3 patients in the Standard group
Application of the ISS to S9321
Transplant vs Standard Chemotherapy
Progression Free Survival
S9321
100%
Median
Events / N in Years
ISS Stage I
251 / 331 2.2 (2,2)
80%
ISS Stage II
160 / 193 1.9 (2,2)
ISS Stage III
208 / 232 1.3 (1,2)
Logrank P-value < .0001
60%
40%
20%
0%
0
2
4
6
8
10
Years from Initial Registration
Comparing ISS and Durie Salmon Stage
· ISS superior to DS Stage
· More equal distribution across 3 stages
· ISS vs DS Stage 1
· Similar survival but only 8% are DS
Stage 1 vs. 28% for the ISS
· DS Stage 2a
· Similar survival to ISS Stage 1
· DS Stage 3b
· Similar survival to ISS Stage 3 but only
16% are DS Stage 3b vs. 33% ISS Stage 3
· ISS Stage 3 superior to the heterogeneous
and numerous DS Stage 3a
Results: Creatinine
· Only 17% of patients (1,382) with a
creatinine >2
· 82% of these had a B2M >5.5 and
were therefore ISS Stage 3
· But over half of ISS Stage 3 patients
had creatinine <2, so B2M ranked 1 in
the multivariate tree analysis while
creatinine ranked 5
Results: Cytogenetics Analysis
(390 patients)
Variable
N
Survival
RR
(mos)
· CA by karyotype
(28%)
42 vs 69 **
1.33
· Complex karyotype
(22%)
29 vs 52
1.76
· Del 13 by karyotype
(13%)
38 vs 72
1.76
· t(11;14) by FISH
(16%)
49 vs 39
0.96
· t(4;14) by FISH
(11%)
26 vs 45
2.06
· FISH del 13
(49%)
36 vs 50
1.23
· -17 by FISH
(10%)
23 vs 44
1.59
** Survival difference significant at p=0.03
Summary
· ISS identifies 3 simple groups with validated
and confirmed differing survival
· Stage 1 -
62 Mos
· Stage 2 -
44 Mos
· Stage 3 -
29 Mos
· ISS prognostic regardless of
· age, geographic region, individual
institution or cooperative group,
standard or transplant therapy
Conclusion
· The ISS should be the only staging
system used until another easily
usable, validated, and confirmed
system replaces it
Working Group Membership
·
Kenneth Anderson, DFCI
·
Philip Greipp, Mayo Clinic
·
Erik Rasmussen, CRAB
·
Michel Attal, Toulouse
·
David Harrington, DFCI
·
Paul Richardson, DFCI
·
Herve Avet-Loiseau, Nantes
·
Kim Hawkins, Leeds
·
Robert Schlossman, DFCI
·
Bart Barlogie, UAMS
·
Martin Hjorth, Nordic Group
·
Helmuth Schmidt, Germany
·
Regis Bataille, Nantes
·
Vania Hungria, Sao Paulo
·
Jesus SanMiguel, Salamanca
·
Meral Beksac, Ankara University
·
Mohamed Hussein, Cleveland Clinic ·
Kazayuki Shimizu, Japan, MSG
·
Joan Blade, PETHEMA
·
Peter Jacobs, South Africa
·
Chaim Shustik, Montreal
·
Mario Boccadoro, IMMSG (Torino)
·
Joth Jacobson, CRAB
·
Bhawna Sirohi, Royal Marsden
·
Tony Child, Univ of Leeds (MRC)
·
Doug Joshua, Sydney
·
Pieter Sonneveld, HOVON
·
Claudia Corrado, FUNDALEU
·
Aliki Kallinikou-Maniatis, Greece
·
Kari Staat, Toronto
·
John Crowley, CRAB
·
Tadamitsu Kishimoto, Japan MSG
·
Kathrin Strasser, Germany
·
William Dalton, Moffitt
·
Juan Lahuerta - GEM Group
·
Keith Stewart, Toronto
·
Thanos Dimopoulous, Athens
·
Robert Kyle, Mayo Clinic
·
Patrizia Tosi, Italian MMSG
·
Mark Drayson, Birmingham
·
Traci Leong Emory
·
Ingemar Turesson, Nordic
MSG
·
Brian Durie, Cedars Sinai CCC
·
Heinz Ludwig, Wien
·
Ron van der Holt, HOVON
·
Thierry Facon, France
·
Gareth Morgan, Leeds
·
David Vesole, Wisconsin
·
Jean Paul Fermand, St. Louis, Paris ·
Philippe Moreau, Nantes
·
Donna Weber, MD Anderson
·
Rafael Fonseca, Mayo Clinic
·
Hirokazu Murakami, Japan MSG
·
Jan Westin, Nordic Group
·
Gosta Garhton, Karolinska
·
Santiago Pavlosky, FUNDALEU
·
Keith Wheatley, Birmingham
·
Hartmut Goldschmidt, Heidelberg
·
Ray Powles, Royal Marsden
Future Directions for ISS
and the International Myeloma
Working Group
· Recommended use for reporting clinical trial results
and large series, and for clinical trial stratification
· Increase the number and follow up for transplant
· Work toward implementation of cytogenetic and
molecular markers for prognosis
Factors Predicting Lower Risk*
(>5 year survival)
Median
Deaths / N
in Months
Low Risk
460 / 711
62 (59,67)
100%
Low Risk: Age<60, Albumin>3.5 and B2M<3.5
80%
60%
40%
20%
0%
0
24
48
72
96 120144168192216
Months from initial chemo treatment
Little information added by other favorable factors:
absence of CA, FISH t (4;14), FISH 13,
Platelets >200,000, normal LDH
Factors Predicting Higher Risk
Median
Median
Deaths / N in Months
Deaths / N in Months
High Risk + Normal PLT
268 / 298 18 (15,24)
High Risk + Normal LDH
60 / 73
18 (11,30)
High Risk + Low PLT
90 / 97
10 (7,15)
High Risk + LDH>ULN
39 / 44
9 (4,16)
Logrank P-value = .001
Logrank P-value = .30
100%
100%
80%
High Risk: Albumin<3.5 and B2M>10 80%
ULN- Upper Limit Normal
Normal PLT>130
60%
60%
Low PLT<130
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
* Standard therapy patients only
ISS - 3 Stages
Stage 1 - B2M <3.5 and albumin 3.5+
Stage 2 - B2M <3.5 and albumin <3.5, or B2M 3.5-5.5
Stage 3 - B2M
Median
Deaths / 5.5+
N
in Months
Stage 1
685 / 1241 62 (57,66)
Stage 2
1077 / 1615 44 (41,46)
Stage 3
1081 / 1425 29 (26,31)
Median
Logrank P-value < .0001
Deaths / N
in Months
Stage 1
635 / 1160 61 (58,64)
100%
Stage 2
1095 / 1663 44 (42,48)
Stage 3
1002 / 1345 29 (26,32)
100%
Logrank P-value < .0001
80%
80%
60%
60%
40%
40%
20%
20%
0%
0
24 48 72 96 120144168192216
Months from initial chemo treatment0% 0 24 48 72 96 120144168192216
Months from initial chemo treatment
Validation Set
Test Set
Overall Survival by Grouping
100%
Median
Deaths / N in Months
Overall Survival
B2M<3.5/ALB>3.5 685 / 1241 62 (57,66)
Median
B2M<3.5/ALB<3.5 318 / 528 48 (42,55)
100%
Deaths / N
in Months
80%
Overall
7323 / 11171 44 (43,45)
B2M: 3.5-5.5
759 / 1087 43 (40,45)
B2M: 5.5-8.0
426 / 606 33 (31,37)
80%
B2M>8.0
655 / 819 24 (21,27)
60%
Logrank P-value < .0001
60%
40%
40%
20%
20%
0%
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
0%
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Overall
From Test Dataset
Regression Tree Model
(Five groupings using Test Data)
B2M<5.5
B2M<3.5
B2M<8.0
N=606
N=819
N=1087
Albumin 3.5
RR=1.9
RR=2.7
RR=1.6
RR = Relative Risk
N=1241
N=528
* Reference Group
RR=1*
RR=1.3
Distributions
1%
2%
3%
<.1%
4%
10%
18%
IgG
IgA
White
Asian
Light Chain Only
Black
24%
IgD
Other
61%
Other
Biclonal
77%
Race
Ig type
5%
45
17%
14%
40
42%
35
PS 0
>3
30
Bone
PS 1
25
Lesions
PS 2
20
22%
PS 3
15
24%
No
PS 4
10
bone
5
lesions
40%
0
Bone Lesions
PS
Bone Disease
Strategy for an International
Staging System (ISS)
International Myeloma Working Group
· Statistics support, World-wide representation,
Expertise in prognostication
· Intensive data gathering and analysis
· Identify 2 or 3 commonly available variables
· Identify additional high and low risk patients from
commonly available factors
Background
· 1960's
- Single prognostic factors
· 1970
- Durie Salmon tumor burden
· 1975
- Durie Salmon stage (in use today)
· 1980's
- Beta 2-microglobulin
· 1990's
- Other staging systems offered
Why a New Staging System to Replace
Durie Salmon as the International
Standard?
· Difficult to remember cutoffs for DS Stage
· Subjective interpretation of bone lesions
· Relatively good survival for DS Stage 3 patients
· B2M based risk groups appropriately being
used by investigators in clinical trials, rather
than DS Stage, but no consensus on B2M
cutoffs
Methods
· Series of International Meetings, 2000-2002
· Agreement on a simple, easy to use, staging system to
replace Durie Salmon
· Participation from 17 institutions and groups worldwide
· ECOG (Eastern Cooperative Oncology Group)
· Initial data collection issues (D. Harrington, T. Leong)
· CRAB (Cancer Research and Biostatistics)
· Developed data spread sheets
· Coordinated data collection
· Corrected/evaluated incomplete data
· Performed the data analysis
· Executive Committee
· Supervised collection and analysis of data
· Series of bi-weekly teleconferences
Figure 1- 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
Electrophoresis: NCIC, Royal Marsden, ECOG, SWOG
Chemistry: Leeds, Italy, Turkey,Japan MM
ISS Stage 1 vs 2: Differentiated by Albumin
ecog
ISS Stage 1 vs 2: Differentiated by Albumin
100%
gem
Median
Deaths / N
in Months
100%
Median
Stage 1
151 / 171
55 (49,65)
Deaths / N
in Months
80%
Stage 2
73 / 77
35 (30,46)
Stage 1
99 / 276
74 (64,84)
Logrank P-value = .007
80%
Stage 2
33 / 120
63 (49,95)
Logrank P-value = .56
60%
60%
40%
40%
20%
20%
0%
0
24
48
72
96
120
144
168
192
216
0%
Months from initial chemo treatment
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
ISS Stage 1 vs 2: Differentiated by Albumin
ISS Stage 1 vs 2: Differentiated by Albumin
france
italy
100%
Median
100%
Median
Deaths / N in Months
Deaths / N
in Months
Stage 1
13 / 111
NR
Stage 1
50 / 73
78 (59,93)
80%
Stage 2
7 / 22
53 (22,.)
80%
Stage 2
12 / 17
49 (40,72)
Logrank P-value = .002
Logrank P-value = .33
60%
60%
40%
40%
20%
20%
0%
0%
0
24
48
72
96
120
144
168
192
216
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Months from initial chemo treatment
ISS Stage 1 vs 2: Differentiated by Albumin
ISS Stage 1 vs 2: Differentiated by Albumin
japan
leeds
100%
Median
100%
Median
Deaths / N
in Months
Deaths / N
in Months
Stage 1
132 / 256
58 (47,64)
Stage 1
33 / 93
71 (59,90)
80%
Stage 2
48 / 85
49 (41,57)
80%
Stage 2
19 / 37
48 (31,63)
Logrank P-value = .03
Logrank P-value = .01
60%
60%
40%
40%
20%
20%
0%
0%
0
24
48
72
96
120
144
168
192
216
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Months from initial chemo treatment
ISS Stage 1 vs 2: Differentiated by Albumin
ISS Stage 1 vs 2: Differentiated by Albumin
mayo
ncic
100%
Median
100%
Median
Deaths / N
in Months
Deaths / N
in Months
Stage 1
142 / 185
47 (41,53)
Stage 1
56 / 61
51 (41,64)
80%
Stage 2
96 / 119
36 (30,41)
80%
Stage 2
28 / 30
32 (24,43)
Logrank P-value = .03
Logrank P-value = .45
60%
60%
40%
40%
20%
20%
0%
0%
0
24
48
72
96
120
144
168
192
216
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Months from initial chemo treatment
ISS Stage 1 vs 2: Differentiated by Albumin
ISS Stage 1 vs 2: Differentiated by Albumin
nordic
pethema
100%
Median
100%
Median
Deaths / N
in Months
Deaths / N
in Months
Stage 1
135 / 300
68 (56,75)
Stage 1
117 / 211
55 (46,60)
80%
Stage 2
85 / 156
56 (48,66)
80%
Stage 2
51 / 90
49 (37,69)
Logrank P-value = .05
Logrank P-value = .30
60%
60%
40%
40%
20%
20%
0%
0%
0
24
48
72
96
120
144
168
192
216
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Months from initial chemo treatment
ISS Stage 1 vs 2: Differentiated by Albumin
ISS Stage 1 vs 2: Differentiated by Albumin
royalm
swog
100%
Median
100%
Median
Deaths / N
in Months
Deaths / N
in Months
Stage 1
54 / 108
95 (73,99)
Stage 1
236 / 258
50 (44,58)
80%
Stage 2
40 / 77
71 (48,92)
80%
Stage 2
132 / 143
42 (37,51)
Logrank P-value = .04
Logrank P-value = .18
60%
60%
40%
40%
20%
20%
0%
0%
0
24
48
72
96
120
144
168
192
216
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Months from initial chemo treatment
Characteristics of Patients by ISS
ISS Stage
Factor
Stage 1
Stage 2
Stage 3
HGB<10 (g/dL)
433/2389 (18%)
1317/3259 (40%)
1829/2749 (67%)
Creatinine>=2 (mg/dL
46/2385 (2%)
209/3249 (6%)
1169/2739 (43%)
PLT<130 (x10^3/uL)
125/2219 (6%)
322/3108 (10%)
510/2612 (20%)
Calcium>=10 (mg/dL)
540/2174 (25%)
894/3010 (30%)
1178/2562 (46%)
>3 Lytic Lesions
875/1955 (45%)
1237/2683 (46%)
1192/2343 (51%)
CRP>=0.8 (mg/dL)
231/1259 (18%)
490/1531 (32%)
457/1162 (39%)
LDH (above normal)
201/997 (20%)
278/1186 (23%)
365/997 (37%)
BMPC>=33%
974/2291 (43%)
1868/3112 (60%)
1936/2609 (74%)
PS 2+
669/2212 (30%)
1249/3103 (40%)
1381/2649 (52%)
Durie Salmon Stage 3
798/2118 (38%)
1501/2820 (53%)
1664/2412 (69%)
n/N (%): n- Number with Factor for Group Level, N- Number Known with or without Factor for Group Level
Survival by ISS
For Age < 60 or 60+
Median
Median
Deaths / N in Months
Deaths / N in Months
Stage 1
652 / 1050 50 (48,53)
Stage 1
665 / 1347 73 (67,77)
Stage 2 1350 / 1840 39 (37,41)
Stage 2
819 / 1433 54 (49,58)
Stage 3 1311 / 1639 26 (24,28)
Stage 3
764 / 1123 35 (32,38)
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
60+
<60

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