PROGNOSTIC FACTOR ANALYSES OF MYELOMA SURVIVAL OUTCOMES ON INTERGROUP TRIAL S9321 (INT 0141):
EXAMINING WHETHER DIFFERENT VARIABLES GOVERN DIFFERENT TIME SEGMENTS OF SURVIVAL
Redefining Cancer Research and Clinical Trials
John Crowley, Vanessa Bolejack, Robert Kyle, Kenneth Anderson and Bart Barlogie
SWOG 9321 Schema and Patient Flow
Cancer Research And Biostatistics, Seattle WA; Mayo Clinic; Dana Farber Cancer Center;
N = 45
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences; Southwest Oncology Group, for ECOG and CALGB
HDCTX
N = 39
GVHD
Col ection
Al o Tx
Prophylaxis
Al o Tx
Visit us at www.crab.org
V
V A
A D
D
N = 290
3
3 -
- 4
4 C
C y
y c
clle
e s
s
HDCTX
N = 233
N = 143
8
8 9
9 9
9 e
e n
n rro
oll e
e d
d
Col ection
Autotx
IFN
Autotx
MEL, TBI
ize
ize
Random
N = 285
Landmarked Survival
*
Random
82 ineligible
HDCTX
N = 237
Col ection
VBMCP
N = 138
Chemo
Observation
*Patients randomized to VBMCP were eligible for salvage transplant
Prognostic Factors in Multivariate
Overall Survival
S9321
Landmarked at 3 years from Registration
Landmarked at 5 years from Registration
Landmarked at 7 years from Registration
Analysis
Non Proportional Hazards
100%
Median
100%
Median
100%
Median
Deaths / N in Years
Deaths / N in Years
Deaths / N in Years
Multivariate model:
% of N
HR
P-value
S9321 268 / 483 4.9 (4,6)
S9321 136 / 344 5.3 (5,6)
S9321 65 / 226 4.6 (4,5)
Baseline
(N=600)
Age > 60 years
21
1.37
0.007
80%
80%
80%
Calcium >=10 mg/dL
21
1.40
0.004
· Time-dependent Cox Models Indicate Non
Overall Survival
SWOG 9321: Overall Survival from Randomization
Creatinine >2 mg/dL
16
1.31
0.045
S9321
Serum 2M > 3.5 mg/L
50
1.35
0.004
100%
100%
Median
60%
60%
60%
Proportional Hazards for
LDH >= 190 U/L
41
1.31
0.005
Deaths / N in Years
PCLI >1%
17
1.81
<.001
S9321 596 / 817 4.0 (4,4)
3 years from Registration
(N=439)
80%
80%
40%
40%
40%
Age > 60 years at Reg
19
1.52
0.007
Serum 2M > 3.5 mg/L
43
1.43
0.005
Calcium (NS)
5 years from Registration
(N=284)
60%
60%
20%
20%
20%
PCLI >1%
10
1.98
0.008
Creatinine
7 years from Registration
(N=177)
Age >60 years at Reg
14
2.30
0.021
40%
40%
0%
0%
0%
PCLI >1%
10
2.23
0.042
LDH
0
3
6
9
12
0
2
4
6
8
10
0
2
4
6
8
5-Year
Years from Registration + 3 years
Years from Registration + 5 years
Years from Registration + 7 years
20%
Deaths / N Estimate
Auto BMT
190 / 290
52%
20%
Standard Therapy 197 / 285
45%
Logrank P-value = .35
0%
0%
0
5
10
15
0
5
10
15
Years from Randomization
Years from Registration
Prognostic Baseline Covariates
Survival Adjusted for Normal Mortality
Is There a Cure Fraction in Multiple Myeloma?
· Age > 60
· Calcium >= 10
Age is Stil a Prognostic Factor
MODELING FOR CURE FRACTION IN MYELOMA
· Creatinine > 2
· Serum B2m > 3.5
· LDH >= 190
· Plasma Cel Labeling Index > 1%
Overall Survival
Overall Survival
Overall Survival
S9321
S9321
S9321
100%
Median
100%
Median
100%
Median
Deaths / N in Years
Deaths / N in Years
Deaths / N in Years
Age <= 60 455 / 644 4.2 (4,5)
Calcium <10
443 / 629 4.4 (4,5)
Creat <=2 471 / 669 4.6 (4,5)
80%
Age > 60
141 / 173 3.2 (3,4)
Calcium >=10 143 / 175 2.8 (2,3)
Creat >2
116 / 138 1.9 (1,2)
Logrank P-value = .0001
80%
Logrank P-value < .0001
80%
Logrank P-value < .0001
60%
60%
60%
40%
40%
40%
Prognostic Factors in Multivariate
20%
20%
20%
Analysis
Conclusions
0%
0%
0%
Multivariate model:
% of N
HR
P-value
RER
P-value
0
5
10
15
0
5
10
15
0
5
10
15
Baseline
(N=600)
Years from Registration
Years from Registration
Years from Registration
Age > 60 years
21
1.37
0.007
1.23
0.116
Calcium >=10 mg/dL
21
1.40
0.004
1.42
0.003
· Prognostic Influence of LDH, Calcium,
Creatinine >2 mg/dL
16
1.31
0.045
1.37
0.021
Serum 2M > 3.5 mg/L
50
1.35
0.004
1.38
0.003
Creatinine Attenuate with Time
LDH >= 190 U/L
41
1.31
0.005
1.35
0.003
PCLI >1%
17
1.81
<.001
1.82
<.001
3 years from Registration
(N=439)
Age > 60 years at Reg
19
1.52
0.007
1.42
0.047
· Serum B2M and Especial y PCLI Retain
Serum 2M > 3.5 mg/L
43
1.43
0.005
1.44
0.007
5 years from Registration
(N=284)
PCLI >1%
10
1.98
0.008
1.99
0.010
Prognostic Value
Overall Survival
Overall Survival
Overall Survival
S9321
S9321
S9321
7 years from Registration
(N=177)
100%
Median
100%
Median
100%
Median
Age >60 years at Reg
14
2.30
0.021
3.43
0.001
Deaths / N in Years
Deaths / N in Years
Deaths / N in Years
PCLI >1%
10
2.23
0.042
2.20
0.054
Serum B2M <=3.5 471 / 669 4.6 (4,5)
LDH >= 190 259 / 333 3.4 (3,4)
PCLI >1% 109 / 121 2.1 (2,2)
· Age is a Prognostic Factor Beyond Normal
80%
Serum B2M >3.5 116 / 138 1.9 (1,2)
LDH<190
308 / 447 4.9 (4,6)
PCLI<1% 401 / 569 4.3 (4,5)
Logrank P-value < .0001
80%
Logrank P-value < .0001
80%
Logrank P-value < .0001
Mortality
60%
60%
60%
· There May Be a Fraction of Myeloma Patients
40%
40%
40%
Cured of Their Disease
20%
20%
20%
0%
0%
0%
0
5
10
15
0
5
10
15
0
5
10
15
Years from Registration
Years from Registration
Years from Registration