PROGNOSTIC FACTOR ANALYSES OF MYELOMA SURVIVAL OUTCOMES ON
INTERGROUP TRIAL S9321 (INT 0141): EXAMINING WHETHER DIFFERENT
VARIABLES GOVERN DIFFERENT TIME SEGMENTS OF SURVIVAL
·
John Crowley, Vanessa Bolejack, Robert Kyle, Kenneth Anderson and Bart
Barlogie
­ Cancer Research And Biostatistics, Seattle WA
­ Mayo Clinic
­ Dana Farber Cancer Center
­ Myeloma Institute for Research and Therapy, University of Arkansas for
Medical Sciences
­ Southwest Oncology Group, for ECOG and CALGB
SWOG 9321 Schema and Patient Flow
N = 45
HDCTX
N = 39
GVHD
Collection
Allo Tx
Prophylaxis
Allo Tx
VAD
VAD
N = 290
3-4
3-4 Cy
Cy cl
cl es
es
N = 233
HDCTX
N = 143
899
899 enroll
enroll ed
ed
Autotx
Collection
MEL, TBI
IFN
Autotx
Randomize
N = 285
*
Randomize
82 ineligible
HDCTX
N = 237
Collection
VBMCP
N = 138
Chemo
Observation
*Patients randomized to VBMCP were eligible for salvage transplant
SWOG 9321: Overall Survival from Randomization
100%
80%
60%
40%
5-Year
20%
Deaths / N Estimate
Auto BMT
190 / 290
52%
Standard Therapy
197 / 285
45%
Logrank P-value = .35
0%
0
5
10
15
Years from Randomization
Overall Survival
S9321
100%
Median
Deaths / N in Years
S9321
596 / 817 4.0 (4,4)
80%
60%
40%
20%
0%
0
5
10
15
Years from Registration
Prognostic Baseline Covariates
· Age > 60
· Calcium >= 10
· Creatinine > 2
· Serum B2m > 3.5
· LDH >= 190
· Plasma Cell Labeling Index > 1%
Overall Survival
S9321
100%
Median
Deaths / N in Years
Age <= 60
455 / 644 4.2 (4,5)
80%
Age > 60
141 / 173 3.2 (3,4)
Logrank P-value = .0001
60%
40%
20%
0%
0
5
10
15
Years from Registration
Overall Survival
S9321
100%
Median
Deaths / N in Years
Calcium <10
443 / 629 4.4 (4,5)
80%
Calcium >=10
143 / 175 2.8 (2,3)
Logrank P-value < .0001
60%
40%
20%
0%
0
5
10
15
Years from Registration
Overall Survival
S9321
100%
Median
Deaths / N in Years
Creat <=2
471 / 669 4.6 (4,5)
80%
Creat >2
116 / 138 1.9 (1,2)
Logrank P-value < .0001
60%
40%
20%
0%
0
5
10
15
Years from Registration
Overall Survival
S9321
100%
Median
Deaths / N in Years
Serum B2M <=3.5 471 / 669 4.6 (4,5)
80%
Serum B2M >3.5
116 / 138 1.9 (1,2)
Logrank P-value < .0001
60%
40%
20%
0%
0
5
10
15
Years from Registration
Overall Survival
S9321
100%
Median
Deaths / N in Years
LDH >= 190 259 / 333 3.4 (3,4)
80%
LDH<190
308 / 447 4.9 (4,6)
Logrank P-value < .0001
60%
40%
20%
0%
0
5
10
15
Years from Registration
Overall Survival
S9321
100%
Median
Deaths / N in Years
PCLI >1% 109 / 121 2.1 (2,2)
80%
PCLI<1%
401 / 569 4.3 (4,5)
Logrank P-value < .0001
60%
40%
20%
0%
0
5
10
15
Years from Registration
Landmarked Survival
Landmarked at 3 years from Registration
100%
Median
Deaths / N in Years
S9321
268 / 483 4.9 (4,6)
80%
60%
40%
20%
0%
0
3
6
9
12
Years from Registration + 3 years
Landmarked at 5 years from Registration
100%
Median
Deaths / N in Years
S9321
136 / 344 5.3 (5,6)
80%
60%
40%
20%
0%
0
2
4
6
8
10
Years from Registration + 5 years
Landmarked at 7 years from Registration
100%
Median
Deaths / N in Years
S9321
65 / 226
4.6 (4,5)
80%
60%
40%
20%
0%
0
2
4
6
8
Years from Registration + 7 years
Prognostic Factors in Multivariate
Analysis
Multivariate model:
% of N
HR
P-value
Baseline
(N=600)
Age > 60 years
21
1.37
0.007
Calcium >=10 mg/dL
21
1.40
0.004
Creatinine >2 mg/dL
16
1.31
0.045
Serum 2M > 3.5 mg/L
50
1.35
0.004
LDH >= 190 U/L
41
1.31
0.005
PCLI >1%
17
1.81
<.001
3 years from Registration
(N=439)
Age > 60 years at Reg
19
1.52
0.007
Serum 2M > 3.5 mg/L
43
1.43
0.005
5 years from Registration
(N=284)
PCLI >1%
10
1.98
0.008
7 years from Registration
(N=177)
Age >60 years at Reg
14
2.30
0.021
PCLI >1%
10
2.23
0.042
Non Proportional Hazards
· Timedependent Cox Models Indicate Non
Proportional Hazards for
­ Calcium (NS)
­ Creatinine
­ LDH
Survival Adjusted for Normal Mortality
Age is Still a Prognostic Factor
Prognostic Factors in Multivariate
Analysis
Multivariate model:
% of N
HR
P-value
RER
P-value
Baseline
(N=600)
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
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
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 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
7 years from Registration
(N=177)
Age >60 years at Reg
14
2.30
0.021
3.43
0.001
PCLI >1%
10
2.23
0.042
2.20
0.054
Is There a Cure Fraction in Multiple
Myeloma?
MODELING FOR CURE FRACTION IN MYELOMA
Conclusions
· Prognostic Influence of LDH, Calcium,
Creatinine Attenuate with Time
· Serum B2M and Especially PCLI Retain
Prognostic Value
· Age is a Prognostic Factor Beyond Normal
Mortality
· There May Be a Fraction of Myeloma Patients
Cured of Their Disease
Redefining Cancer Research and Clinical Trials
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