LONG TERM FOLLOW UP OF
AUTOTRANSPLANT TRIALS
FOR MULTIPLE MYELOMA
On behalf of:
Intergroupe Francophone du Myelome (IFM)
Southwest Oncology Group (SWOG)
Bart Barlogie (SWOG, MIRT)
Michel Attal & Jean-Luc Harousseau (IFM)
John Crowley (SWOG, CRAB)
Myeloma Institute for Research and Therapy
University of Arkansas for Medical Sciences
Little Rock, AR, USA
Universite´ de Toulouse, France
Rene Gauducheau Cancer Center, Nantes, France
Cancer Research and Biostatistics
Seattle, WA, USA
OBJECTIVES
· Update several quintessential autotransplant
trials for newly diagnosed multiple myeloma
· Thus provide long-term perspective of the
"gold-standard" as a frame of reference for
novel agent combinations
· Examine whether and how early trial reports
differ from this long-term update
· Perform multivariate and pair-mate analyses
to address individual trials' merits and
progress made
· Determine relative survival rates in context of
US mortality data
· Determine whether a cure fraction has
emerged
DETAILS OF UPDATED TRIALS
·IFM
·SWOG
­ IFM 90
­ S9321 Intergroup
· 1 transplant v
· 1 transplant v
standard
standard Rx
chemotherapy
· MIRT Arkansas
­ IFM 94
· 2 v 1 transplants
­TT1
­ IFM 99
· Tandem transplant
phase 2
· Low-risk (99-02)
­TT2
­ 2 transplants
­ Randomize:
· Tandem transplant
phase 3 +/- thal
» PAM + thal v
PAM v placebo
­TT3
· High-risk (99-04)
· Phase 2 w/
­ 2 transplants, -IL6
bortezomib
PATIENT CHARACTERISTICS
Para-
IFM
IFM
IFM
IFM
S
TT1
TT2
TT3
meter
90
94
99-02
99-04
9321
N=194 N=402 N=692 N=197 N=817 N=231
N=668
N=303
Age
2%
0%
2%
4%
7%
9%
20%
28%
>65yr
B2M
24%
19%
13%
39%
29%
19%
18%
21%
>5.5mg/L
Albumin
32%
28%
29%
51%
36%
27%
18%
26%
<3.5g/dL
DS>I
100%
92%
92%
97%
74%
94%
87%
90%
ISS>I
63%
54%
44%
87%
67%
52%
44%
54%
CA
NA
NA
NA
NA
NA
33%
30%
33%
Median
7.4 yr 11.6 yr 5.7 yr
5.0 yr
8.4 yr 15.6 yr
7.2 yr
3.9 yr
F/U
LONG-TERM
Overall Survival
MIRT TT, IFM and SWOG Survival Outcomes
100%
Median
Deaths / N in Years
FOLLOW-UP OF
IFM 99-02
226 / 692
NR
80%
TT3
68 / 303
NR
TT2
292 / 668
9.0
TT1
183 / 231
5.7
IFM 90
160 / 194
4.5
IFM
60%
IFM 94
303 / 402
4.3
S9321
596 / 817
4.0
IFM 99-04
114 / 197
3.9
S9321
40%
50% @ 10yr
20%
TT
0%
PROTOCOLS
0
4
8
12
16
20
Years from Enrollment
Event-free Survival
MIRT TT, IFM and SWOG Event-Free Survival Outcomes
TT3: all risk, age <75
100%
Median
Events / N in Years
TT3
84 / 303
NR
TT2: all risk, age <75
80%
TT2
415 / 668
4.8
IFM 99-02
490 / 692
3.4
IFM99-02: low risk, age <65
TT1
207 / 231
2.6
IFM 90
177 / 194
2.5
60%
IFM 94
367 / 401
2.3
TT1: all risk, age <75
IFM 99-04
169 / 197
2.0
S9321
718 / 817
1.9
IFM90: all risk, age <65
40%
IFM94: all risk, age <65
20%
IFM99-04: high risk, age <65
30% @ 10yr
S9321: all risk, age <70
0%
0
4
8
12
16
20
Years from Enrollment
RE-ITERATIVE SURVIVAL ANALYSES
IN TT, S9321 & IFM TRIALS
TT1
TT2
Total Therapy 1 (TT1) Overall Survival Outcomes
Total Therapy 2 (TT2) Overall Survival Outcomes
Total Therapy 3 (TT3) Overall Survival Outcomes
TT3
First Patient Enrolled August 21, 1990
First Patient Enrolled October 14, 1998
First Patient Enrolled Februrary 25, 2004
100%
5-Year
100%
100%
Deaths / N
Estimate
a) TT1 OS (Yr 1)
1 / 42
97% (91,100)
80%
b) TT1 OS (Yr 3)
19 / 145
61% (33,89)
80%
80%
c) TT1 OS (Yr 5)
59 / 231
51% (38,63)
d) TT1 OS (Yr 6)
79 / 231
52% (43,62)
e) TT1 OS (Yr 7)
91 / 231
59% (51,66)
60%
f) TT1 OS (Yr 8)
110 / 231
56% (50,63)
60%
60%
g) TT1 OS (Yr 9)
122 / 231
57% (50,63)
5-Year
h) TT1 OS (Yr 10)
131 / 231
57% (50,63)
Deaths / N
Estimate
a) TT2 OS (Yr 1)
5 / 112
94% (88,99)
40%
40%
b) TT2 OS (Yr 3)
46 / 381
65% (44,86)
40%
c) TT2 OS (Yr 5)
125 / 616 64% (58,71)
d) TT2 OS (Yr 6)
160 / 668 66% (61,71)
5-Year
20%
20%
e) TT2 OS (Yr 7)
201 / 668 65% (61,69)
20%
Deaths / N
Estimate
f) TT2 OS (Yr 8)
232 / 668 66% (62,70)
a) TT3 OS (Yr 1)
7 / 146
91% (85,98)
g) TT2 OS (Yr 9)
263 / 668 66% (63,70)
b) TT3 OS (Yr 3)
36 / 303
84% (79,90)
h) TT2 OS (Yr 10)
287 / 668 66% (63,70)
c) TT3 OS (Yr 5)
67 / 303
72% (62,81)
0%
0%
0%
0
3
6
9
12
15
0
3
6
9
12
15
0
3
6
9
12
15
Years from Enrollment
Years from Enrollment
Years from Enrollment
S9321
SWOG S9321 Overall Survival Outcomes
First Patient Enrolled Februrary 4, 1994
100%
NO CHANGE IS
5-Year
Deaths / N
Estimate
a) S9321 OS (Yr 1)
3 / 81
95% (89,100)
80%
b) S9321 OS (Yr 3)
75 / 385
64% (56,72)
c) S9321 OS (Yr 5)
201 / 667
45% (37,53)
d) S9321 OS (Yr 6)
273 / 761
45% (38,51)
OBSERVED
e) S9321 OS (Yr 7)
349 / 817
45% (40,49)
60%
f) S9321 OS (Yr 8)
419 / 817
43% (39,47)
g) S9321 OS (Yr 9)
482 / 817
43% (39,46)
h) S9321 OS (Yr 10)
511 / 817
44% (40,47)
AS DATA MATURE
40%
20%
FROM YR 1 - YR 10
0%
0
3
6
9
12
15
Years from Enrollment
IFM90 Overall Survival Outcomes
IFM94 Overall Survival Outcomes
IMF90
IMF94
IMF99-02
First Patient Enrolled January 6, 1990
First Patient Enrolled July 15, 1994
100%
5-Year
100%
5-Year
100%
Deaths / N
Estimate
Deaths / N
Estimate
a) IFM90 OS (Yr 1)
1 / 30
92% (78,100)
a) IFM94 OS (Yr 1)
4 / 128
91% (81,100)
80%
b) IFM90 OS (Yr 3)
19 / 171
80% (72,89)
80%
b) IFM94 OS (Yr 3)
76 / 402
70% (64,77)
80%
c) IFM90 OS (Yr 5)
71 / 194
48% (37,60)
c) IFM94 OS (Yr 5)
169 / 402
45% (36,54)
d) IFM90 OS (Yr 6)
92 / 194
42% (32,51)
d) IFM94 OS (Yr 6)
202 / 402
45% (39,51)
e) IFM90 OS (Yr 7)
107 / 194
42% (33,50)
e) IFM94 OS (Yr 7)
236 / 402
44% (39,49)
60%
f) IFM90 OS (Yr 8)
119 / 194
43% (36,50)
60%
f) IFM94 OS (Yr 8)
259 / 402
44% (39,49)
60%
g) IFM90 OS (Yr 9)
133 / 194
43% (36,50)
g) IFM94 OS (Yr 9)
270 / 402
44% (39,49)
h) IFM90 OS (Yr 10)
138 / 194
43% (36,50)
h) IFM94 OS (Yr 10)
279 / 402
44% (39,49)
5-Year
Deaths / N
Estimate
40%
40%
40%
a) IFM99 OS (Yr 1)
0 / 122
100% (100,100)
b) IFM99 OS (Yr 3)
17 / 455
91% (86,96)
c) IFM99 OS (Yr 5)
71 / 540
71% (61,81)
20%
20%
20%
d) IFM99 OS (Yr 6)
104 / 540
75% (70,79)
e) IFM99 OS (Yr 7)
129 / 540
77% (73,80)
f) IFM99 OS (Yr 8)
160 / 540
76% (72,80)
g) IFM99 OS (Yr 9)
161 / 540
76% (72,80)
0%
0%
0%
0
3
6
9
12
15
0
3
6
9
12
15
0
3
6
9
12
15
Years from Enrollment
Years from Enrollment
Years from Enrollment
LONG-TERM FOLLOW-UP OF IFM90/94,
S9321 & TOTAL THERAPY PROTOCOLS
IFM 90 - Survival
IFM 94 Survival
100%
100%
80%
80%
Double Transplant (144 / 203)
Single Transplant (73 / 96)
60%
Single Transplant (159 / 199)
Standard Therapy (87 / 98)
60%
40%
40%
20%
20%
P = 0.005
P = 0.08
0%
0%
0
5
10
15
20
0
5
10
15
Years from Registration
Years from Registration
TT - Survival
S9321 - Survival
100%
100%
80%
TT3 (61/303)
80%
Standard Therapy (197 / 285)
Transplant (190 / 290)
60%
TT2 + THAL (123/323)
60%
40%
TT2 - THAL (164/345)
40%
TT1 (61/303)
20%
P = 0.03
20%
P = 0.35
0% 0
5
10
15
20
0%0
5
10
15
Years from Registration
Years from Randomization
SURVIVAL BENEFIT FROM THALIDOMIDE
IN TANDEM TRANSPLANT SETTING
IFM 99-02 +/- Thal Survival*
TT2 +/- Thal Survival
100%
100%
TT3 (61/303)
80%
80%
TT2 + Thal
60%
60%
(123/323)
No Maintenance (48 / 172)
TT2 - Thal
40%
Pamidronate (55 / 173)
40%
(164/345)
20% Pamidronate + Thalidomide (47 / 179)
20%
Thal v no Thal:
Thal v no Thal: P=0.39
P =0.03
TT1 (61/303)
0%
0%
0
2
4
6
8
0
5
10
15
20
Years from Maintenance Randomization
Years from Registration
NO BENEFIT APPARENT WHEN
BENEFIT APPARENT WHEN
EMPLOYED AS MAINTENANCE
EMPLOYED FOR INDUCTION
* Subset with available FISH data (88%)
PREMATURE REPORTING OF MYELOMA TRIALS
Lessons from Total Therapy 2 +/- Thalidomide
RE-ITERATING SURVIVAL ANALYSES
Survival Outcomes at Year 1
Survival Outcomes at Year 3
Survival Outcomes at Year 5
100%
+ Thal: 1 / 54
100%
100%
- Thal: 4 / 58
+ Thal: 21 / 183
80%
80%
- Thal: 25 / 198
80%
+ Thal: 65 / 299
60%
- Thal: 60 / 317
60%
60%
40%
40%
40%
20%
Log-rank P-value = .20
20%
Log-rank P-value = .68
20%
Log-rank P-value = .41
0%
0%
0%
0
3
6
9
12
15
0
3
6
9
12
15
0
3
6
9
12
15
Years from Enrollment
Years from Enrollment
Years from Enrollment
Survival Outcomes at Year 6
Survival Outcomes at Year 7
Survival Outcomes at Year 8
100%
100%
100%
80%
80%
80%
+ Thal: 82 / 323
+ Thal: 95 / 323
+ Thal: 106 / 323
60%
60%
60%
- Thal: 78 / 345
- Thal: 106 / 345
40%
40%
40%
- Thal: 126 / 345
20%
Log-rank P-value = .40
20%
20%
Log-rank P-value = .81
Log-rank P-value = .45
0%
0%
0%
0
3
6
9
12
15
0
3
6
9
12
15
0
3
6
9
12
15
Years from Enrollment
Years from Enrollment
Years from Enrollment
Survival Outcomes at Year 9
Survival Outcomes at Year 10
100%
100%
NOTE THE LATE
80%
80%
+ Thal: 116 / 323
+ Thal: 123 / 323
60%
60%
DIVERGENCE OF
40%
- Thal: 147 / 345
40%
- Thal: 164 / 345
SURVIVAL CURVES
20%
Log-rank P-value = .16
20%
Log-rank P-value = .04
AFTER 5 YEARS
0%
0%
0
3
6
9
12
15
0
3
6
9
12
15
Years from Enrollment
Years from Enrollment
TT2/3 & IFM99-02 CONFER SUPERIOR SURVIVAL
Overall Survival
Analysis
Variable
Percent
HR
P-value
Univariate
TT 1
7
0.98
0.838
TT 2/3
28
0.61
<.001
SWOG 9321
23
1.60
<.001
IFM 90/IFM 94
17
1.43
<.001
IFM 99-02
25
0.68
<.001
Age > 60 yr
28
1.34
<.001
Albumin < 3.5 g/dL
27
1.42
<.001
B2M > 3.5 mg/L
44
1.80
<.001
B2M > 5.5 mg/L
22
1.94
<.001
Hb < 10 g/dL
35
1.59
<.001
LDH > ULN
30
1.41
<.001
Multivariate
TT 2/3
31
0.52
<.001
N=3077
SWOG 9321
24
1.09
0.172
IFM 99-02
22
0.53
<.001
Age > 60 yr
28
1.47
<.001
Albumin < 3.5 g/dL
26
1.15
0.011
B2M > 3.5 mg/L
43
1.43
<.001
Hb < 10 g/dL
34
1.18
0.002
LDH > ULN
30
1.42
<.001
LONG-TERM FOLLOW-UP OF IFM, S9321 & TT
Pair-mate Analyses (Albumin, B2M, LDH, Hemoglobin)
Overall Survival
Event-free Survival
100%
100%
80%
TT3 (61 / 301)
80%
TT3 (80 / 301)
P=0.24
60%
60%
TT2 (127 / 301)
P<0.001
40%
P=0.007
40%
TT2 (182 / 301)
P<0.001
20%
20%
TT1/IFM/S9321 (183 / 301)
TT1/IFM/S9321 (236 / 301)
0%
0%
0
5
10
15
20
0
5
10
15
20
Years from Start of Treatment
Years from Start of Treatment
NOTE THE PROGRESSIVELY SUPERIOR OUTCOMES
OBSERVED WITH TT3 > TT2 > TT1 AND OTHER TRIALS
RELATIVE SURVIVAL RATIOS FOR TT PROTOCOLS
NOTE THE
TT3
TT2
TT1
PROGRESSIVELY
?
FASTER RECOVERY
OF RELATIVE
SURVIVAL RATIOS
WITH TRANSITION
FROM
TT1 TO TT2 TO TT3
YEARS
The relative survival ratio is the observed survival in the patient group
divided by the expected survival of a comparable group from the general
population.
A ratio of 1 indicates that the observed survival is equal to the expected
survival.
Annual (interval specific) ratios are shown.
MODELING FOR CURE IN MULTIPLE MYELOMA
A Reality with TT3 in Low-Risk Disease?
TT3 low-risk
TT3 high-risk
Cure
Cure
TT3
N
Fraction
P Value
TT3
N
Fraction
P Value
Low-risk
235
0.74
0.06
High-risk
40
0.00
1.0
CONCLUSIONS
· Long-term follow-up
· Comparing TT1 to TT2 to
revealed:
TT3 trials:
­ Stable survival curves in
­ Relative survival rates
re-iterative analyses
recovered progressively
­ Exception was late
earlier (from 0.9 to 1.0
segregation of TT2+thal
and above) at 17yr, 10yr
from TT2-thal at 5 years
and 5yr
· Cure fractions projected:
· Relative survival rates
­ 8.5% in S9321 (P<0.001)
above 1.0 may reflect:
­ 9.0% in TT1 (P=0.002)
­ Closer medical
­ 8.5% in TT2 (P<0.05)
supervision of patients v
general population
­ 74% in TT3/low-risk
(P=0.06)
­ Rejuvenating effects of
therapy or autograft
· Thalidomide's benefit in maintenance of IFM99-02 not
confirmed but evolving over 5 years when used for
induction & maintenance in TT2
THANKS TO
· Patients for wanting and enduring
· Caregivers for their love and
support
· Referring MD's for embracing
clinical research
· IFM, SWOG, ECOG investigators
·NIH
· IMF, MMRF, individual donors
Overall Survival by Thalidomide
and Cytogenetic Abnormalities
100%
80%
Thalidomide/no CA
60%
Control/no CA
40%
Thalidomide/CA
P=0.02
20%
Blood 2008
Control/CA
0% 0
2
4
6
8
10
Years from start of treatment