FISH improves the prognostic value
of the ISS: an IMWG study
Hervé AVET-LOISEAU, MD, PhD
Center for Research in Myeloma
Nantes, France
France
The International Staging System (ISS)
Prognostic model based on 2m and albumin
Overall Survival by ISS-
ISS Validation Set
100%
Median
Deaths / N in Months
Stage I
606 / 1111 62 (58,65)
80%
Stage II
1054 / 1606 44 (42,48)
Stage 1: 2m < 3.5 & alb < 35
Stage III
968 / 1305 29 (26,32)
60%
Stage 2: others
40%
Stage 3: 2m > 5.5
20%
0%
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
FISH predicts outcome in myeloma
Prognostic impact of t(4;14) and del(17p)
p=2.10-8
p=4.10-12
Impact of t(4;14) on OS
Impact of del(17p) on OS
Avet-Loiseau et al., Blood 2007;109:3489
IMWG analysis
Patient enrolment
Country (study)
Any CA
Hypodip
Hyperdip
Deletion 13
t(4;14) FISH
Deletion 13FISH
Deletion17FISH
t(14;16)
t(11;14)
Total
Argentina
34
34
34
34
0
0
0
0
0
34
Ark
Ar a
k n
a s
n a
s s
a (TT2
(T ,TT3
TT )
3
1136
11
1136
11
1136
11
113
11 6
3
0
536
53
0
0
0
1148
11
Berlin
76
76
76
76
3
41
36
4
6
104
Canada
0
0
0
0
0
0
0
0
0
584
Czech Republic
149
149
149
149
102
175
104
0
135
618
ECOG(E9487)
0
0
0
0
325
377
0
52
326
538
Heidelberg
0
0
0
0
120
143
127
0
137
543
Hovon(24, 50)
582
0
0
582
0
295
0
0
0
978
IFM(99)
0
0
0
0
673
884
787
0
703
889
Italy
0
0
0
0
0
32
0
0
0
135
Korea
318
318
278
320
106
326
187
66
132
359
Nordic
0
0
0
0
0
0
0
0
0
754
SWOG(S9321)
0
0
0
0
0
172
00
0
817
Spain(GEM)
0
0
0
0
224
245
245
244
244
2396
Total
2295
1713
1673
2309
1573
3226
1486
366
1683
9897
IMWG analysis
Distribution of abnormalities
Vari
Va ab
a le
Yes
Ye
No
Tota
To l
%
Any CA
765
1530
2295
33%
Hypodiploidy
162
1551
1713
9.5%
Hyperdiploidy
275
1398
1673
16%
Deletion 13
294
2015
2309
12.7%
t(4;14) FISH
199
1374
1573
12.6%
Deletion 13 FISH
1380
1846
3226
43%
Deleti
t on 17
17 FI
FISH
S
121
1365
1486
8%
t(14;16) FISH
10
356
366
2.7%
t(11;14) FISH
316
1367
1683
19%
IMWG analysis
Prognostic impact of any chromosomal abnormality
Event-free survival by Cytogenetic abnormalities
Overall survival by Cytogenetic abnormalities
100%
4-Year
100%
4-Year
Events / N
Estimate
Deaths / N
Estimate
a -CA
776 / 1515 67% (64,69)
a -CA
513 / 1514 73% (70,75)
80%
b +CA
488 / 758 52% (48,55)
80%
b +CA
370 / 758 57% (53,61)
Logrank P-value < .0001
Logrank P-value < .0001
60%
60%
40%
40%
20%
20%
0%
0%
0
5
10
15
0
5
10
15
Years from start of treatment
Years from start of treatment
IMWG analysis
Prognostic impact of t(4;14)
Event free
-
survival by t(4;14)
Overall survival by t(4;14)
100%
100%
4-Year
4-Year
Events / N
Estimate
Deaths / N
Estimate
a -t(4;14)
1014 / 1371 60% (57,63)
a -t(4;14)
697 / 1371 64% (61,66)
80%
b +t(4;14)
179 / 199 32% (25,38)
80%
b +t(4;14)
141 / 199 36% (29,43)
Logrank P-value < .0001
Logrank P-value < .0001
60%
60%
40%
40%
20%
20%
0%
0%
0
5
10
15
0
5
10
15
Yf
Years from start of treatment
Yf
Years from start of treatment
IMWG analysis
Prognostic impact of t(4;14) with ISS
Overall survival by ISS and t(4;14)
P-values: a v b<0.0001, c v d<0.0001, e v f=0.007
100%
80%
60%
4-Year
40%
Deaths / N
Estimate
a ISS I/-t(4;14)
106 / 402 81% (76,84)
b ISS I/+t(4;14)
26 / 48
52% (37,66)
20% c ISS II/-t(4;14)
330 / 568 63% (59,67)
d ISS II/+t(4;14)
75 / 96
30% (21,40)
e ISS III/-t(4;14)
219 / 319 44% (38 49)
,
f ISS III/+t(4;14)
33 / 39
22% (8,35)
0%
0
5
10
15
Years from start of treatment
IMWG analysis
Prognostic impact of del(17p)
Event-free survival by FISH 17
Overall survival by FISH 17
100%
4-Year
100%
4-Year
Events / N
Estimate
Deaths / N
Estimate
a -FISH 17
926 / 1362 63% (61,66)
a -FISH 17
526 / 1362 68% (66,71)
80%
b +FISH 17
94 / 121 42% (32,51)
80%
b +FISH 17
72 / 121 44% (35,54)
Logrank P-value < .0001
Logrank P-value < .0001
60%
60%
40%
40%
20%
20%
0%
0%
0
5
10
15
0
5
10
15
Years from start of treatment
Years from start of treatment
IMWG analysis
Prognostic impact of del(17p) with ISS
Overall survival by ISS and Deletion 17 by FISH
P-values: a v b 0
= 02
. , c v d<0 0001
.
, e v f 0
= 02
.
100%
80%
60%
4-Year
40%
Dt
Dea h
ths / N
Et
Es itimate
a ISS I/-Del 17
137 / 520 81% (77,84)
b ISS I/+Del 17
14 / 35
64% (47,80)
20% c ISS II/-Del 17
185 / 470 68% (63,72)
d ISS II/+Del 17
25 / 37
42% (26,59)
e ISS III/-Del 17
159 / 273 48% (42,55)
f ISS III/+Del 17
27/3
27 / 9
39
28% (13 43)
,
0%
0
5
10
15
Years from start of treatment
IMWG analysis
Prognostic impact of t(4;14)/del(17p) with ISS
Overall survival by ISS and t(4;14) or del17 by FISH
P-values: a v b<0.0001, c v d<0.0001,
,, e v f=0.002
100%
80%
a . ISS 1 /N o rmal
80 /31 7
8 2% (78 ,86 )
b. ISS 1/t(4;14 ) or del 17 by FIS H
37 /79
53% (47,70 )
c. ISS 2/N orma l
11 3/293
6 8% (63,74 )
60%
d. ISS 2 /t(4 ;14 ) or d el 1 7 b y FIS H
92 /12 4
3 5% (27 ,44 )
e. ISS 3/Normal
10 3/173
49% (41,58 )
f. ISS 3 /t( 4;14 ) or d el 17 b y FISH
54 /72
2 7% (16 ,38 )
40%
20%
0%
0
5
10
15
Years from start of treatment
IMWG analysis
Prognostic impact of t(4;14)/del(17p) with ISS
Overall survival by ISS and t(
y(4;14) or del17 by FISH
P-values: a v b<0.0001, a v c<0.0001, b v c<0.0001
4-year
100%
Deaths/N
estimate
a ISS I or ISS II and Normal FISH
193/610
76% (72,79)
b ISS I and Abnormal FISH/ISS III and Normal FISH
140/252
52% (45,58)
80%
c ISS II or ISS III and Abnormal FISH
146/196
32% (26,39)
60%
40%
20%
0%
0
5
10
15
Years from start of treatment
IMWG analysis - Conclusion
FISH t(4;14) and del(17p) are prognostic
Independent of the ISS
3 groups of patients:
· ISS 1 or 2-No FISH abnormality
· SS
I
3-No
S/
FISH abn / S
I S
SS 1
S
-FI H abn
· ISS 2 or 3-FISH abnormality
Herve Avet-Loiseau1, Brian G.M. Durie2, Jeff Haessler3, John Crowley3, Antje Hoering3, Bart Barlogie4,
John Shaughnessy4, Orhan Sezer5, Chaim Shustik6, Roman Hajek7, Hartmut Goldschmidt8, Pieter
Sld9 Phili
M
10 Mi h l Att l11 At
i P l
b 12 Mi B
d
12 JH
L
13
Sonneveld9, Philippe Moreau10, Michel Attal11, Antonio Palumbo12, Mario Boccadoro12, Jae Hoon Lee ,
Norma Guttierez16, Jesus San Miguel16, Joan Blade17, Juan Lahuerta18, Santiago Pavlovsky19, Dorotea
Fantl20, S. Vincent Rajkumar21 and Rafael Fonseca22
1Institute de Biologie, Nantes, France, 2Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA,
3Cancer
Cance Resear
Resea ch
rch and Biostatistics
Biostatistics, Seattle
Seattle, WA
WA, USA 4
USA, University of Arkansas
Arkansa for Medical
Medical Sciences
Science , Little Rock
Rock, AK
AK, USA 5
USA, Charite University
University Hospital
Hospital, Berlin
Berlin,
Germany, 6Royal Victoria Hospital/McGill University, Montreal, Quebec, Canada, 7University Hospital Brno, Brno, Czech Republic, 8University of Heidelberg,
Heidelberg, Germany, 9Erasmus MC, Rotterdam, Netherlands, 10University Hospital, Nantes, France, 11Hopital Purpan, Toulouse, France, 12Universita di Torino,
Torino, Italy, 13Gachon University Medical School/Gil Hospital, Incheon, Korea, 14Sahlgrenska University Hospital, Gothenburg, Sweden, 15Malmo University
Hospital, Malmo, Sweden, 16Universidad de Salamanca, Salamanca, Spain, 17Hospital Clinic, Barcelona, Spain, 18Hospital Universitario, Madrid, Spain,
19Fundaleu, Buenos Aires, Argentina, 20Hospital Italiano de Buenas Aires, Caba, Argentina, 21Mayo Clinic, Rochester, MN, USA, 22Mayo Clinic, Scottsdale, AZ,
USA