Rafael Fonseca MD
Mayo Clinic
Role of FISH in Myeloma Risk Stratification
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Disclosures
The talk is greatly biased in
favor of FISH
CME activities funded by Celgene,
yg
Millennium.
Consulting Genzyme, AMGEN, Halozyme
Research support Pfizer
Classification Schemes
Schemes
· BIOLOGY CLASSIFICATION
(chr 13)
· Pathophysiologic
· Progression events
(MGUS)
· PROGNOSTIC CLASSIFICATION
(hyperdipl)
· Bl
Base iline features
· Natural history
· Therapy independent
independent
· PREDICTIVE CLASSIFICATIONS
(bor, len)
len)
· Therapy specific
What is the value of
of FISH
FISH in
in 2009?
· Et
Es i
timati
tion of outcome?
· Selection/sequence of
treatment?
· Targeted therapy?
· Clinical trial evaluation?
· What is really the true value?
Molecular Prognostic Model
Model
1.0
All others including
lity
P<0.001
t(11;14)
t(1
l 08
0.8
13
robabi 0.6
Poor
24.7 mos
p
Intermediate
42.3 mos
Good
51.0 mos
0.4
rvival
Su
t(4;14)
0.2
t(14;16)
-17p13
-
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Months
Fonseca et al Blood 101:4569, 2003
SCTa
SCT nd
and PFSi
PFS np
in atients
patients witht
with (4;14)
t(4;14)
Gertz, M. A. et al. Blood 2005;106:2837-2840
IFM: SCT in
in patients
patients with
with t(4;14)
Avet-Loiseau, H. et al. Blood 2007;109:3489-3495
p53 in Relapsed MM
Overallll
i
surv val and p53 d l
e ti
e ons/
t
mu ti
a ons in
l
re apse MM patients
1.0
Log Rank
OS for relapse/refractory
py
.8
P=0 0155
.
MM patients with or
p53 deletion
without p53 deletion was
.6
4.2 months vs 37.8
p 0
015
.
no p53 deletion
months, p <0.01
Per Cent
.4
.2
0.0
0
12
24
36
48
60
72
84
96
months
Chromosome 1 in
in MM
MM
Hanamura, I. et al. Blood 2006;108:1724-1732
Fonseca et al Leukemia (2006) 20, 20342040
VISTA Trial
Trial
High Risk FISH: t(4;14)(p16;q32), t(14;16)(q32;q23), or 17p-
Best M-protein
Tot
To al
High Risk
Std Risk
Risk
Response, n
(%)
(N=165)
(N=26)
(N=139)
CR (IF-)
32%
35%
32%
PR
82%
81%
82%
TTP
OS
VMP standard risk
VMP standard risk
VMP high risk
VMP high risk
VMP standard risk (N=142): 23.1 months (34 events)
VMP standard risk (N=142): not reached (16 events)
VMP high risk (N=26): 19.8 months (7 events)
VMP high risk (N=26): not reached (3 events)
HR = 1.297 (95% CI: 0.55, 3.06)
HR = 1.009 (95% CI: 0.278, 3.663)
Impact of Hi Risk Features on Outcome of
of
Newly Diagnosed MM on Lenalidomide + Dex
100 patients treated with Len/Dex 3/04 -> 11/07
16 w/Hi Risk features:
del 13 CC, t(4
( ;14),t
), (14
( ;1
; 6) FISH
S , PCLI
C 3%
VGPR
PR
OS
PFS
All
nr
31mo
STD
45%
89%
37
HI
38%
81%
19
11
Kapoor et al. ASH 2008, abstract #95
How Bad
Bad Does "High Risk
-
"
Risk Have to Be?
100
90
80
70
Omics
60
Need better treatments
treatments
50
FISH
Bad versus really bad MM
40
ISS
Sequencing issues
30
2m
20 IgA
10
10
20
30
40
50
60
70
80
90 100
The Future: conversion
of GEP to FISH
Combination of probes
Chromosome 1p del
Chromosome 1q amp
Other
Translocations
The Future: conversion
of aCGH to FISH
Chromosome 1q amp
Chromosome 12 del
Chromosome 5 amp
TRAF deletion
LTBR amp
IgH Locus
The Future ?
"Unbiased testing"
30K genes in
in
1 patient
Identify Genes
1-20+
Keats JJ, et al. Cancer Cell. 2007;12:131-144
Prediction TRAF3 and Bortezomib Sensitivity
Low TRAF3 (<
(< 0.6)
p100
CR+PR
p52
Dexamethasone
4/20
10%
Bortezomib
18/19
89%
100
Dexamethasone
80
Bortezomib
NFKB1 CEP4
60
40
20
0 0
100
200
300
400
500
Time
PFS 83d vs 193d (p<0.0001)
Keats JJ, et al. Cancer Cell. 2007;12:131-144
Diagnostic Zebras
Zebras
p53 pathway
n
pPCL
sPCL
p
Allelic p53 mutation
25
25
23
-
Allelic p53 deletion
20
50
75
0.37
Combined
15
56
83
0.58
Placebo
60mg/kg
30mg/kg
Diploid MM
MM
IgM MM (>95%)
LP morphology
AL amyloidosis (50%)
PCL (50%)
FISH vs. CHIPs
Features
FISH based
Genomic based
Power to predict outcome
++
+++/++++
Clinical test
Yes
Not yet
Information obtained
Limited
Global genomics
Expense
Similar
Similar*
Can do overnight testing?
Yes
Yes
Can be done by smal er laboratories?
No
No
Ease of interpretation
Simple
Moderate**
Number of cells needed for analysis
100
>100,000
Requires cel enrichment/purification?
No for cIg
Yes
Suitable for cases of minimal plasmacytosis?
Yes
No
Number of cases with informative results
Most (>90%)
()
Low (<50%)
()
Covered by insurance
Yes
No
Level
FISH tests
Recommended
Validation
testing frequency
Minimal proposed testing (essential testing)
Established
Primary events
Once
Validated by
markers
several studies
t(4;14)(p16;q32)
t(14;16)(q32;q23)
Progression
Can be repeated
Validated by
events
several studies
Recommended
17p deletion
FISH Testing
Expanded panel
FISH Testing
Markers with
Hyperdiploidy
Once
Almost always
modest effects
favorable but
t(11;14)(q13;q32)
weak effect
Chromosome 13
May be repeated
Always negative
but effect weak
Emerging markers
Other
Other
Once
Rare events and
translocations
not routinely
tested
Chromosome 1
1q deletion
May be repeated
While conflicting
studies, seem to
1p amp
predict outcome
SNP/aCGH
16q deletion
May be repeated?
Data not validated
yet. Could
12p deletion
convert markers of
aCGH and SNP
5q amplification
into FISH testing
Proverbial Table 1
Bottom line FISH
FISH testing
testing
· Needs to be done on sorted cells
· cIg (unreliable if only done with nuclei)
· CD138 sorting
· Panel approach
approach
· Minimal panel t(4;14)(p16;q32), 14;16 and -17
· Can be expanded
· PROS
· easy, GLP, CLIA, clear answers, reference lab
· With enough cells near perfect (20 100
-
cells)
· CONS
· Limited answers
mSMART : Classification of
of Active
Active MM
MM
High Risk
-
(25%)
Standard Risk
-
(75%) *
FISH
Del 17p
All others including:
t(4;14)*
Hyperdiploid
t(14;16)
t(11;14)
t(1
Cytogenetic Deletion 13
t(6;14)
Cytogenetic Hypodiploidy
PCLI >3%
>
*P ti
a
t
en s i
w th
ith t(4 14)
;
, 2M<4
/l
mg
d
an Hb
Hb 10 /dl
g
may have i t
n
di
erme
t
a e irsk di
disease
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Revised and updated: January 2008
mSMART Off-Study
Transplant Eligible
High
g Risk
Standard Risk
4-6 cycles of bortezomib
4 cycles of Rd*
containing regimen (CBD, VRd, VTD etc)
Collect Stem Cells**
Collect Stem Cells
If not in CR, consider autologous stem
Autologous stem cell
OR
Continue
cell transplant (ASCT)
transplant (ASCT)
Rd
All pati
ti
t
en s receive Rd
Rd
If not in CR/VGPR after
til
If not in CR/VGPR
until
progression
1st ASCT, consider
consolidation (eg.,
second ASCT or IMiD)
* Bortezomib containing regimens preferred in
renal failure
failure or if rapid response
response needed
needed
Continuing Rd is an option for patients
(**If age >65 or > 4 cycles of Rd
responding well to induction with low toxicities;
Consider G-CSF plus cytoxan or plerixafor )
Dex is usually discontinued after first year
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009
mSMART Off-Study
Transplant Ineligible
High Risk
Standard Risk*
MP + Bortezomib**
MP + Thalidomide** or Rd
Observation
Ob
i
servat on
*Bortezomib containing regimens preferred in
renal failure or if rapid response needed
Continuing Rd is an option for patients
responding well to induction with low toxicities;
** In patients in whom administration of
Dex is usually discontinued after first year
thalidomide or bortezomib is of concern,
consider MP or Rd
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009
That cool guy
Time to Collect a Bet
is me!
Time to Collect a Bet
Leif
Mike Kuehl
One size does not fit all!
all!