Rafael Fonseca MD
Mayo Clinic, Scottsdale, AZ
Clinical and Pathological
Pathological Implications
of Myeloma Subtypes
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Classification schemes
· Biology classification (chromosome 13)
Pathophysiologic
Progression events (MGUS)
()
· Prognostic classification (hyperdiploidy)
Bl
Base iline features
Natural history
Therapy independent
· Predictive classifications
classifications (novel agents)
Therapy specific
Interaction Between Host and Genetic Factors
A.
Disease course (years)
B.
Host factors
C.
Genetic factors
D.
Progression factors
E.
Intramedullary
Extramedullary
disease
progression
F.
Classification of
of MM
MM
Bone
Ploidy
Prognosis
H
/
Morph
CD20
ras
-13
CCND
DKK1
t(11;14)
NH
Good
G
LPL
+++
++
-/+
++
D1
(CCND3)
D3
t(14;16)
NH
Poor
A
PB
-
-
++
+/-
D2
(other MAF)
t(4;14)
NH/h
Poor
A
PB
-
-
+++
+/-
D2
/
Other IgH
H/NH
Poor
?
?
/
?
?
?
--/+
?
+
Hyper
H
Good
G
Mature
-
++
+/-
++
D1>D2
Author
Year
N
Rx
OS (mos)
EFS (mos)
p-Value
Assay
Avet-Loiseau 17
2007
100/714 (14%)
HDT
41 vs
79
21 vs
66
<0.0001
FISH
<0.0001
Gutierrez18
2007
29/260 (11%)
HDT
24 vs
48
NA
<0.0001
FISH
Gertz19
2005
26/153 (17%)
HDT
19 vs
44
NA
0.001
FISH
Fonseca15
a
2003
42/332 (15%)
Conv.
26 vs
45
17 vs
31
<0.01
FISH
<0.01
Moreau20
2002
22/168 (13%)
HDT
23 vs
66
21 vs
29
<0.0001
FISH
0.002
Keats21
2003
31/208 (15%)
Conv/HDT
21 vs
NA
NA
0.003
RT-PCR
Chang22
2004
15/120 (13%)
HDT
18 vs
48
10 vs
26
<0.0001
FISH
0.0003
Dewald23
ld
2005
10/154 (7%)
Vi
Various
13 vs
45
NA
00
<0. 1
01
FISH
Cavo24
2006
17/63 (27%)
HDT
NA
23 vs
30
0.01
RT-PCR
FISH
Chiec
e cio25
cio
2006
28/535 (5%)
Various
9
vs. 41
NA
<0.001
Karyotype
85/729 (12%)
19 vs. NR
NA
0.004
FISH
59/490 (11%)
19 vs. 44
NA
0.002
Combined
Chang26
2005
16/85 (19%)
HDCTX
19 vs
46
12 vs
26
<0.01
FISH
<0.01
IHC
Ploidy and Chromosome 13
Bone
Ploidy
Prognosis
H
L
Morph
CD20
ras
-13
CCND
DKK1
t(11;14)
NH
Good
G
LPL
+++
++
-/+
++
D1
(CCND3)
D3
t(14;16)
NH
Poor
A
PB
-
-
++
+/-
D2
(other MAF)
t(4;14)
NH/h
Poor
A
PB
-
-
+++
+/-
D2
Other IgH
H/NH
Poor
?
?
?
-
-/+
?
+
?
Hyper
H
Good
G
Mature
-
++
+/-
++
D1>D2
Prognosis for Hyperdiploidy
1.0
Log Rank Test p=0.47
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
10
20
30
40
50
60
70
80
90 100 110 120 130 140 150 160 170
Time in Months
del13hyp
TOTAL
DEAD
ALIVE
MEDIAN
No
65
63
2
49.8
Yes
43
41
2
46.7
Chromosome 13 importance?
· Most common abnormality/monosomy
· Associations with prognosis
· Contains Rb
Biallelic d l
e t
e i
tions
· Clonally selected
· Never trisomy
· Increases incidence with progression
pg
Molecular Prognostic Model
1.0
All others including
t(11;14)
P<0.001
ity 08
0.8
13
0.6
robabil
Poor
24.7 mos
rp
Intermediate
42.3 mos
Good
51.0 mos
0.4
ivalv
t(4;14)
Sur 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
Identification of Candidate Deleted Genes
MDR (N=54)
Genes with dosage
dependence
(N=26 pt
pt and
and 42 HMCL)
Genes bi-allelically
deleted
Candidate Gene
8.4 Mb overlapping region - 40
genes (RB1, RFP2, DLEU1/2/7)
RB1 can explain transcription profile of 13
Te
Test
st Set (N=26)
(N=26) - t(4;14) and maf translocations
translocations exclude, other TC class equally
distributed between chromosome 13 deleted and non-deleted samples
79 genes up-regulated in 13
73 genes up-regulated in non- 13
Validation Set (N=72) - Include t(4;14) and maf translocations)
Genes up-regulated in
13 are enriched for
E2F targets and cell
cycle genes
= RB1
Strong correlation between RB gene copy
and protein
protein expression in MM
Nl
Normal
Ml
Monoa lllelilic
Bi ll
a
li
e c
Primary patient samples
Rb Effects on Cell Growth
None category
Evidence of RB haploinsufficiency in
Animal Models
·D ff
eficiency of RB1 in mouse embryonic
stem cell leads to genetic instability
(Zheng et al Cancer Res 2002; 62:
2498-2505)
·
Tumorigenesis in Drosophila (Ferres-
Marco et
et al
al Nature
Nature 2006; 439: 430-436)
436
·
Accelerate Lymphoma development in
Emu-Myc mice
mice (Schmitt et
et al
al Genes
Genes
Dev 1999; 13: 2670-2677)
Hyperdiploid
Genetic prognostic
prognostic factors
factors
125
Cluster 1
100
Cluster 2
Cluster 3
75
Cluster 4
50
25
0
0
250
500
750
1000
1250
Survival (days)
Role of Novel Therapy; Bortezomib
. Del(13) Associated With Poor Survival in
Del(13) Has No Impact on Survival in
Patients Tr
T eated
r
With
With Dexamethasone
Patients Tr
T eated Wi
With
th Bortezomib
No deletion
Del(13)
()
No
(N 24)
=
(N=9)
deletion
(N=17)
Del(13)
()
(N=12)
HR=1.61 (95% confidence interval, 0.35,
HR=9.31 (95% confidence interval,
7.46); P=
P NS
188 4606); P=0 0020
1.88, 46.06); P=0.
Jagannath et al Leukemia. 2007;21:151.
t(11;14)(q13;q32)
t(4;14)(p16;q32)
Hyperdiploidy
1X1012
1X10
t(14;16)(q32;q23)
1X1011
1X1010
1X109
1X103
Origin
MGUS
SMM MM
Acknowledgements
MAYO
Technologists
TGEN
P. Leif Bergsagel
Greg Ahmann
Jeff Trent
A Keith Stewart
Scott Van Wier
Catherine Mancini
Marta Chesi
Tammy Price-Troska
John Carpten
Phil Greipp
Rachel Rempel
Angela Baker
Robert Kyle
Kim Henderson
Seungchan Kim
Craig Reeder
Jennifer Himes
Tae-Hoon Chng
Dysproteinemia Group
Jennifer Little
Michael Barret
Chang-
g Xin Shi
Fellows and Post Docs
Yuan-Xiao Zhu
Millennium Pharmaceuticals
Jonathan Keats
Homer Fogle
Barb Bryant
Wee-Joo Chng
George Mulligan
Rodger Tiedeman
ECOG
Michael Sebag
Brian Van Ness
Agilent
Esteban Braggio
Martin M Oken
Laurakay Bruhn
Azzah Al Masri
Travis Henry
Cytogenetics
NCI
Rld
Roelan t
dt Schop
Syed Jalal
Mike Kuehl
Natalia Gonzalez
Rhett Ketterling
Rafael Santana
Dana Farber
Ken Anderson