P O
. E
. M
. S
. . Syndrome
Syndrome
Angela Dispenzieri, M.D.
Mayo Clinic
June 28, 2007
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida

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POEMS Syndrome
Syndrome
· C
Fk
row-Fukase Syndrome
· Takatsuki's Syndrome
y
· P eripheral neuropathy
· O rganomegaly
· E ndocrinopathy
· Monoclonal protein
· S kin changes

---

POEMS Syndrome
Syndrome
· Hi t
s ory
· Diagnosis
· Pathogenesis
· Treatment / Outcomes
· Future Directions
Directions

---

History of
of POEMS
POEMS Syndrome
· 1956. Crow, OSM
OSM with neuriti
itis
d
an
t
o h
ther
`striking features'
· 1970s. Multiple cases, `striking features'
more likely in OSM than MM
Iwashita H (1977). Neurology 27:675-
27:675 681;
Driedger H (1979). Arch Intern Med 139:892-896.
· 1980. Bardwick, two cases, review of
literature
d
an `POEMS'
· 1980s. Two series of >100 pts from
Japan Takatsuki K (1983). Jpn J Clin Oncol 13:543-555.
Nakanishi T (1984). Neurology 34:712-720.

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POEMS Syndrome
Syndrome
· Hi t
s ory
· Diagnosis
· Pathogenesis
· Treatment / Outcomes
· Future Directions
Directions

---

Diagnosis: Illustrative Case (Mr. B)
· 40 y.o. A A
. . presenti
ts w th
ith 48
48
months of progressive neuropathy,
weight loss
-
, fatigue anasarca,
hypertrichosis, hyperpigmentation
· 1 year into symptoms, dx "CIDP,"
CIDP, no
response to PE, pred, azathioprine

---

Diagnosis: Illustrative Case (Mr. B)
48 months into symptoms
· Perih
iph
l
era
t
neuropa h
thy
· E tl
xtravascular
l
vo ume
overload (anasarca)
· Organomegaly (LA &
mild spleen)
· Sclerotic bone
· Endocrinopathy (1°
gonadal insuff. &
· Abn PFT
gynecomastia)
PFT
· Monoclonal protein
· VEGF & IL-6
(IgG lambda)
· BMPC 5%
· Skin (hyperpig, hair)
· Metaphase cyto,
t(9
( ;17
; )(q22
)(q ;q25)

---

POEMS Syndrome
Syndrome
100
100 60-96
100
90
80
%
>66 30-60
70
cted, 60
>50
~50
affe 50
40
30-50 30-90
tients 30
Pa 20
10
0
Dispenzieri A (2003) Blood. 101:2496. Nakanishi T (1984) Neurology.
Neurology 34:712. Takatsuki
T
K
(1983) Jpn J Clin Oncol. 13:543. Soubrier
Soubrier MJ (1994) Am J Me
M d 1994; 97, 543.

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POEMS Syndrome
Syndrome
· Md
Me i
dian age 51
51
· 2/3
~

· Per. neuropathy
· Papilledema
· Organomeg
gg (LN*,
(
· Edema (incl
(incl
liver, spleen)
ascites, effusions)
· Endocrine
· Sclerotic bone
· M-spike
lesions
· Skin
· Thrombocytosis
* Often Castleman's
Castleman' on biopsy

---

POEMS Survival
Survival by Number of Features
Bardwick-5
Mayo-9
100
100
2
80
3 or 4
% 80
%
4
5 or 6
60
60
rvival,
7, 8, or 9
u
5
us 40
3
Features
N
40
Features
N
verall
27
O
3
32
3 or 4
25
O
32
20
20
431
5 or 6
49
529
7, 8, or 9
25
0
0
0
20 40 60 80 100 120
0 20 40 60 80 100 120 140
Time, months
Dispenzieri et al Blood 2003; 101:2496

---

Caveats in
in Making
Making Diagnosis
Diagnosis
Diagnoses l
a ong th
the
D'
Don t
't be fl
fool d
e by...
way...
· Neg SPEP (47%)
· Chronic inflammatory
·Only IFE+ in 31%
demyelinating
·Only Bx+ in 16%
polyneuropathy (CIDP)
(CIDP)
· Benign bone lesions
· Guillian-Barré
·aneurysmal bone
· B12 deficiency
deficiency
cyst
· Myeloproliferative
·benign bone island
disorder
·non-ossifying
fibroma
·Fibrous dysplasia

---

MAJOR
1. Polyneuropathy
CRITERIA
2. Monoclonal plasma cell dyscrasia (almost always )
3. Sclerotic bone lesions
4. Castleman's disease
5. Va
V scular endothelial growth
growth factor
factor elevation
elevation
MINOR
6. Organomegaly (splenomegaly, hepatomegaly, or LA)
CRITERIA
7. Extravascular
Extravascular volume
volume overload
overload (edema, pleural
pleural eff
ef , or
or ascites)
ascites)
Over-
Under-
8. Endocrinopathy
diagnosis
diagnosis
9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid
hemangiomata, plethora
plethora, acrocyanosis
acrocyanosis, flushing, white nails)
10. Papilledema
11. Thrombocytosis / polycythemia
* Polyneuropathy and monoclonal plasma cell disorder present in all patients; to make
diagnosis at least one other major criterion and 1 minor criterion is required to make diagnosis

---

It's a
rope
It'sa
s a
It's a
tree
dagger
It's a
k
sna e

---

Peripheral neuropathy
neuropathy
9 noncompacted lamellae in
St i l
di
inner part
part of
of myelin
myelin sheath
· Symmetrical, ascending
·Occasionally painful
· Motor dominance
· Onset either insidious or
rapidly
py pro
p gressin
g
g
· High cerebrospinal fluid
protein levels
· Chronic, distal, large fiber
sensorimotor PN
· Al
Axonal & demyelili
t
na i
ting
x30,450. Taken from: Vital J of Periph
Nerv Sys (2003). 8:136-144

---

POEMS Syndrome
Syndrome
· Hi t
s ory
· Diagnosis
· Pathogenesis
· Treatment / Outcomes
· Future Directions
Directions

---

Clues to
to Pathogenesis
Pathogenesis
· Nl
Nearly l
a lll
t
pa i
tients light h
c
i
a n
restricted
· Unique blood cytokine profile
· Bone sclerosis
· Overlap with Castleman Disease (aka
angiof lli
o
l
cu ar lymph node
hyperplasia)

---

Cytogenetic Abnormalities
Abnormalities
FISH
POEMS
MGUS,
MM,
Abn
AL, %
Abn
(n=27), %
%
%
Del 13
44
25-50
33
50
t(11;14)
11
15-30
46-55
16
t(4;14)
02-10
0
15
17p-
7
Updated from Bryce et al ASCO, 2007

---

Myeloma FISH in 27 POEMS
Patients
t(
T
(
· 14 normal
Del
IgH
11;14)
t(9;15)
etratpl.
t(3;7)
l
17p-
13
Tx
16-
· 13 abn (48%)
Patient
1
2
3
·44% del 13
4
·12%
·
t(11;14)
5
6
·16% any IgH tx
7
8
·3%
·
del 17p
9
10
· None hyperdiploid
11
12
13
Updated from Bryce et al ASCO, 2007

---

Clues to
to Pathogenesis
Pathogenesis
· Nl
Nearly l
a lll
t
pa i
tients light h
c
i
a n
restricted
· Unique blood cytokine profile
· Bone sclerosis
· Overlap with Castleman Disease (aka
angiof lli
o
l
cu ar lymph node
hyperplasia)

---

Pro inflammatory
-
Cytokines Increased
Increased
in POEMS
250
POEMS, n=15
Other cytokines
200
Multiple myeloma, n=15
NOT increased:
150
· IL-4, IL-10, TGF1
pg/mL 100
levels of cytokine
50
receptors:
0
IL
· -1r, sTNFr(p55&p75)
IL-1 TNF
IL-6
IL-2
IFN
p<0.0001 p<0.005 p<0.0001
Gherardi et al, Blood 87:1458-65, 1996

---

VEGF in
in POEMS
POEMS
· Id
Increased l
l
eve s f
o
VEGF in POEMS
3500
Watanabe 1996;
3000
Soubrier 1997
2500
F,pg/mL 2000
· Angiogenesis factor
G
factor
1500
·endothelial survival VE
& proliferation
1000
erumS 500
0
· Factor of vascular
permeability
Normal
POEMS
MGUS
N=60
N=11
N=11
Scarlato M (2005). Brain 128:1911
128:1911--1920
1920

---

VEGF in
in POEMS
POEMS & Other
Other
Neurological Disorders
4000
3000
/mLgp, 2000
VEGF
1000
m
Seru
0
Normal
POEMS
Guillain-
Guillain
CIDP
Other
Barré
neurological
disorders
Watanabe et al Muscle Nerve 21:1390-7, 1998

---

Clues to
to Pathogenesis
Pathogenesis
· Nl
Nearly l
a lll
t
pa i
tients light h
c
i
a n
restricted
· Unique blood cytokine profile
· Bone sclerosis
· Overlap with Castleman Disease (aka
angiof lli
o
l
cu ar lymph node
hyperplasia)

---

Sclerotic bone lesions
BMPC concentrated
near trabeculae or
around lymphoid nodules

---

PET Avid Sclerotic Bone Lesion

---

Clues to
to Pathogenesis
Pathogenesis
· Nl
Nearly l
a lll
t
pa i
tients light h
c
i
a n
restricted
· Unique blood cytokine profile
· Bone sclerosis
· Overlap with Castleman Disease (aka
angiof lli
o
l
cu ar lymph node
hyperplasia)

---

Abnormal LN
LN follicle
follicle diagnostic of
of CD
CD
HE, 100x
HE, 400x
O
OSM +
CD+
CD +
CD+
S
POEMS
CD
M
POEMS
+OSM
POEMS
PN

---

POEMS Syndrome
Syndrome
· Hi t
s ory
· Diagnosis
· Pathogenesis
· Treatment / Outcomes
· Future Directions
Directions

---

Commonly Used
Used Treatments for
for
POEMS Syndrome
Improvement
Treatment
rates
Radiation
50%
St
St
d
an ard dose alklt
lkylator

based therapy
40%
Corticosteroids
15%
High-
High dose chemotherapy
chemotherapy

with PBSCT
90%

---

POEMS Sy
SS ndrome
y
Overall Survival (99 Mayo Patients)
100
(%) 80
val 60
lsurvi 40
20
Overal
Median 13.8 years
0
0
50
100
150
200
250
300
350
Months

---

Overall Survival, Mayo 1975-2003
n=137
1.0
0.9
08
0.8
0.7
0.6
0.5
urvivingS
04
0.4
0.3
0.2
Median OS 12 years
0.1
0.0
0
50
100
150
200
250
Survival in months
J.S. Allam et al Submitted

---

Outcomes in POEMS
Rf
Reference
N
Md
Me i
dian Survival
Takatsuki, 1983
109
"clinical course is very
chronic s
... ome
some patients
patients
survived greater than 10
years"
Nakanishi, 1984 102
33 months
Soubrier, 1994
25
8% dead at med f/u of 40 mo
Dispenzieri,
99
13.8 years
2003

---

Novel Treatments-Case Reports
· Strontium-89
· Sternberg AJ (2002) Br J Haem 118:821
118:821--824.
824.
· Thalidomide
· Sinisalo M (2004) Am J Hem 76:66
76:66--68.
68.
· Bevacizumab: 3 cases
· Badros A (2005) Blood 106:1135.
· Straume O et al (2006) Blood 107:4972
107:4972--4973;
4973;
th
au or
th
reply
l 4973-4974
· Lenalidomide
· Dispenzieri (In
((In press) Blood 2007

---

PBSCT for
for POEMS
Published Cases
1.0
0.9
0.8
gn 07
0.7
0.6
Survivi
0.5
n
0.4
0.3
N=38
roportioP 02
0.2
Median follow-up 19 months
0.1
0.0
0
102030405060 708090 100 110 120
Follow-up, months
Dispenzieri Blood Reviews (in press)

---

First 16
16 POEMS
POEMS Patients
Transplanted at Mayo
100
80
ving
60
· Patients in ICU
6
survi
rcent 40
· Intubated
5
Pe
20
· BiPAP
1
0
· Renal failure
2
0
1020
30
4050
60
Ti
Time
me, months
Dispenzieri et al Blood 2004; 104:3400-3407

---

Baseline Pulmonary
Pulmonary Tests (n=16)
110
100
90
d
80
redicte
70
P
%
60
50
40
30
TLC
FEV1
PImax
PEmax DLCO
Dispenzieri et al Blood 2004; 104:3400-3407

---

POEMS PBSCT
PBSCT Results
· It
Improvement in
i
per h
p
l
era
t
neuropa h
thy in
all patients
· High hematologic resp. rate: >75%
· Improvement in other paraneoplastic
features in ~ 2/3 of cases
· P
d
roce ure
l
re t
a d
e
bidit
mor
y may be
substantial

---

Pre
Post
Pd
Pre i
dicted
Pi
Patient
Post-dilator
July 10, 2002
Jan. 12, 2005
July 9, 2002
TLC
60%
January 1
TLC 2
12, 2005
98%
2005
TLC 60%
FVC
47%
TLC 93%
FVC
93%
FEV1 45%
FEV1
45%
FEV1
91%
FEV1 80%
PI max 42%
PI max 96%
PI max 42%
PI
PI max 111%
111
PEmax 78%
PEmax 82%
DLCO 55%
DLCO
55%
DLCO 92%
DLCO
88%

---

Illustrative Case (Mr. B )
.
· B
l
are y bl
a e to rollll over in bed; unable
to bathe, dress, or transfer himself;
wheel chair
-
restricted
· Started on lenalidomide 15 mg days 1-
21 every 28 days with dexamethasone
40 mg once weekly & daily ASA
· 9 cycles administered with dramatic
clinical and laboratory improvements

---

Anasarca
Pre-treatment
Pt
Post tt
-treatment

---

Illustrative Case (Mr. B )
.
· Obj ti
ec ve neuro impr. (NIS
(NIS, NCS)
· Persistence of IgG
· BMPC 5%
10% polyclonal
· VEGF 948 pg/ml 203 pg/ml
· IL-6 140 pg/ml
6 6
. pg/ml
· Testosterone 276 424

---

POEMS Syndrome
Syndrome
· Hi t
s ory
· Diagnosis
· Pathogenesis
· Treatment / Outcomes
· Future Directions
Directions

---

Future Challenges
Challenges
· Identifying the syndrome, correctly
· Understanding mechanism of
disease
· Devising objective response criteria
· Finding safer and more effective
treatments

---

Thank you for
for your attention.

---

MAJOR
1. Polyneuropathy
CRITERIA
2. Monoclonal plasma cell dyscrasia (almost always )
3. Sclerotic bone lesions
4. Castleman's disease
5. Va
V scular endothelial growth
growth factor
factor elevation
elevation
MINOR
6. Organomegaly (splenomegaly, hepatomegaly, or LA)
CRITERIA
7. Extravascular
Extravascular volume
volume overload
overload (edema, pleural
pleural eff
ef , or
or ascites)
ascites)
8. Endocrinopathy
9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid
hemangiomata, plethora
plethora, acrocyanosis
acrocyanosis, flushing, white nails)
10. Papilledema
11. Thrombocytosis / polycythemia
* Polyneuropathy and monoclonal plasma cell disorder present in all patients; to make
diagnosis at least one other major criterion and 1 minor criterion is required to make diagnosis

---