P.O.E.M.S. Syndrome
Angela Dispenzieri, M.D.
Mayo Clinic, Rochester
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Disclosures
Company
Disclosure
Celgene
Research dollars
Millenium
Advisory board
(Unpaid)
Onyx
Advisory board
(Unpaid)
Binding site
Travel award dollars
1
POEMS Syndrome
· Diagnosis / Pathogenesis
· Treatment / Outcomes
· Future Directions
POEMS
(PEST)
And
100
100
60-96
100
90
67-84
High VEGF
% 80
68-89
Abn. PFTs
70
60
>50
45-85
affected, 50
Arterial
40
29-64 30-90
thrombosis
30
Subtle renal
Patients 20
impairment
10
0
Dispenzieri A (2003) Blood. 101:2496. Nakanishi T (1984) Neurology. 34:712. Takatsuki K (1983) Jpn J Clin
Oncol. 13:543. Soubrier MJ (1994) Am J Med 1994; 97, 543. Li (2011) Annals of hematology. Ghandi (2007)
Mayo Clin Proc 2007;82:836-842
2
Both 1 and 2 present
MAJOR
1. Polyneuropathy
CRITERIA
2. Monoclonal plasma cell dyscrasia (almost always )
3. Sclerotic bone lesions
At least one of 3-5
4. Castleman's disease
present
5. Vascular endothelial growth factor elevation
MINOR
6. Organomegaly (splenomegaly, hepatomegaly, or LA)
CRITERIA
7. Extravascular
Over-volume overload (edema, pleural
Under-eff, or ascites)
diagnosis
diagnosis
8. Endocrinopathy
At least
9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid
hemangiomata, plethora, acrocyanosis, flushing, white nails)
1 of 6-11
10. Papilledema
present
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
Clues to Pathogenesis
· Bone sclerosis
· Unique blood cytokine profile
· Nearly all patients light chain
restricted
· Overlap with Castleman Disease (aka
angiofollicular lymph node
hyperplasia)
· How and when patients die
3
Sclerotic bone lesions
BMPC concentrated
near trabeculae or
around lymphoid nodules
PET Avid Sclerotic Bone Lesion
4
Serum VEGF Differentiating
POEMS from other Disorders
AL
TTR POEMS MM
Watanabe et al Muscle Nerve
Scarlato M, et al. Brain.
Briani et al Muscle Nerve
21:1390-7, 1998
2005;128:1911-20
43: 164-7, 2011
Plasma VEGF in POEMS Syndrome
2000
P<0.0001 POEMS/CD vs PCD
P<0.0001 POEMS/CD vs PN
1500
/mLg
P<0.01 POEMS/CD vs CTD
,pF
1000
VEG
Plasma
500
0
S
S
U
lra
MG
eloma
POEM
yloidosis
My
riphe
m
CTD/
Vasculitis
astleman's
isease
A
Pe
neuropathy
C
D
DIAGNOSIS
AL
MM
PN
CTD
CD
POEMS
N=4
N=9
N=29
N=9
N=9
N=29
Median VEGFa
38
68
50
142
412
342
Range
31-42
35-271
31-180
35-403 132-2030
48-2112
D'Souza et al IMW Paris 2011
5
Lambda variable gene usage
100
B-cell (No. seq.
IGLV 1-40
MM
evaluated)
or 1-44, %
Amyloidosis
l
)
80
Polyclonal B cels
(%
POEMS¥
n
(29)
100
POEMS
ccessfu
60
AL Amyloid (354)
16
su
tificatio
ith
Multiple
en
40
12
w
myeloma (92)
ts
eid
en
CLL (182)
13
g
20
Patien
V
Autoantibody
14
(287)
0
Burkitt's
2
VL1
VL2
VL3
VL4-10
Abe D, et al. Blood. 2008;112:836-9. Aravamudan B, et al. Blood. 2008;112:[abstract 2744].
Soubrier M, et al. 2004. Haematologica. 89(1):e4-e5.
Lymphoid aggregates rimmed by
PC in BM biopsy in POEMS
H&E: 200x
CD138
33 of 67
cases had
lymphoid
aggregates
32 of these
had clonal PC
Dao et al Blood prepub.
6
Megakaryocyte clusters and atypia in
POEMS Syndrome
36 of 67
cases had
megakaryocyte
hyperplasia
In toto, only
8/67 with
neither mega,
lymph rimming,
or clonal PC
Dao et al Blood prepub.
POEMS Syndrome
· Diagnosis / Pathogenesis
· Treatment / Outcomes
· Future Directions
7
POEMS Syndrome
Overall Survival (99 Mayo Patients)
100
)
(% 80
60
survival 40
20
Overall
Median 13.8 years
0
0
50
100
150
200
250
300
350
Months
Dispenzieri A, et al. Blood 2003;101(7):2496-506.
Prognostic Factors
NEGATIVE
FAVORABLE
· Clubbing
· Disease amenable
to radiation therapy
· Extravascular
volume overload
· Respiratory
NEUTRAL
symptoms
· Number of features
· Co-existing CD
· Thrombocytosis (CVA)
Dispenzieri et al. Blood 2003;101:2496-2506.
Soubrier et al. AJM 1994;97:543-553.
Allam et al. Chest 2008;133:969-974
Li et al. Annals of hematology 2011.
8
CLONAL PLASMA CELLS ON ILIAC CREST
BIOPSY?
SELINE
VIGOROUS
Yes
No
BA
> 2
SSESSMENTA
bone lesions
SUPPORTIVE
EXTENSIVE
Yes
No
Systemic therapy
Curative doses of radiation to
CA
affected site(s)
RE
Extensive assessments every 3-6 months
Dispenzieri A, et al. Blood 2003;101(7):2496-506.
9
· 31 enrolled
Median age 44
· 12 cycles MDex
Response
type
N
% responding
VEGF
24
96
Hematologic
31
81
Neuro (ONLS)
31
100
Organ
28
64
Volume
28
71
Pulm HTN
15
93
Changes in serum VEGF with
different therapies
Kuwabara et al Neurology 2006; 66:105-7
10
No difference in Plasma VEGF levels among
patients achieving CR versus No-CR
Plasma VEGF in CR
Plasma VEGF in
patients
non- CR patients
,pg/mL
,pg/mL
VEGF
VEGF
Ti Time
me
(day
(days) s)
Median plasma VEGFa at diagnosis (inter quartile
CR patients
Non-CR
range)
patients
Median VEGF on day 180b
131 (n=7)
75 (n=7)
Median VEGF at last follow up
59.5 (n = 10)
69 (n = 15)
D'Souza et al IMW Paris 2011
PBSCT for POEMS
1
0.9
· Engraftment syndrome
0.8
~ 50% of patients
0.7
ing 0.6
iv
· Splenomegaly risk
v 0.5
Sur 0.4
· TRM 3%
tion
0.3
N=38
opor
Pr 0.2
· Major clinical
0.1
Median follow-up 19 months
improvement possible
0.0
without "hematologic"
0
1020 30 4050 607080 90 100 110 120
Follow-up, months
response as long as
Rovira M Br J Haematol2001;115:373375.
VEGF response
Hogan WJ. BMT 2001;28:305309.
Jaccard A. Blood 2002;99:30573059.
Ganti AK. Am J Hematol 2005;79:206210.
Soubrier M. BMT 2002;30:6162.
Giglia F. Neuromuscul Disord 2007;17:980982.
Peggs KS Bone Marrow Transplant 2002;30:401404.
Laurenti L. Leuk Res 2008;32:13091312.
Dispenzieri A. Blood 2004;104:34003407.
Imai N Neuromuscul Disord 2009;19:363365.
Kuwabara S, Neurology 2006;66:105107.
Barete S, Arch Dermatol 2010;146: 615623.
Sanada S. Am J Kidney Dis 2006;47:672679
Kuwabara S. Neurology 2008;71:16911695.
Dispenzieri et al. Eur J Haematol. 2008;80:397-406.
11
Pre
Post
Predicted
Patient
Post-dilator
July 10, 2002
Jan. 12, 2005
July 9, 2002
TLC
60%
January
TL 12,
C
2005
98%
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%
PEmax 78%
PI max 111%
PEmax 82%
DLCO 55%
DLCO
55%
DLCO 92%
DLCO
88%
Novel Treatments--IMiDs
1
Thali after MP
No heme response but improved ascites;
stabilized PN, splenomegaly, pulm htn
2
Thali+Dex after
CD/POEMS: impr ascites, effusions, pulm
CAD
HTN, PN, renal function, IL-6
3
Thali+Dex
N=9; VEGF impr in all; PN impr in 66%;
stable in 33%; impr edema; no HCR
4
Thali after VAD,
Improv cardiopulm status, but no impr PN
CTX, bevacizumab
and rising VEGF
5
Lenalidomide+Dex
Impr ascites, PS, PN, VEGF, testosterone,
pulmonary function tests
6
Lenalidomide+Dex
N=9; Hematologic & VEGF response in all;
Improved PS, PN, edema
1. Sinisalo, (2004). Am J Hematol 76(1): 66-8.
2. Kim (2006). Ann Hematol 85(8): 545-6.
3. Kuwabara (2008). J Neurol Neurosurg Psychi 79(11): 1255-7.
4. Ohwada (2008). BMT 1-2.
5. Dispenzieri (2007) Blood 110(3): 1075-6.
6. Jaccard (2009) ASH;114:3872-
12
Novel Treatments--Bortezomib
1
Bortez + Dex
Improved M-protein, polyneuropathy,
hepatomegaly, testosterone; no EMG
change
2
Bortez x 5 cycles +
Improved anasarca, PN, VEGF, and PET
thalidomide added
scan with Bortez alone, but thali added for
at cycle 6 (prior
persistent edema, M-protein, PN, and slight
Dex and MP)
VEGF. With thali, disappearance of pleural
effusion, ascites, and M-protein and
normalization of VEGF
3
Bortez+AD after
Improved M-protein, VEGF, paresthesias,
VAD, CMP, and AD
splenomegaly, effusions, muscle strength,
gynecomastia, and skin changes
4
Bortezomib
Improved by 3 cycles (but continued for 6):
dexamethasone*
adenopathy, pleural effusion and ascites,
HSM, and IL-6. CR 4 years after completing
therapy.
*Castleman's variant of POEMS
1. Kaygusuzet al. Eur J Haematol 2010;84:175-177. 2. Ohguchi et al. Annals of hematology 2010.
3. Tang et al. Eur J Haematol 2009;83:609-610.
4. Sobas et al. Ann Hematol 2010;89:217-219.
Novel Treatments--Bevacizumab
1
Single
Dead 6 weeks
RIP
2
Single
Worsening PN, anasarca, MOF; died of
pneumonia 5 weeks after Rx
RIP
3
Single
Improved pain, breathing, walking
4
+ Mel-Dex
Improved edema, pain, weakness, VEGF
5Prior
Improved effusions/ascites
VAD/CTX
6
+ CTX-Dex
Initial worsening; repeat with CTX
improved pulmonary HTN, anasarca,
skin changes
7
+ CTX-CS
Initial improvement, but MOF and death
RIP
1 Kanai (2007). Intern Med 46(6): 311-3.
2 Straume (2006). Blood 107(12): 4972-3.
3 Dietrich (2008). Ann Oncol 19(3): 595.
4 Badros (2005). Blood 106(3): 1135.
5 Ohwada (2008). BMT 1-2.
6 Badros (2006). Blood 107(12): 4973-4.
7 Samaras (2007).Haematologica 92(10): 1438-9.
13
How does one define response
in patients with POEMS
Syndrome?
Response Criteria?
Which
score?
DLCO
Ascites
and
effusions:
mild,
moderate
or severe
Dispenzieri et al Blood, in press
14
Summary and Future Challenges
1. Essential to recognize syndrome
2. Commonly responsive to therapy
3. VEGF more reliable than M-spike
4. Bone marrow, VEGF, PET/CT useful
5. Need to understand dz mechanism
6. Need formal study of best treatments
Myeloma, Amyloid, and
Dysproteinemia Group
Rochester
Vince Rajkumar, MD
Arizona
Francis Buadi, MD
David Dingli, MD, PhD
Leif Bergsagel, MD
Morie Gertz, MD
Rafael Fonseca, MD
Phil Greipp, MD
Joseph Mikhael
Suzanne Hayman, MD
Craig Reeder, MD
Shaji Kumar, MD
Keith Stewart, MD
Robert Kyle, MD
Martha Lacy, MD
Nelson Leung, MD
Jacksonville
John Lust, MD
Greg Nowakowski, MD
Vivek Roy, MD
Steve Russell, MD, PhD
Tom Witzig, MD
S Zeldenrust, MD, PhD
15
Don't miss a diagnosis of POEMS
It's a
rope
It's a
It's a
tree
dagger
It's a
snake
Neuropathy Impairment Score
Dyck et al Can J Neurol Sci 29:258-266; 2002
16
Overall Neuropathy Limitations
Scale
Arm scale 0 to 5
Leg scale 0 to 7
Graham and Hughes J. Neurol. Neurosurg. Psych 77:973-6; 2006
17