Novel agents in the treatment of POEMS
(polyneuropathy, organomegaly,
di
endocri
t
nopa h
thy, monoclonal
t
pro ein,
d
an
skin changes)
Angela Dispenzieri, MD
Mayo Clinic,
Rochester, MN, USA
Faculty disclosure information
Consultant: No
Grant/Research Support: Celgene, Millenium
Speakers Bureau: No
Major Stock
Stock Shareholder: No
No
Outline
· Define the disorder
disorder
· Review new data
· Disc s
u s
ss treatments
treatments
Criteria for the diagnosis of
POEMS syndrome
Major criteria
·
Polyneuropathy (mandatory)
·
Monoclonal plasma-cell proliferative disorder (mandatory)
·
Elevation of vascular endothelial growth factor (VEGF) concentration
in serum or plasma
·
Sl
Scl
i
erot c bone l i
es ons
·
Castleman disease
Minor criteria
·
Organomegaly
·
Oedema
·
Endocrinopathy
·
Skin changes
·
Papilloedema
·
Thrombocytosis or polycythaemia (or both)
Definite diagnosis: 3 major
major criteria and at least 1 minor criterion
Probable diagnosis: 2 major criteria, with at least 1 minor criterion
Kuwabara S, et al. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006828.
Important differences from
multiple myeloma
· Bone sclerosis
· Ll
Loca ilized growth
th
d
an lili i
m tit d
e
l
c
l
ona
i
expans on
· Restricted idiotype
· Cytokine milieu
Bone sclerosis
Sclerotic bone lesions1
BMPC concentrated near trabeculae
or around lymphoid nodules
BMPC = bone marrow plasma cells.
1. Dispenzieri A. Blood Rev. 2007:21:285-99.
Bone marrow morphology
Plasma Cell Rimming of Lymph Node
Follicles in
in Bone
Bone marrow
Cytogenetic abnormalities
Chromosomal
AL, %1
POEMS, %2
MM, %1
MGUS, %1
abnormality*
(n = 260)
(n = 37)
del(13)
50
2550
33
38
t(11
t(1 ;14)
16
1530
3955
8
t(4;14)
15
210
0
0
*detected by FISH.
Hyperdiploidy not seen
1. Bryce AH, et al. Am J Hematol. 2008;83:840-1.
FISH = fluorescence in situ hybridization.
2. Bryce AH, et al. Haematologica. [Epub ahead of print 2009 Feb 11].
Lambda variable gene usage
100
IGVL-
IGVL 1-44
MM
IGLVL-1-40
)
Amyloidosis
%
80
Polyclonal B cells
ssful
n(
POEMS
60
succeth entificatiowiid 40
atients
gene
a
P
20
V
0
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.
VEGF in POEMS
Ai
i f t
3 500
· Angiogenesis factor
,
endothelial survival
3,000
and proliferation
/mL)
2,500
proliferation
g
(p
2,000
· Factor of vascular
permeability
1,500
py
VEGFm 1,000
· Increased levels in
Seru
500
POEMS
0
Normal
POEMS
MGUS
(n = 60)
(n = 11)
(n = 16)
Scarlato M, et al. Brain. 2005;128:1911-20
Soubrier M, et al. Arthritis Rheum. 1997;40:786-7.
VEGF = vascular endothelial growth factor.
Watanabe O, et al. Lancet. 1996;347:702.
Role of bone marrow microenvironment
MM cells
IL-
IL 6
TNF
IL-1 BM
Bone Marrow
ICAM-1
Stromal Cells
Bone Marrow
Vessels
VEGF
IL-2
bFGF
PBMC
IFN
CD8+ T Cells
NK Cells
Hideshima et al. Blood 96: 2943, 2000
Davies et al. Blood 98: 210, 2001
Mitsiades et al. Blood 99: 4525, 2002
Gupta et al. Leukemia 15: 1950, 2001
Lentzsch et al Cancer Res 62: 2300, 2002
Novel treatments:
thalidomide and lenalidomide
Regimen
Thal after MP1
No haematological response but improved ascites;
stabilized PN, splenomegaly, pulmonary hypertension
Thal + Dex
Dex after CAD2
CAD
CD/POEMS: improved ascites, eff
ef usions
fusions,
pulmonary hypertension, PN, renal function, IL-6 level
Thal + Dex3
N = 9; VEGF improved in all; PN improved in 66%;
stable in
in 33%; improved
improved oedema; no HCR
Thal after VAD, CTX,
Improved cardiopulmonary status, but no improved PN
bevacizumab4
and rising VEGF
Lenalidomide + Dex5
Improved ascites, PS, PN, VEGF, testosterone, pulmonary
function tests
CD = Castleman
Castleman disease; CTX = cyclophosphami
cyclophospham de;
1. Sinisalo
Sinisalo M, et al. Am J Hematol
Hematol. 2004;76:66 8
- .
HCR = haematological
2. Kim SY, et al. Ann Hematol. 2006;85:545-6.
complete response;
3. Kuwabara S, et al. J Neurol Neurosurg Psychiatry. 2008;79:1255-7.
PN = polyneuropathy;
4. Ohwada C, et al. Bone Marrow Transplant. [Epub ahead of print 2008 Dec 1].
PS = performance status.
5. Dispenzieri A, et al. Blood. 2007;110:1075-6.
Novel treatments: bevacizumab
Regimen
Bevacizumab alone1
Death within 6 weeks
Bevacizumab alone2
Worsening PN, anasarca, multiorg
ggan failure;
died of pneumonia 5 weeks after therapy
Bevacizumab alone3
Improved pain, breathing, walking
Bi
Bevacizumab + Mel-D 4
Dex
Id
Improved effffusions/ascitites
Prior VAD/CTX5
Improved oedema, pain, weakness, VEGF
6
Bevacizumab + CTX-Dex
Initial worsening; repeat with bevacizumab
improved pulmonary HTN, anasarca, skin changes
Bevacizumab + CTX-CS7
Initial improvement, but multiorgan failure and death
1. Kanai K, et al. Intern Med. 2007;46: 311-3. 2. Straume O, et al. Blood. 2006;107:4972-3.
3. Dietrich PY, et al. Ann Oncol. 2008;19:595. 4. Badros A, et al. Blood. 2005;106:1135.
=deceased
5. Ohwada C, et al. Bone Marrow Transplant. [Epub ahead of print 2008 Dec 1].
CS = corticosteroids.
6. Badros A, et al. Blood. 2006;107:4973-4. 7. Samaras P, et al. Haematologica. 2007;92:1438-9.
PBSCT for POEMS
Overall survival
10
1.0
· Ef
Engraftment
d
syn rome in
about 50% of patients
0.8
g
· Splenomegaly risk
risk factor
factor
0.6
·TRM 3%
survivin
· Major clinical
clinical improvement
0.4
possible without
N = 38
Median follow-up 19 months
"haematological" response
roportionP 0.2
as long as VEGF
response
0
0
20
40
60
80
100 120
Follow-up (months)
Dispenzieri A. Blood Reviews. 2007;21:285-99.
TRM = treatment related mortality.
Dispenzieri A, et al. Eur J Haematol. 2008;80:397-406.
Role of bone marrow microenvironment
MM cells
IL-
IL 6
TNF
IL-1 BM
Bone Marrow
ICAM-1
Stromal Cells
Bone Marrow
Vessels
VEGF
IL-2
bFGF
PBMC
IFN
CD8+ T Cells
NK Cells
Hideshima et al. Blood 96: 2943, 2000
Davies et al. Blood 98: 210, 2001
Mitsiades et al. Blood 99: 4525, 2002
Gupta et al. Leukemia 15: 1950, 2001
Lentzsch et al Cancer Res 62: 2300, 2002