Haematologica 2003 - Supplements

Serum osteocalcin
Urinary aminoterminal telopeptide of bone collagen (NTx)
Urinary deoxypyridinoline (DPD)
Skeletal survey
Patients with elevated levels of serum or urinary markers of bone
turnover went on to have a bone mineral density (BMD) test.
The study was discussed with 15 potentially eligible patients. Of
these, 7 declined to participate. Therefore, 8 patients underwent
assessment between July 2002 and February 2003.
Of these 8 patients:
5 had neither abnormal bone markers nor osteopenia.
1 had both elevated bone markers and bony lytic lesions that
indicated that her disease had progressed to multiple myeloma.
1 had elevated deoxypyridinoline (DPD), suggesting bone
resorption, but no evidence of osteopenia on bone mineral density
tests.
1 had elevated deoxypyridinoline (DPD), suggesting bone
resorption, and at the time of writing, we are waiting on the
results of a BMD test.
The treatment phase of the study requires patients to have
abnormalities suggesting bone resorption (raised urinary NTx or
DPD or serum ostase or osteocalcin) and at least two sites of
osteopenia. No patients have been identified who meet these
criteria.
From this limited study (to date) we can conclude that the
incidence of bone disease in MGUS and smouldering myeloma is
low. It is unclear if the introduction of zoledronic acid will
prevent subsequent progression to myeloma but patients will
continue to be accrued and reassessed annually.
4.3 New criteria for differential diagnosis between
MGUS and MM.
084
Expression of Angiogenic Cytokines by Plasma Cells:
A Comparison of MGUS, Smoldering Myeloma and
Newly Diagnosed Symptomatic Myeloma.
Jessica L Haug, Shaji Kumar, Thomas E Witzig, Michael A
Thompson, Linda Wellik, Michael M Timm, Philip R Greipp,
and S. Vincent Rajkumar
Division of Hematology, Mayo Clinic, Rochester, MN, 55905
Background: Bone marrow (BM) angiogenesis is a striking
feature of multiple myeloma that correlates with plasma cell
proliferation and overall survival. There is a progressive increase
in the BM angiogenesis along the spectrum of plasma cell
proliferative disorders from MGUS to smoldering myeloma
(SMM) and newly diagnosed symptomatic myeloma (NMM). We
studied the expression of VEGF, bFGF and their receptors on
plasma cells from patients with MGUS, SMM, and NMM using
various methods to address this question.
Methods and Materials: BM angiogenesis was studied using
immunohistochemical staining for CD34 and graded as
previously described. Expression of VEGF, bFGF, flt1, KDR
(flk-1), FGFR-2 and FGFR-3 were studied by
immunohistochemical staining of BM biopsy sections from
patients with MGUS, SMM and NMM; results were expressed as
the percentage of total plasma cells with cytoplasmic staining for
the cytokine. Plasma levels of VEGF, bFGF and IL-6 were
estimated using ELISA. Expression of VEGF, bFGF, flt-1 and
KDR were studied using quantitative RT-PCR on CD138 sorted
plasma cells from patients with MGUS, SMM and NMM.
Results: Angiogenesis and angiogenic cytokine expression were
studied by immunohistochemistry on 57 bone marrow biopsy
samples (15 MGUS, 19 MM, 23 SMM). Plasma cells in MGUS,
SMM, and NMM expressed VEGF, bFGF and their receptors
(Table1), however there was no statistically significant difference
between the three groups.When the expression pattern was
correlated with grade of angiogenesis, patients with low grade of
angiogenesis had significantly lower % of PC's expressing
VEGF, bFGF and flt1. There was no difference in VEGF and
bFGF plasma levels between SMM and NMM, P=0.79 and 0.62,
respectively. Plasma levels of VEGF and bFGF did not correlate
significantly with BM microvessel density (MVD) except in
patients with SMM where there was correlation between MVD
and bFGF. There was no significant difference in the mRNA
expression of VEGF, bFGF, flt1 and KDR between the three
groups by quantitative RTPCR.
Conclusion: Plasma cells express the angiogenic cytokines
VEGF, bFGF and their receptors. We found trends correlating
degree of BM angiogenesis with the expression of these
cytokines/receptors. However, there was no significant difference
in expression of VEGF, bFGF, and their receptors by plasma cells
between MGUS, SMM and NMM. Increased angiogenesis along
the spectrum of plasma cell disorders may therefore be a function
of increased levels of VEGF and bFGF that occur as a result of
increasing BM plasma cell % from MGUS to SMM to NMM.
Percentage of cytokine positive plasma cells
VEGF flk1 KDR bFGF FGFR-2 FGFR-3
MGUS 50 20 33 19 50 40
(0-100) (0-100) (0-100) (0-100) (0-100) (0-100)
33 38 25 13 33 25
SMM
(4-100) (4-100) (4-100) (0-100) (0-100) (0-100)
50 50 40 20 37 30
NMM
(6-100) (0-100) (0-100) (0-100) (0-73) (0-70)
P NS NS NS NS NS NS
All values expressed as median (range);pg/mL
085
UTILITY OF SERUM CYTOKINES IN THE STUDY OF
MONOCLONAL GAMMOPATHIES AND BONE DISEASE
OF MULTIPLE MYELOMA (MM)
J.M. Hernández Martín*, R.M.Fisac*, J.A.Queizan*,
C.Olivier*, B.Suquía**, R.García-Sanz**, M.J.Calmuntia*,
J.A.Portero***, C.Aguilera****, J.J.Sanchez*****, J.F. San
Miguel**.
* Hospital General de Segovia, ** Hospital Clínico de
Salamanca,*** R.S. “Virgen de la Concha”-Zamora, **** Hospital
del Bierzo-Ponferrada, ***** Universidad Autónoma de
Madrid.Cooperative Group of Castilla-León for study of Monoclonal
Gammopathies
The marrow microenvironment plays a fundamental role in the
etio-pathogenesis of bone disease of Multiple Myeloma (MM),
either through direct cell-to-cell stimulus or through the
interaction of a network of cytokines produced by stromal, tumor
or bone marrow cells. These cytokines are detectable in the
patient’s serum.
We investigate the value of a series of serum cytokines for the
study of bone disease of Multiple Myeloma and the distinction
between MM and Monoclonal Gammopathy of Unknown
Significance (MGUS).
MATERIALS AND METHODS: 176 newly diagnosed patients
were included: 107 MM and 69 MGUS. As control groups we
selected 25 patients with benign Osteoporosis (BO) and 32
healthy individuals (HI). In all patients, the serum levels of the
following cytokines were measured by ELISA (Quantikine®-
R&D System): IL-6, soluble IL-6 receptor (sIL-6R), Oncostatine-
M (OSM), IL-1β, TNF-α and TNF-β, Vascular Endothelial
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