Haematologica 2003 - Supplements

(MRI); some have claimed that levels of hemoglobin or marrow
plasmacytosis were also useful.
In order to clarify the prognostic features of these patients we
updated our previous experience which identified low,
intermediate and high risk groups based on 3 variables (M protein
> 3 g/dl, IgA protein type, and BJP > 50 mg/d) for time to
progression. Patients with any lytic bone lesions by skeletal x-
ray survey were excluded because this feature had been
associated with early progression at multiple centers. The features
evaluated included serum myeloma protein level (M protein),
B 2 M, marrow plasmacytosis, levels of uninvolved
immunoglobulins, myeloma protein type, level of Bence Jones
protein, age, albumin, and hemoglobin. For those patients with
an available MRI of the spine, the impact of this study was also
assessed. Univariate analysis revealed abnormal MRI, myeloma
(M) protein >3 g/dl, B 2 M >2.5 mg/L, marrow plasmacytosis
>25% and suppression of uninvolved IgM to < 30 mg/dl to be
indicators of a shortened time to progression and multivariate
analysis was limited to 5 covariates after eliminating highly
codependent variables (72 pts with complete information for all 5
variables). Three risk categories were identified for time to
disease progression identified as follows: low risk (33 pts) –
normal MRI and serum M protein < 3 g/dl (median TTP 79 mos),
intermediate risk (28 pts) – abnormal MRI or M protein > 3 g/dl
(median TTP 30 mos), and high risk (11 pts) – abnormal MRI
and M protein > 3 g/dl (med TTP 17 mos.) (p 3 g/dl or IgA type (median TTP 25 mos), and
high risk (8 pts) – M protein > 3 g/dl and IgA type (med TTP 9
mos.) (p 3 g/dl or IgA type). An abnormal pattern (n=38)
distinguished patients more likely to have a shorter time to
symptomatic progression (median 25 months) than 3 patients
with a normal MRI (median 97 months). Thus, the addition of
MRI for intermediate risk patients effectively identified a group
of patients likely to have prolonged stability (no positive features
or 1 risk factor and normal MRI, median TTP 57 months) in
contrast to those with earlier progression (2 risk factors or 1 risk
factor and abnormal MRI, median TTP 20 months). (Validation
of this analysis in an independent data set is necessary because of
the small numbers of patients evaluated). Because a serious
complication (fracture, hypercalcemia, renal failure) occurred in
approximately one quarter of patients with early disease
progression, standard chemotherapy or a trial of new agents may
be justified for such patients. The remaining patients are at such
low risk for early progression that they may be followed at long
intervals without treatment.
P4.3
CYTOGENETIC CHANGES IN THE EVOLUTION OF
MONOCLONAL GAMMOPATHY OF UNDETERMINED
SIGNIFICANCE (MGUS) TO MULTIPLE MYELOMA (MM).
Thierry Facon, Hervé Avet-Loiseau, Xavier Leleu, Régis
Bataille
CHU Lille and Nantes, on behalf of the IFM group.
Monoclonal gammopathy of undetermined significance (MGUS)
is a condition defined by the detection of a monoclonal protein in
the serum without evidence of any causal disease, such as
multiple myeloma (MM), Waldenström macroglobulinemia,
primary amyloidosis or any related disorder. MGUS is not
unusual, corresponding to 1% of the population over 50 years of
age, and 3% of the population over 70 years of age. The origin of
MGUS is largely unknown and the condition is heterogeneous.
Some patients (pts) remain asymptomatic for decades, whereas
others evolve to malignant diseases in less than 1 year. The
overall incidence of MM transformation is estimated to be 1-2%
per year, but little is known about what triggers the occasional
progression from MGUS to MM.
As fas as conventional cytogenetics is concerned, the evaluation
of MGUS is unsuccessful. Some years ago, we and others
reported the use of fluorescence in situ hybridization (FISH) on
interphase cells for the investigation of numeric chromosomal
abnormalities [1-3]. We demonstrated that numeric abnormalities
were shared both by MGUS and MM pts and were thus not
related to an overt disease. Using FISH at diagnosis and followup,
we also showed that MGUS pts acquire slowly, gradually, but
ineluctably numerical chromosome changes, distributed within
several related subclones but not directly related to
transformation into MM [3].
To extend the knowledge of MGUS to structural chromosomal
abnormalities our group and others performed FISH experiments
with probes directed to 14q32 (immunoglobulin H locus) and
13q14 chromosomal regions. Chromosomal translocations
involving 14q32 are thought to be early events in the
pathogenesis of many B-cell neoplasms, including MM. These
translocations involve non random, recurrent, partner
chromosomes, especially loci 4p16.3, 11q13 and 16q23. In a
recent study, we evaluated such abnormalities in 855 pts with
MGUS, smoldering MM (SMM) and overt MM. The results are
presented in the Table [4]. The incidence of 14q32
rearrangements was almost 50% in MGUS and SMM, suggesting
that they occur early in the clonal development, and the incidence
of t(11;14) was similar in all conditions (approximately 15%). In
contrast, t(4;14) was almost never encountered in MGUS/SMM,
possibly because this translocation directly precipitates clonal
plasma cells (PCs) into fully malignant PCs, bypassing a stable
MGUS. Chromosome 13 deletion (del(13)) was observed in all
stages. We found a lower incidence in MGUS compared to MM
(21% versus 43%), but other authors found a similar 50%
incidence [5]. Del(13) is an early event in MM oncogenesis but
the issue whether del(13) is of importance in the progression from
MGUS to MM is still debated. In our experience, the presence of
a t(14;16)(q32;q23) was very rare, in MGUS as well as in MM.
Overall, similar translocations are found in MGUS and MM. In
MM, 14q32 and 13q abnormalities correlate with natural history,
immunological features, and clinical presentation. In contrast, no
obvious clinical or biological correlations have been found in
MGUS. Very recently, it was thought that microarray analysis
could provide insight into the mechanisms of disease progression
[6,7]. It could identify genes or gene families important in the
transition of MGUS to MM and these genes might be future
therapeutic targets. In two concordant studies, the number of
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