Haematologica 2003 - Supplements

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P7.2
THE MAJOR PROGNOSTIC VALUE OF CYTOGENETICS
IN MYELOMA
Guido Tricot, MD, PhD
Cytogenetic information is limited in multiple myeloma because
it is a malignancy composed mainly of almost terminally
differentiated B-cells with low proliferative activity. Abnormal
karyotypes are found in only 30 to 50% of cases. Typically,
previously treated and relapsed patients have a higher frequency
of chromosomal abnormalities compared with newly diagnosed
patients. This is a reflection of the more proliferative nature of
myeloma in its advanced stages. The presence of abnormal
cytogenetics by conventional karyotyping has been associated
with an inferior outcome. Flow cytometry-derived aneuploidy
data and fluorescence in situ hybridization (FISH) analysis
indicate the presence of cytogenetic abnormalities in at least 90%
of myeloma patients. Therefore, the majority of normal
karyotypes in myeloma are derived from normal hematopoietic
cells and not from the myeloma clone. Even at the stage of
monoclonal gammopathy of undetermined significance, flow
cytometry and FISH analysis demonstrate aneuploidy or
cytogenetic abnormalities in at least 50% of cases.
Of the myeloma patients with cytogenetic abnormalities,
approximately 65% have a hyperdiploid karyotype. A
pseudodiploid and hypodiploid karyotype are found in
approximately 15 and 20% of patients, respectively. The most
common abnormalities are gains of a whole chromosome 3, 5, 7,
9, 11, 15 and 19. Every single chromosome can potentially be
involved in either deletions, gains, additions or translocations.
The finding of a 13q abnormality with conventional karyotyping
has been associated with poor outcome in patients treated with
either conventional chemotherapy or with tandem transplants. By
conventional cytogenetics, deletion of chromosome 13 has been
detected in approximately 15 to 20% of patients. Using interface
FISH, deletions of 13q is present in 50% of patients. The
presence of 13q deletion as assessed by FISH studies has also
been associated with poor outcome. To assess the impact of
FISH-13 compared to abnormalities of chromosome 13 by
conventional cytogenetics, we have evaluated event-free and
overall survival of our Total Therapy II patients, all of whom had
both of those tests performed. Patients without FISH-13 had an
excellent outcome with a three year event-free survival of 75%.
For patients with FISH-13, there was a major difference between
those with cytogenetic abnormalities and those without any
cytogenetic abnormalities as determined by conventional
cytogenetics. Those with FISH 13 and no cytogenetic
abnormalities had a three year event-free survival of 75%, while
those with cytogenetic abnormalities had a three year event-free
survival of only 30%. (p = < 0.0001)
The second cytogenetic abnormality associated with poor
outcome is hypodiploidy. Hypodiploidy is often associated with
deletion of chromosome 13. Analysis of our data on 1,475
myeloma patients scheduled to receive tandem transplants
showed that 65% of patients with hypodiploid or hypotetraploid
karyotypes had deletion of chromosome 13 compared with 29%
of those with pseudodiploid karyotypes and 36% of those with
hyperdiploid karyotypes. Median event-free survival for patients
with hypodiploid/hypotetraploid karyotype was 10 months;
median overall survival 19 months, compared with a median
event-free survival of 28 months and an overall survival
of 51 months for patients with normal karyotypes and 19 and 36
months, respectively, for patients with abnormal non-hypodiploid
karyotypes. Event-free survival and overall survival were poor
in patients with chromosome 13 abnormalities irrespective of
their ploidy status, but survival was also poor in patients with
hypodiploidy irrespective of deletion of chromosome 13.
Recently, we have also observed that patients who have a MDS
signature (-5/5q-, -7/7q-, +8, t(1;7), del 20q) in an otherwise
typical myeloma karyotype (MM-MDS) also have a poor
outcome. The median event-free survival of previously treated
and untreated patients with MM-MDS is 11 months and the
overall survival 18 months. This compares to an event-free
survival of 13 months and an overall survival of 24 months for
patients with chromosome 13 abnormalities or hypodiploidy.
Patients with other cytogenetic abnormalities not including
chromosome 13 abnormalities or hypodiploidy or MM-MDS, had
a median event-free survival of 20 months and a median overall
survival of 41 months. Patients with no cytogenetics at all had a
median event-free survival of 25 months and an overall survival
of 56 months.
In summary, cytogenetic abnormalities are the strongest predictor
of poor outcome after tandem transplants. Biologically,
cytogenetic abnormalities as detected by conventional
cytogenetics have a different meaning than those found by FISH
analysis. To detect cytogenetic abnormalities by FISH, there is
no requirement for proliferation. In contrast, finding cytogenetic
abnormalities by conventional cytogenetics is an indication of
stroma independence. When plasma cells are taken away from
stroma support, they will quickly undergo apoptosis. If myeloma
cells can be removed from the stroma and still grow and divide,
they have become stroma-independent. As such it is an excellent
marker, probably the best available at this point in time, to detect
stroma-independent myeloma.
P7.3
THE IMPORTANCE OF IMAGING IN MYELOMA
STAGING, PROGNOSTIC CLASSIFICATION AND
MONITORING.
Brian G.M. Durie, MD 1 ; Alan D. Waxman, MD 2 ; Allesandro
D’Agnolo, MD 2 ; and Cindy M. Williams, BS 2
1
Division of Hematology/Oncology, Department of Medicine,
Cedars-Sinai Comprehensive Cancer Center, Cedars-Sinai
Medical Center, Los Angeles, California; and 2 Division of Nuclear
Medicine, Department of Imaging, Cedars-Sinai Medical Center,
Los Angeles, California
Appropriate imaging is essential for myeloma management.
Imaging establishes the (1) presence, (2) location, and (3)activity
of myeloma lesions. This information allows prognostic
classification and provides discrete information for monitoring
purposes.
Considering each of the imaging techniques sequentially:
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