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MATEOS AND SAN MIGUEL
previously mentioned. However, the new imaging assessments
can also help predict progression risk in patients with
SMM. The fırst studies with spinal MRI were conducted in
patients with asymptomatic MM and the presence of a focal
pattern was associated with a shorter TTP than those patients
with a diffuse or variegated pattern (median, 6 vs. 16 vs. 22
months, respectively). Hillengass et al recently evaluated the
role of MRI during the follow-up of patients with SMM. Radiologic
progressive disease (MRI-PD), defıned as the detection
of new focal lesions or the increase in diameter of
existing focal lesions, and a novel or progressive diffuse infıltration
was identifıed as a feature for classifying patients with
SMM at high risk of progression to symptomatic disease. 21
The role of PET/CT has also been evaluated in SMM. The
Italian group recently reported that in a series of 73 patients
with SMM, approximately 10% had a positive result with
PET/CT with no underlying osteolytic lesion and were predicted
to be at high risk of progression to symptomatic disease
(48% at 2 years compared with 32% for PET/CTnegative
patients; p 0.007). 22 The Mayo Clinic group also
identifıed a subgroup within a series of 132 patients with
SMM who had a positive result with PET/CT in which the
rate of progression to MM within 2 years was 56% compared
with 28% among patients who had a negative PET/CT result
(p 0.001). The rate of progression was even higher among
patients in whom PET/CT was performed within 3 months of
their diagnosis of SMM (74% vs. 27% in PET/CT-negative
patients). 23
CYTOGENETIC ABNORMALITIES
Neben et al have identifıed t(4;14), gain of 1q21, or hyperdiploidy
as independent prognostic factors of shorter TTP. The
median TTP for patients with del(17p13) was 2.7 years compared
with 4.9 years for patients without the deletion (p
0.019), 2.9 years for patients with t(4;14) compared with 5.2
years for patients without the deletion (p 0.021), and 3.7
years for patients with 1q21 compared with 5.3 years for
those without the deletion (p 0.013). In addition, hyperdiploidy
was associated with a signifıcantly shorter median
TTP of 3.9 years compared with 5.7 years for patients without
hyperdiploidy (p 0.036). 24 The Mayo Clinic group also analyzed
the cytogenetic abnormalities in a series of 351 patients
with SMM and identifıed a high-risk subgroup of
patients with t(4;14) and/or del(17p) with a substantially
shorter median TTP (24 months) than the intermediate-,
standard- and low-risk patient subgroups. 25 Finally, the
SWOG evaluated the Gene Expression Profıling 40 (GEP40)
model in a group of 105 patients with SMM, and estimated
7.05 to be the optimal cut point for risk of progression to active
disease. The 3-year TTP probability was 83% compared
with only 11% for patients with scores below this threshold. 26
In summary, the diagnosis of SMM is associated with a
variable risk of progression to active disease, and the presence
of the aforementioned prognostic factors can discriminate
subgroups of patients with respect to their degree of risk
(Sidebar 2).
MANAGEMENT OF SMM
The standard of care for the management of SMM was observation
until MM develops. However, because of the heterogeneity
of the disease, several groups evaluated the role of
early intervention in patients with SMM using conventional
and novel agents.
Three small studies compared early therapy consisting of
melphalan and prednisone (MP) with observation alone. In
the Hjorth study, the response rate to therapy in patients
treated at diagnosis was similar to that of patients who received
deferred therapy at the time of progression (52% vs.
55%). 27 In the other two trials, there were no differences in
OS between early treatment and observation (54 vs. 58
months in the former, and 64 vs. 71 months in the latter). 28,29
Two small phase II trials, one by the Mayo Clinic and the
other by The University of Texas MD Anderson Cancer Center,
evaluated the role of thalidomide as a single agent in patients
with SMM. 30,31 The rates of partial response (PR) or
better were 34% and 36%, respectively, and most patients
who discontinued treatment did so because of peripheral
neuropathy. Barlogie et al conducted another nonrandomized
phase II trial with thalidomide plus pamidronate in 76
patients with SMM, obtaining a PR rate of at least 42%, with
a 6-year median TTP to symptomatic disease. The development
of peripheral neuropathy was the main problem in patients
who received long-term thalidomide treatment. 32
Novel agents have also been evaluated in SMM. Anakinra is
an antagonist of the receptor of interleukin (IL)-1 and produced
stabilization of the disease (in 8 patients), minor responses
(3 patients), and partial responses (5 patients) in a
group of 47 patients with SMM, with a median TTP of 37
months. 33 A phase II study of an anti-KIR monoclonal antibody
in 21 patients found no clinical response. 34 Immunotherapy
using a vaccine consisting of peptides from unique
regions of three MM-associated antigens is currently being
evaluated in patients with SMM and is producing promising
effıcacy results. 35 It is diffıcult to draw fırm conclusions from
the results of these trials, only one of which was randomized,
although we can be confıdent that approximately one-third
of patients with SMM responded to thalidomide. Only one
randomized trial has compared the outcome of thalidomide
plus zolendronic acid and that of zolendronic acid alone in
patients with SMM. The rate of PR was a minimum of 37% in
the thalidomide arm compared with 0% in the zoledronic acid–only
arm, but there were no differences in the TTP to symptomatic
MM (4.3 vs. 3.3 years) or in the 5-year OS (74% vs.
73%). 36 The role of bisphosphonates has also been analyzed in
three trials, considering pamidronate as a single agent in one of
them, 37 pamidronate versus abstention in another, 38 and zolendronic
acid versus observation in the third. 39 All three studies
confırmed that bisphosphonates have no antitumoral effect but
reported an increase in bone density and a decrease in bone resorption,
both of which were related to the bone markers. It is
important to note that in the two randomized trials comparing
bisphosphonates with abstention, a substantial reduction in the
incidence of skeletal-related events in the bisphosphonate arms
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