NcXHF

SMOLDERING MULTIPLE MYELOMA
TABLE 1. Differential Diagnosis of MGUS, SMM, and
Symptomatic MM
Feature MGUS SMM MM
Serum-M protein 3 g/dL and 3 g/dL and/or
Clonal BMPC
infiltration
Symptomatology
10% 10-60% 10% or biopsyproven
plasmacytoma
Absence of
CRAB*
Absence of MDE**
or amyloidosis
Presence of MDE**
Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; SMM,
smoldering multiple myeloma; MM, multiple myeloma; BMPC, bone marrow plasma cell;
CRAB, hypercalcemia, renal failure, anemia, and bone; MDE, myeloma-defining event.
*CRAB includes (1) hypercalcemia: serum calcium 0.25 mmol/L ( 1 mg/dL) higher than
the upper limit of normal or 2.75 mmol/L ( 11 mg/dL); (2) renal insufficiency: serum
creatinine 177 mol/L (2 mg/dL) or creatinine clearance 40 mL/minute; (3) anemia:
hemoglobin value of 2 g/dL below the lower normal limit, or a hemoglobin value 10
g/dL; (4) bone lesions: one or more osteolytic lesion revealed by skeletal radiography, CT,
or PET-CT.
**MDE: Myeloma-defining events include CRAB symptoms (above) or any one or more of the
following biomarkers of malignancy: clonal bone marrow plasma cell percentage 60%;
involved/uninvolved serum free light-chain ratio 100; 1 focal lesions revealed by MRI
studies.
age, then myeloma-related symptomatology should be considered.
Finally, if there is a single bone lesion present with no
other symptoms, it is essential to rule out the presence of a
benign bone cyst.
DIAGNOSTIC EVALUATION
Initial investigation of a patient with suspected SMM should
include the tests shown in Sidebar 1, which are coincidental
KEY POINTS
Smoldering multiple myeloma is not a homogeneous plasma
cell disorder and includes patients at low, intermediate,
and high risk of progression to symptomatic multiple
myeloma.
All newly diagnosed SMM patients should be stratified
according to their risk.
It is essential to identify asymptomatic patients at high
risk of progression to symptomatic disease, in which the
progression risk is 50% at 2 years following diagnosis,
because they require close follow-up and, if possible,
inclusion in clinical trials.
Although the standard of care has been not to administer
treatment until symptoms arise, early treatment with
lenalidomide plus dexamethasone has helped change the
treatment paradigm for patients with high-risk SMM.
The updated International Myeloma Working Group criteria
allow us to initiate therapy in patients who would
previously have been considered asymptomatic on the
basis of the absence of calcium, renal insufficiency,
anemia, or bone lesions (CRAB) features, but who possess
a specific biomarker predicting ultra-high risk of
progression.
In the future, novel therapeutic approaches will determine
whether early treatment of patients with asymptomatic
high-risk disease can definitively prevent the development
of myeloma-related symptoms.
SIDEBAR 1. Evaluation of Patients Newly
Diagnosed With SMM
Medical history and physical examination
Hemogram
Biochemical studies, including of creatinine and calcium
levels; beta 2-microglobulin, LDH, and albumin
Protein studies
- Total serum protein and serum electrophoresis (serum M-
protein)
- 24-hour urine sample protein electrophoresis (urine M-protein)
- Serum and urine immunofixation
Serum free light-chain measurement (FLC ratio)
Bone marrow aspirate with or without biopsy: infiltration by
clonal plasma cells, flow cytometry, and fluorescence in situ
hybridization analysis
Skeletal survey, CT, or PET-CT
MRI of thoracic and lumbar spine and pelvis; ideally wholebody
MRI
Abbreviations: SMM, smoldering multiple myeloma; LDH, lactate dehydrogenase; PET-CT,
18 F-fluorodeoxyglucose (FDG) PET/CT.
with those used for a correct diagnosis of symptomatic MM. 5
However, as result of the updated IMWG criteria for the diagnosis
of MM, there are some specifıc assessments to be
aware of in order to make a correct diagnosis of SMM. 2
First, the IMWG recommends that bone disease be evaluated
by x-ray, [ 18 F]fluorodeoxyglucose (FDG) PET/CT or
low-dose whole-body CT in all patients with suspected SMM,
with the exact modality determined by availability and resources.
The aim is to exclude the presence of osteolytic bone
lesions, currently defıned by the presence of at least one lesion
( 5 mm) revealed by x-ray, CT, or PET-CT. In addition,
a whole-body MRI of the spine and pelvis is a necessary
component of the initial evaluation. It provides detailed information
about not only bone marrow involvement, but
also the presence of focal lesions that predict more rapid progression
to symptomatic myeloma. Hillengass et al reported
in 2010 that the presence of more than one focal lesion in
whole-body MRI was associated with a substantially shorter
median time to progression (TTP) to active disease (13
months) compared with the period when no focal lesions
were present. 6 Kastritis et al reported similar results after the
analysis of a subgroup of patients who underwent spinal MRI
and were followed for a minimum of 2.5 years. The median
TTP to symptomatic disease was 14 months when more than
one focal lesion was present. 7 Therefore, if more than one
focal lesion in MRI is present in patients with SMM, the disease
should no longer be considered as SMM but as MM, according
to the current IMWG criteria.
Second, with respect to bone marrow infıltration, the Mayo
Clinic group evaluated BMPC infıltration in a cohort of 651
patients and found that 21 (3.2%) had extreme infıltration (
60%). 8 This group of patients had a median TTP to active
disease of 7.7 months, with a 95% risk of progression at 2
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e485