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MATEOS AND SAN MIGUEL
Smoldering Multiple Myeloma: When to Observe and When
to Treat?
María-Victoria Mateos, MD, PhD, and Jesús-F San Miguel, MD, PhD
OVERVIEW
Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of at least 3 g/dL of serum M-protein
and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple
myeloma (MM) is not uniform and several markers are useful for identifying patients at high risk of progression. The definition of the
disease has recently been revisited and patients with asymptomatic MM at 80% to 90% of progression risk at 2 years are now
considered to have MM. Although the current standard of care is not to treat, a randomized trial in patients with high-risk SMM that
compared early treatment versus observation demonstrated that early intervention resulted in substantial benefits in terms of time
to progression and overall survival (OS). These findings highlight the need to follow a correct diagnosis by an accurate risk stratification
to plan an optimized follow-up according to the risk of disease progression.
Smoldering multiple myeloma is an asymptomatic plasma
cell disorder defıned in 1980 by Kyle and Greipp on the
basis of a series of six patients who met the criteria for MM
but whose disease did not have an aggressive course. 1
At the end of 2014, the International Myeloma Working
Group (IMWG) updated the defınition of SMM as a plasma
cell disorder characterized by a minimum of 3 g/dL of serum
M-protein and/or 10% to 60% bone marrow plasma cells
(BMPCs), but with no evidence of myeloma-related symptomatology
(hypercalcemia, renal insuffıciency, anemia, or bone lesions
[CRAB]) or any other myeloma-defıning event (MDE). 2
According to this recent update, the defınition of SMM excludes
asymptomatic patients with BMPCs of 60% or more, serum
free-light chain (FLC) levels of 100 or greater, and those with
two or more focal lesions of the skeleton as revealed by MRI. The
new criteria were introduced because independent studies
showed that patients with these features have an ultra-high risk
of progression to MM (80% to 90% at 2 years), and that they
should therefore be considered as patients with MM.
The incidence of SMM differs from one series to another,
and the median age of the patients at diagnosis, as with other
plasma cell disorders, ranges from 65 to 70 years. 3 Kristinsson
et al, through the Swedish Myeloma Registry, recently
reported that 14% of patients diagnosed with myeloma had
SMM and, taking the world population as a reference, that
the age-standardized incidence of SMM was 0.44 cases per
100,000 people. 4
In this article, we focus on SMM, evaluate the prognostic
factors that predict progression to symptomatic MM, and examine
how patients may be managed, particularly with respect
to the possibility of early treatment.
DIFFERENTIAL DIAGNOSIS WITH OTHER ENTITIES
SMM must be distinguished from other plasma cell disorders,
such as monoclonal gammopathy of undetermined signifıcance
(MGUS) and symptomatic MM (Table 1). The
MGUS entity is characterized by a level of serum M-protein
of less than 3 g/dL plus less than 10% of plasma cell infıltration
in the bone marrow, with no CRAB and no MDE.
Symptomatic MM must always have CRAB symptomatology
or MDE, in conjunction with a minimum of 10%
clonal BMPC infıltration or biopsy-proven bony or extramedullary
plasacytoma. 2
End-organ damage often needs to be correctly evaluated to
distinguish myeloma-related symptomatology from some
signs or symptoms that could otherwise be attributed to comorbidities
or concomitant diseases, 3 such as anemia due to
iron, vitamin B12 or folic acid defıciency, or to the presence
of autoimmune or chronic diseases, or myelodysplastic syndromes.
In the case of moderate or severe renal impairment,
patients with hypertension or diabetes should be carefully assessed.
In patients who have isolated hypercalcemia without
bone lesions, the presence of hyperparathyroidism should be
considered, and diffuse osteoporosis should always be carefully
evaluated, especially in women, to determine whether it
is related to myeloma. If osteoporosis starts suddenly or is
more extensive than expected for someone of the patient’s
From the University Hospital of Salamanca/IBSAL, Salamanca, Spain; Clínica Universidad de Navarra/CIMA, Navarra, Spain.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: María-Victoria Mateos, MD, PhD, University Hospital of Salamanca/IBSAL, Paseo San Vicente, 58-182, 37007 Salamanca, Spain; email: mvmateos@usal.es.
© 2015 by American Society of Clinical Oncology.
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2015 ASCO EDUCATIONAL BOOK | asco.org/edbook