International Journal of Laboratory Hematology

The Official journal of the International Society for Laboratory Hematology

REVIEW ARTICLE INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY

Diagnosis, risk stratification and management of monoclonal

gammopathy of undetermined significance and smoldering
multiple myeloma
N. W. C. J. VAN DE DONK*, T. MUTIS*, P. J. PODDIGHE † , H. M. LOKHORST*, S. ZWEEGMAN*

*Department of Hematology, VU
University Medical Center,
Amsterdam, The Netherlands
†
Department of Clinical
Genetics, VU University Medical
Center, Amsterdam, The
Netherlands
Correspondence:
Dr Niels W. C. J. van de Donk,
Department of Hematology, VU
University Medical Center, De
Boelelaan 1117, 1081HV Ams-
terdam, The Netherlands. Tel.:
+31 (0)20 4442604; Fax: +31
(0)20 44442601; E-mail:
n.vandedonk@vumc.nl
doi:10.1111/ijlh.12504
accepted for publication 5 April
2016
Keywords
Monoclonal gammopathy of
undetermined significance,
smoldering multiple myeloma,
multiple myeloma, diagnosis,
management, treatment
S U M M A RY
Monoclonal gammopathy of undetermined significance (MGUS) is
one of the most common premalignant disorders. IgG and IgA
MGUS are precursor conditions of multiple myeloma (MM),
whereas light-chain MGUS is a precursor condition of light-chain
MM. Smoldering MM (SMM) is a precursor condition with higher
tumor burden and higher risk of progression to symptomatic MM
compared to MGUS. Assessment of the risk of progression of
patients with asymptomatic monoclonal gammopathies is based on
various factors including clonal burden, as well as biological char-
acteristics, such as cytogenetic abnormalities and light-chain pro-
duction. Several models have been constructed that are useful in
daily practice for predicting risk of progression of MGUS or SMM.
Importantly, the plasma cell clone may occasionally be responsible
for severe organ damage through the production of a M-protein
which deposits in tissues or has autoantibody activity. These disor-
ders are rare and often require therapy directed at eradication of
the underlying clone. Importantly, recent studies have shown that
asymptomatic patients with a bone marrow plasma cell percentage
≥60%, free light-chain ratio ≥100, or >1 focal lesion on MRI (mye-
loma-defining events) have a 80% risk of developing symptomatic
MM within 2 years. These patients are now considered to have
MM requiring therapy, similar to patients with symptomatic dis-
ease. In this review, we provide an overview of the new diagnostic
criteria of the monoclonal gammopathies and discuss risk of pro-
gression to active MM. We also provide recommendations for the
management of patients with MGUS and SMM including
risk-adapted follow-up.

110 © 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122

INTRODUCTION
Nearly all symptomatic plasma cell disorders are pre-
ceded by an asymptomatic precursor state [1, 2],
which is the most common form of the plasma cell
dyscrasias. Progression of an asymptomatic plasma
cell disorder involves a multistep transformation pro-
cess occurring as a consequence of the sequential
acquisition of genetic events such as chromosomal
abnormalities, mutations, and epigenetic alterations
leading to altered gene expression [3–6]. Multiple
myeloma (MM) development is also accompanied by
altered interactions of the tumor cells with various
components of their bone marrow microenvironment
such as osteoclasts, endothelial cells, and cells of the
immune system [6]. Recent data suggest that progres-
sion from monoclonal gammopathy of undetermined
significance (MGUS) to smoldering multiple myeloma
(SMM) and then to MM is also mediated via competi-
tion between subclones and outgrowth of the fittest
[3].
IgG or IgA MGUS patients typically progress to
MM, and IgM MGUS patients progress to Walden-
str€
om’s macroglobulinemia (WM) or other lympho-
proliferative disorders [7]. Patients with a light chain
only asymptomatic monoclonal gammopathy are at
risk of developing light-chain MM or immunoglobulin
light-chain amyloidosis (AL amyloidosis) [2, 8, 9].
In this review, we will not discuss IgM MGUS,
smoldering WM, or symptomatic WM, but we will
focus on the diagnosis and risk stratification of mye-
loma and its asymptomatic precursor states.
DEFINITIONS
Monoclonal gammopathy of undetermined significance
Monoclonal gammopathy of undetermined signifi-
cance affects approximately 3.5% of the population
older than 50 years [8, 10, 11]. IgG and IgA MGUS
are defined by a M-protein <30 g/L, bone marrow
(BM) plasma cell percentage <10%, and absence of
signs or symptoms related to MM (CRAB criteria:
hypercalcemia, renal insufficiency, anemia, or bone
lesions; Table 1) or other lymphoproliferative disor-
ders [11, 12]. Light-chain MGUS is defined by an
abnormal j/k free light-chain (FLC) ratio, increase in
concentration of the involved light chain, and absence
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM 111
of expression of a monoclonal peak of immunoglobu-
lin heavy chain in the serum on immunofixation [8].
In case of renal disease or polyclonal B-cell activation,
increased levels of j and k chains may be observed,
but with a normal ratio. In persons aged 50 years and
older, light-chain MGUS has a prevalence of
~0.7–0.8% [8, 10]. Obesity and personal history of
autoimmune diseases, inflammatory conditions, and
infections are associated with increased risk of MGUS
[4]. Furthermore, occupational studies have demon-
strated that exposure to radiation or pesticide is asso-
ciated with the development of MGUS [4]. Also,
Vietnam war veterans exposed to the herbicide agent
orange had a 2.4-fold increased risk for MGUS [13].
Smoldering multiple myeloma
Smoldering MM (SMM) is a premalignant plasma cell
disorder with a higher tumor burden (M-protein
≥30 g/L and/or BM plasma cells 10–60%) and higher
risk of progression compared to MGUS (Table 1) [14].
Similar to MGUS, SMM is characterized by the
absence of CRAB features. Importantly, SMM patients
with a BM plasma cell percentage ≥60%, FLC ratio
≥100, or >1 lesion on MRI (either with whole-body
MRI [15] or axial MRI [16]) have approximately an
80% risk of developing CRAB features within 2 years
[17, 18]. Using these biomarkers of malignancy, a
small subgroup of ultra-high-risk SMM patients is
identified, which according to the revised IMWG crite-
ria are now considered to have MM requiring therapy
irrespective of the presence or absence of CRAB fea-
tures. Treatment should be considered in these
patients to prevent serious end-organ damage such as
bone fractures or renal failure, which can have long-
term effects on the quality of life of patients. How-
ever, two recent studies showed that SMM patients
with a FLC ratio ≥100 have a 2-year progression risk
of 30% and 64% [19, 20], which is lower than
reported in two previous studies (progression risk at
2 years: ~80%) [21, 22] that were used for these
updated IMWG criteria [18]. The authors from these
studies conclude that FLC ratio ≥100 as a sole crite-
rion for treating as active MM may not be justified,
but that very close monitoring is warranted for this
group.
The light-chain equivalent of SMM (light-chain
SMM or idiopathic Bence Jones proteinuria) is
112 N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM

Table 1. Diagnostic criteria

International Myeloma Working Group (IMWG) consensus diagnostic criteria [18]

Non-IgM MGUS* Serum M-protein <30 g/L and

Clonal bone marrow plasma cells <10% and
Absence of end-organ damage†,‡
IgM MGUS Serum IgM M-protein <30 g/L and
Bone marrow lymphoplasmacytic infiltration <10% and
Absence of end-organ damage‡,§
Light-chain MGUS Abnormal FLC ratio (<0.26 or >1.65) and
Increased level of the involved light chain and
No immunoglobulin heavy-chain expression on immunofixation and
Clonal bone marrow plasma cells <10% and
Urinary monoclonal protein <500 mg/24 h and
Absence of end-organ damage†,‡
Smoldering MM Serum M-protein ≥30 g/L and/or
Clonal bone marrow plasma cells 10–60% and
Absence of myeloma-defining events¶ or amyloidosis
Idiopathic Bence Jones Urinary M-protein ≥500 mg/24 h and/or
proteinuria Clonal bone marrow plasma cells 10–60%
No immunoglobulin heavy-chain expression on immunofixation
Absence of myeloma-defining events¶ or amyloidosis
Symptomatic MM Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary
plasmacytoma and any one or more of the myeloma-defining events (end-organ damage
or biomarker of malignancy)¶

*Almost all patients have IgG or IgA MGUS. IgD isotype is found in only ~0.04–0.1% of MGUS patients. Very rarely,
cases of IgE MGUS have been reported.
†
End-organ damage includes 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)], renal insufficiency [Creatinine clearance <40 mL/min or serum creatinine
>177 lmol/L (>2 mg/dL)], anemia [Hemoglobin value of >20 g/L (>1.25 mM) below the lower limit of normal, or a
hemoglobin value <100 g/L (<6.2 mM)], and lytic bone lesions (one or more osteolytic lesions on skeletal radiography,
CT, or PET-CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish
from solitary plasmacytoma with minimal bone marrow involvement) (CRAB) that can be attributed to the plasma cell
proliferative disorder.
‡
In particular, in elderly persons, other causes should be considered such as deficiencies of vitamin B12, folic acid or
iron for anemia; primary hyperparathyroidism for hypercalcemia; diabetes and hypertension for renal insufficiency;
metastatic carcinoma for lytic bone lesions [75].
§
End-organ damage includes anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hep-
atosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
¶
Myeloma-defining events: evidence of end-organ damage that can be attributed to the underlying plasma cell prolifer-
ative disorder, specifically hypercalcemia, renal insufficiency, anemia, or bone lesions, or any one or more of the fol-
lowing biomarkers of malignancy [clonal BM plasma cell percentage ≥60%, involved:uninvolved serum free light chain
ratio ≥100 (the involved free light chain must be ≥100 mg/L), or >1 focal lesions on MRI studies (each focal lesion
must be 5 mm or more in size)].

defined by complete loss of immunoglobulin heavy-
chain expression, plus either urinary light-chain
excretion of ≥0.5 g/24 h or BM plasma cells 10–60%
[23]. These patients are at increased risk of developing
light-chain MM or light-chain amyloidosis [23]. The
FLC assay is easier to obtain than 24-h urine M-pro-
tein measurements. However, at this moment, it is
unknown which FLC threshold can be used to
differentiate between light-chain MGUS and light-
chain SMM [23].
Multiple myeloma
As described in the previous section, the IMWG crite-
ria for multiple myeloma were updated in November
2014 and now include also validated biomarkers in

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122

addition to existing requirements of attributable CRAB
features (hypercalcemia, renal failure, anemia, and
bone lesions) [18]. As discussed in the section on
SMM, these biomarkers are BM plasma cell percent-
age ≥60%, FLC ratio ≥100, or >1 focal lesion on MRI
[15, 16, 24] (Table 1).
PROGRESSION OF MGUS
Progression of MGUS to MM or other related malig-
nancies occurs at a rate of approximately 1% per year
[12, 25, 26]. Even after >25 years of follow-up, the
risk of progression does not decrease. As many MGUS
patients have advanced age and comorbidities, they
will often die from unrelated diseases.
The risk of progression for light-chain MGUS is
lower when compared to the risk of progression in
conventional MGUS. In a population-based cohort
study, only 3 of 133 light-chain MGUS patients expe-
rienced progression to MM (all three developed light-
chain MM) during 1100 patient-years of follow-up
(progression rate: 0.27% per year) MM [8]. Similarly,
in another study, none of 34 light-chain MGUS cases
had progression during a median observation time of
5 years [10]. Importantly, it is possible that a small
proportion of the patients with apparent light-chain
MGUS do not have a true clonal disorder but rather
renal dysfunction or polyclonal activation [8].
Predictors of malignant transformation in MGUS
Various presenting features are helpful in predicting
risk of progression of MGUS to symptomatic disease
and therefore in individualizing follow-up. The size of
the MGUS clone as determined by BM plasma cell
percentage [25–30] or M-protein level [12, 25–29, 31–
37] is an important risk factor for progression of
MGUS.
In addition, several biological characteristics of the
clone have predictive value in conventional MGUS
including heavy-chain isotype (IgA/IgM > IgG) [12,
25, 28, 31, 32, 34, 35, 38]; light-chain production as
determined by abnormal serum FLC ratio [31, 39] or
presence of Bence Jones proteinuria [25, 27, 37];
detection of circulating plasma cells [34] or clonal B
cells [40]; increased bone resorption in bone biopsy
[41]; clonal heterogeneity [42]; DNA aneuploidy
determined by flow cytometry [27]; and abnormal
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM 113
metaphase cytogenetics [42]. Gene expression profil-
ing of purified plasma cells has recently been demon-
strated to have prognostic value [43]. It is currently
unknown whether specific chromosomal abnormali-
ties, including del(17p) and t(4;14), are predictive of
malignant progression in MGUS.
Furthermore, suppression of nonclonal BM plasma
cells, based on multiparameter flow cytometric analy-
sis, has been identified as a risk factor for progression
[27, 44], which explains the predictive value of
reduced levels of polyclonal serum immunoglobulins
[25, 27, 35, 37, 45]. Moreover, several imaging tech-
niques may be useful in predicting progression of
MGUS. In this respect, detection of focal lesions by
MRI at baseline [36, 43, 46] and development of focal
lesions by MRI or PET-CT are predictive for progres-
sion to active MM [46].
Not only baseline characteristics but also the
dynamics of the plasma cell clone during the first
years of follow-up is helpful in predicting the risk of
transformation to a malignant plasma cell disorder.
Indeed, Rosinol et al. [28] showed that a progressive
increase of the M-protein (evolving MGUS) predicted
progression.
Until now, no predictive factors for progression
have been identified for light-chain MGUS. It is cur-
rently unknown whether higher levels of the involved
light chain result in a higher risk of malignant trans-
formation in light-chain MGUS.
Prediction models in MGUS
The Mayo Clinic MM group constructed a model for
predicting risk of progression of MGUS based on three
parameters: the size of the M-protein (≥15 g/L), type
of M-protein (non-IgG), and the presence of an
abnormal FLC ratio [31]. In this model, the absolute
risk of progression at 20 years was 5% for patients
without risk factors (low-risk MGUS), 21% for
patients with 1 risk factor (low-intermediate-risk
MGUS), 37% for patients with two risk factors (high-
intermediate-risk MGUS), and 58% for patients with
three risk factors (high-risk MGUS) (Table 2). Another
prognostic stratification system was proposed by
Perez-Persona et al. [27] which is based on the per-
centage of aberrant plasma cells and DNA aneuploidy,
which were both assessed by flow cytometric analysis.
Also, the combination of the presence of an evolving
114 N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM

Table 2. Models that predict risk of progression of monoclonal gammopathy of undetermined significance

Perez-Persona et al. [27] Perez-Persona et al. [44]

Rajkumar et al. [31] (n = 1148) (n = 276) (n = 311)

Serum M-protein ≥15 g/L ≥95% aberrant bone ≥95% aberrant bone
Non-IgG subtype marrow plasma cells marrow plasma cells
Abnormal FLC ratio DNA aneuploidy Evolving MGUS*
Number of risk Risk of progression at % Of Risk of progression at % Of Risk of progression at % Of
factors 20 years (%) total 5 years (%) total 7 years (%) total

0 5 39 2 46 2 49
1 21 37 10 48 16 45
2 37 20 46 6 72 6
3 58 5 – – – –

*Evolving MGUS is defined as an increase of M-protein of at least 10% by the third year, confirmed by two consecu-
tive measurements separated by at least 1 month.

M-protein and percentage of aberrant plasma cells (a) (b)

identifies three different risk groups of MGUS patients
[44] (Table 2).

PROGRESSION OF SMM
Smoldering multiple myeloma represents an interme-
diate stage between MGUS and MM and has a risk of
progression of approximately 10% per year for the
first 5 years and decreases thereafter. This contrasts
with MGUS, in which the rate of progression is con-
stant over time [47]. The risk of progression of
patients with SMM is dependent on tumor mass, as
reflected by M-protein level and bone marrow plasma
cell percentage [25, 27, 47, 48].
Other factors that predict progression to symp-
tomatic disease include abnormal plasma cell pheno-
type in ≥95% of cells, high plasma cell proliferative
rate, hypogammaglobulinemia, gene expression
profile of the purified MM cells, abnormal free light-
chain ratio, increasing M-protein, presence and devel-
opment of MRI abnormalities, or peripheral blood
circulating plasma cells [27, 43, 44, 49–54]. Also,
hyperdiploidy, del(17p), t(4;14), and ampl(1q) are
adverse prognostic factors in SMM, independent of
tumor load [55, 56] (Figure 1).
Newer imaging techniques have a higher sensitivity
compared to conventional X-rays for the detection of
MM bone lesions. The IMWG also recently stated that
evidence of osteolysis on CT or 18-F-FDG PET-CT
Figure 1. FISH analysis of smoldering myeloma cells.
(a) Hyperdiploidy as detected by interphase FISH
with a probe for chromosome 5 (green),
chromosome 9 (bright blue) and chromosome 15
(red). Five hyperdiplo€ıd cells, containing three or
four copies of chr5, 9 and 15. There are two normal
cells (arrow) with two copies of chr5, 9 and 15. The
cells are counterstained with DAPI (blue). The probe
used: D5S23, D5S721/CEP9/CEP15 FISH Probe Kit
(Abbott). (b) Deletion 17p13.1 (TP53) as detected by
interphase FISH with a probe for TP53 (red) and
centromere 17 (green). Five of the seven cells show
one red and two green signals, indicative for del
(17p) (TP53). The cells are counterstained with DAPI
(blue). The commercial probe used: P53 Deletion
Probe (Cytocell).
meets the definition of bone disease in MM [18].
However, PET-CT also identifies patients with SMM
who present with focal areas of visually detectable
increased tracer uptake (hypermetabolic lesions) or
diffuse BM hypermetabolism in the absence of under-
lying osteolysis. Two studies showed that SMM
patients with an increased focal uptake or BM

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122

hypermetabolism without underlying osteolysis on
PET-CT (8–16% of the patients with SMM) have a
higher probability of progression, compared to patients
without these abnormalities [57, 58]. Risk of progres-
sion to symptomatic MM within 2 years was 58–61%
[57, 58].
Risk progression in light-chain SMM is approxi-
mately 5% per year during the first 5 years and
decreases thereafter [23]. This risk of progression is
lower when compared to conventional SMM, but
higher when compared to light-chain MGUS. In light-
chain SMM, the risk of progression was higher in
patients with 24-h M-protein levels ≥1.0 g/24 h com-
pared to patients with urinary M-protein levels 0.5–
1.0 g/24 h (5-year risk of progression: 39% vs. 19%;
10-year risk of progression: 58% vs. 32%) [23].
Prediction models in SMM
Several prognostic models have been developed to
predict risk of progression in SMM, but the Mayo
Clinic model and PETHEMA classification are most
widely used. The Mayo Clinic Model identified three
groups of patients based on the percentage of bone
marrow plasma cells (≥10% or <10%), the M-protein
level (≥30 or <30 g/L), and the FLC ratio (<0.125 or
>8) [49]. Patients with three risk factors have a risk of
progression toward symptomatic MM at 10 years of
84%, while this was 50% and 65% with 1 or 2 risk
factors [49]. The Spanish PETHEMA group uses the
percentage of abnormal plasma cells in multiparamet-
ric flow cytometry (≥95% or <95%) and absence or
presence of immunoparesis [27]. Risk of progression
to symptomatic disease at 5 years was 4% in patients
without risk factors, and 46% and 72% for patients
with 1 or 2 risk factors, respectively [27].
Several other prognostic models have been pub-
lished, including a recent Danish model derived from
a population-based study, in which M-protein ≥30 g/
L and immunoparesis were markers for time to pro-
gression to MM in SMM (Table 3) [20]. In addition,
the Arkansas group generated a risk-stratification
model based on expression levels of only four genes
combined with serum M-protein (≥30 g/L) and albu-
min levels (<35 g/L). The high-risk, intermediate-
risk, and low-risk groups had a 2-year progression
probability of 5.0%, 44.8%, and 85.7%, respectively
[54].
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM 115
M - P R OT E I N - R E L AT E D D I S O R D E R S
Although patients with MGUS and SMM are at
increased risk of developing active MM, the vast
majority of these patients has no symptoms that can
be attributed to the plasma cell clone. However,
sometimes the MGUS/SMM plasma cell clone is
responsible for the development of severe organ
damage through the production of a M-protein with
autoantibody activity. This may result in rare hema-
tologic conditions such as immune thrombocytopenic
purpura (ITP) [59], acquired von Willebrand’s disease
[60], or acquired deficiency of FVIII [61]. Also, sev-
eral renal diseases are caused by toxic M-proteins
produced by the plasma cell clone: monoclonal
immunoglobulin deposition disease (MIDD), light-
chain proximal tubulopathy, immunotactoid
glomerulopathy, proliferative glomerulonephritis with
monoclonal immunoglobulin deposits (PGNMID), and
type 1 and type 2 cryoglobulinemic glomerulonephritis
[62–64]. In these disorders, the M-protein is the direct
cause of the kidney disease and these diseases are char-
acterized by the presence of monoclonal deposits in kid-
ney biopsies. Also, several skin disorders, neurologic
disorders, and metabolic disturbances have been identi-
fied in which a M-protein with auto-antibody activity
plays an important role in the pathogenesis of the dis-
ease [4].
The plasma cell clone may also produce mono-
clonal antibodies or misfolded immunoglobulin light
chains that deposit in tissues leading to M-protein-
related disorders with systemic manifestations (e.g.,
AL amyloidosis and type I cryoglobulinemia) [65].
The understanding of the pathogenesis of some of
these associated disorders is limited and may be
related to both M-protein and growth factors pro-
duced by the underlying clone, such as in POEMS
syndrome.
D I AG N O S T I C C O N S I D E R AT I O N S
Patients with symptoms or laboratory abnormalities,
which may be related to the underlying MGUS or SMM
clone
Monoclonal gammopathy of undetermined signifi-
cance or patients with SMM are frequently identified
when serum protein electrophoresis is ordered as part
116 N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM

Table 3. Models that predict risk of progression of SMM

Perez-Persona et al. [27]

Dispenzieri et al. [49] (n = 273) (n = 106) Sorrig et al. [20] (n = 297)

≥95% aberrant bone

marrow plasma cells
Bone marrow plasma Immunoparesis (reduction M-protein ≥30 g/L
cell percentage ≥10% in the levels of 1 or 2 Immunoparesis (reduction in
M-protein ≥30 g/L uninvolved the levels of 1 or 2 uninvolved
FLC ratio <0.125 or >8 immunoglobulins immunoglobulins
Risk of Risk of Risk of Risk of
Number progression progression progression progression
of risk at 5 years at 10 years % Of Risk of progression % Of at 2 years at 5 years % Of
factors (%) (%) total at 5 years (%) total (%) (%) total

0 – – – 4 36.8 4.8 9 30.3

1 25 50 29.7 46 36.8 18.1 24 55.6
2 51 65 41.8 72 26.4 38.4 55 14.1
3 76 84 28.6 – – – – –

of a diagnostic assessment for various symptoms

including back pain, fatigue, and recurrent infections.
Similarly, serum protein electrophoresis is often
requested in case of laboratory abnormalities such as
anemia, hypercalcemia, elevated total protein, or
renal failure, as well as when osteolytic bone lesions
are detected. In these cases, the European Myeloma
Network (EMN) recommends to exclude the presence
of a symptomatic plasma cell disorder (MM, WM, AL
amyloidosis, or CLL) by laboratory tests (complete
blood count with differential, blood chemistry [includ-
ing calcium, albumin, and creatinine], serum and
urine protein electrophoresis with immunofixation,
and measurement of FLCs), BM biopsy and aspiration,
and imaging studies. The IMWG recommends to eval-
uate bone disease by whole-body X-ray, whole-body
CT, or PET-CT [18].
In addition, fat, BM, or rectum biopsy with
Congo red staining should be performed in case AL
amyloidosis is suspected. A kidney biopsy is often
indicated to exclude a monoclonal gammopathy of
renal significance, when a patient has significant
proteinuria or renal insufficiency. To demonstrate
monoclonal deposits and their pattern of organiza-
tion, immunofluorescence and electron microscopic
studies should part of the diagnostic evaluation [62,
64].
Asymptomatic patients
A large Italian study showed that the risk of detect-
ing a plasma cell infiltration ≥10% in patients with-
out bone pain with a M-protein ≤15 or ≤10 g/L is
very low (7.3% and 5.0%, respectively). But this risk
is dependent on heavy-chain isotype (4.7% and
3.5% for IgG isotype; 20.5% and 14.0% for IgA)
[66]. This study also showed that the likelihood of
finding bone lesions at skeletal survey is very low for
IgG (1.7% and 2%) as well as IgA isotypes (6.4%
and 0.0% for M-protein ≤15 and ≤10 g/L, respec-
tively) [66]. Therefore, most specialists do not rou-
tinely recommend BM examination in asymptomatic
patients with apparent IgG MGUS if the serum M-
protein is ≤15 g/L and without end-organ damage,
until there is evidence of progression to symptomatic
disease. However, for all IgA M-proteins, BM exami-
nation should be part of the diagnostic work-up. The
EMN does not routinely recommend imaging when
patients have a serum IgG M-protein ≤15 g/L or IgA
M-protein ≤10 g/L without bone pain, while for all
other asymptomatic patients imaging should be con-
sidered. Importantly, in case of limited life expec-
tancy, it can be justified to exclude bone marrow
investigation and imaging from the diagnostic work-
up.

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 N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM 117

Concerning asymptomatic patients with light chain
only disease, there are currently no data available that
guide diagnostic work-up. The EMN does not recom-
mend to routinely perform BM examination and
imaging in asymptomatic patients with apparent light-
chain MGUS [4]. However, in patients with high
levels of the involved light chain (e.g., FLC ratio >10
or <0.10), BM evaluation and imaging should be con-
sidered.
Additional considerations in SMM
At the time of SMM diagnosis, similar tests have to
performed as in MGUS including bone marrow evalu-
ation and a skeletal survey (preferably by whole-body
CT). In case of absence of osteolytic lesions on CT,
one could consider to perform a MRI of the spine and
pelvis to identify patients who have >1 focal lesion
and therefore should be considered for treatment.
Also, assessment of cytogenetic abnormalities may be
helpful to estimate risk of progression [67].
F O L L OW- U P
Follow-up of MGUS patients
Current guidelines recommend lifelong follow-up of
MGUS patients to diagnose malignant transformation
before the onset of serious complications. This may
avoid hospitalizations and costs and also preserve
quality of life. Indeed, two recent population studies
have shown benefits of MGUS follow-up [68, 69].
First, a Swedish study showed improved survival of
survival from the time of myeloma diagnosis, compared
to suboptimal follow-up [70]. Progression between
screening visits may explain the inadequacy of follow-
up in this study [70].
By taking into account the patient’s risk of progres-
sion and life expectancy, follow-up can be individual-
ized. The recent EMN guideline recommends to use
the Mayo Clinic risk-stratification model to predict
progression [31], because the three prognostic vari-
ables in this model can be easily assessed in all MGUS
patients (Table 2). Follow-up consists of a careful his-
tory, physical examination, and laboratory studies
(quantitation of M-protein, complete blood count, cal-
cium, and creatinine). Therapy should be started only
when symptomatic disease develops.
The EMN guideline recommends that patients with
intermediate risk (risk of progression at 20 years: 21–
37% according to Mayo Clinic risk-stratification
model [31]) or high-risk MGUS (risk of progression at
20 years: 58%) should be monitored more strictly (at
6 months, and annually thereafter) than patients with
low-risk MGUS (risk of progression at 20 years: 5%)
for whom less frequent follow-up is reasonable (at
6 months, and every 1–2 years thereafter) [4] (Fig-
ure 2). Many MGUS patients can receive appropriate
follow-up in primary care. On the other hand,
patients with low-risk MGUS may not need annual
follow-up, but only laboratory investigations, imaging,
MGUS
M-protein <30 g/l
SMM
M-protein ≥30 g/l
MM
BM PC ≥10% or biopsy proven bony or
BM PC <10% BM PC%: 10-60% extramedullary plasmacytoma
No end-organ damage FLC ratio ≤100
Focal lesions on MRI <2
PLUS
End-organ damage (CRAB features)
Risk of progression: 1%/year No end-organ damage or

MM patients with prior knowledge of MGUS, suggest- Risk of progression:

10%/year for first 5 years
Biomarker of malignancy (BM PC%
≥60%; FLC ratio ≥100; ≥2 focal lesions on
MRI)
and decreases thereafter
ing that earlier treatment of MM leads to better sur- Risk factors
-non-IgG subtype
Risk factors
-M-protein ≥15 g/l
Risk factors -ISS (albumin and β2-microglobulin
vival [69]. Secondly, the SEER database analysis -Abnormal FLC ratio
-BM PC% ≥10%
-M-protein ≥30 g/l
-FISH abnormalities (e.g. del(17p); t(4;14); ampl(1q))
-Elevated LDH
-FLC ratio <0.125 or >8
Low-risk (no risk factors):
showed that MGUS follow-up was an independent Follow-up at 6 months, and if stable
every 1-2 years
or
predictor of lower rates of complications at the diag- No further follow-up but additional
investigations only in case of Low-risk (1 risk factor):
Follow-up at 2-3 months, and every 6-
Treatment (based on patient and tumor-characteristics

symptoms suggestive of progression 12 months thereafter

nosis of malignancy [68]. Furthermore, patients with Intermediate-risk (2 risk factors):
Non low risk (≥1 risk factor):
Follow-up at 2-3 months, and every 3-
MGUS follow-up examination had improved OS calcu- Follow-up at 6 months, and annually
thereafter
6 months thereafter

High-risk (3 risk factors):

lated from the time that they developed an active MGUS and life expectancy <5 years:
Consider no follow-up but additional
Follow-up at 2-3 months, and every 2-
3 months thereafter
investigations only in case of

malignancy, compared to those without MGUS follow- symtoms suggestive of progression

up [68]. In contrast to these two studies, a smaller

retrospective analysis from the Mayo Clinic of symp-
tomatic myeloma patients with preceding MGUS
(n = 116) demonstrated that follow-up (at least every
3 years) did not lead to reduced hospitalizations,
decreased myeloma-related complications, or improved
Figure 2. Follow-up of Monoclonal gammopathy of
undetermined significance (MGUS) and smoldering
multiple myeloma (SMM). Follow-up of MGUS and
patients with SMM is based on risk of progression to
active disease.

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
118 N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM
or BM analysis when symptoms suggestive of MM or
related diseases develop. In addition, no follow-up can
also be justified in elderly patients or in patients with
significant comorbidity with a short life expectancy.
Because of competing causes of death, these patients
will probably die before progression of MGUS [4].
Although the rate of progression in light-chain
MGUS is low (~0.3% per year), there is a substantial
risk of developing renal disease [8]. The EMN there-
fore recommends that patients with light-chain
MGUS should receive follow-up at 6 months, and
every year thereafter [4, 8]. MGUS patients with ele-
vated free light chains should also be checked for the
development of amyloidosis or LCDD by measuring
NT-pro-BNP and urine albumin during follow-up. In
case of abnormal results, additional investigations
should be considered including 24-h urine for total
protein, echocardiography, and ultrasound for orga-
nomegaly.
Follow-up of SMM patients
A different follow-up strategy is needed in SMM,
because risk of progression is markedly higher than in
MGUS. Patients should be re-evaluated 2–3 months
after diagnosis to determine the stability of laboratory
parameters such as serum and urine M-component,
hemoglobin, calcium, and creatinine levels [67]. Out-
side the clinical trial setting, additional radiologic
examination is only recommended if there is evidence
for progressive disease from the routine work-up.
Subsequent follow-up should be based on the
patient’s individual risk of progression. In our clinic,
we generally use the Mayo Clinic prognostic scoring
system, because it uses three easily assessable markers,
but we also take into account all other available infor-
mation to classify patients with SMM such as MRI
findings, evolving nature of the M-protein, and pres-
ence of cytogenetic abnormalities.
Low-risk patients should be followed every 6–
12 months, while intermediate-risk patients should
undergo follow-up every 3–6 months. High-risk
patients require a closer follow-up every 2–3 months
[6, 67, 71]. Alternatively, these high-risk patients may
be treated in the setting of a clinical trial (Figure 2).
Similar to light-chain MGUS, also in patients with
light-chain SMM, we recommend to monitor NT-
proBNP and urine albumin.
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
T R E AT M E N T O F M G U S A N D S M M
Treatment of SMM
Outside of the clinical trial setting, treatment for SMM
or MGUS is not recommended. Treatment is initiated
upon symptomatic progression.
In the past attempts at early intervention with alky-
lating agents, bisphosphonates, interleukin-1beta antag-
onists, or thalidomide failed to show a significant
benefit [71]. However, a recent Spanish randomized
phase 3 study showed benefit for early intervention in
patients with high-risk SMM (BM plasma cells ≥10%
and M-protein [defined as ≥30 g/L if IgG; ≥20 g/L if IgA;
or Bence Jones proteinuria >1 g/24 h], or only one of
the two criteria described above, plus at least 95% phe-
notypically aberrant plasma cells in the BM plasma
cell compartment, with reductions in one or two unin-
volved immunoglobulins of more than 25%, as
compared with normal values). In this study, early
treatment consisting of nine cycles of lenalidomide–
dexamethasone induction followed by lenalidomide
maintenance was compared with observation only. CR
was achieved in 14% of the patients during induction and
in 26% during maintenance. There was a significant ben-
efit in terms of time to progression (TTP) and OS for the
lenalidomide–dexamethasone group (median TTP: not
reached vs. 21 months; 3-year OS: 94% vs. 80%) [72].
Also, the triple combination of carfilzomib, lenalido-
mide, and dexamethasone (KRd) followed by lenalido-
mide maintenance was well tolerated and had high
efficacy in high-risk SMM (n = 12) with CR achieved
in all patients. Deeper responses are expected to result
in improved TTP and OS, and although the follow-up
of this study is short, up till now no patients experi-
enced disease progression [73]. Based on these promis-
ing results, the Spanish group is currently evaluating
in SMM a more intensive approach with carfilzomib,
lenalidomide, and dexamethasone (KRd) in induction,
followed by autologous stem cell transplantation, and
then consolidation with KRd (NCT02415413).
Furthermore, there are currently multiple trials
that are evaluating immunotherapy in patients with
high-risk SMM. Monoclonal antibodies that are
currently being evaluated include daratumumab
(anti-CD38), siltuximab (anti-interleukin-6), and
elotuzumab (anti-SLAMF7) as single agent or com-
bined with lenalidomide [67, 74].

Treatment of M-protein-related disorders
Although MGUS and patients with SMM are generally
not treated, patients with M-protein-related disorders
may benefit from clone-directed therapies.
In case of only mild symptoms, supportive care alone
may be sufficient. However, in general, the most effec-
tive treatment of M-protein-related disorders is directed
to the underlying plasma cell clone. This clone-directed
therapy should only be considered in case of aggressive
and disabling disease, because this approach is poten-
tially toxic. In addition, therapy directed at eradication
of the MGUS or SMM clone should only be instituted
when there is a clear causal relationship between
MGUS/SMM and the associated disorder [4].
In non-IgM MGUS/SMM-related disorders, anti-
myeloma agents should be used. In younger patients
(≤65–70 years), high-dose melphalan with autologous
SCT to induce a durable remission can be considered
if the symptoms are severe, progressive, and/or dis-
abling. In case of a small clone, induction therapy pre-
ceding autologous SCT is probably not needed.
However, induction therapy may be advantageous for
patients with a poor performance status due to the
MGUS/SMM-associated disorder, and in case of a sig-
nificant plasma cell clone (M-protein ≥10 g/L). In
patients with neuropathy, we consider a lenalido-
mide-based regimen as the first choice, while borte-
zomib has the highest efficacy in M-protein-associated
renal disorders, because it rapidly reduces tumor load
and toxic M-proteins. In addition, bortezomib clear-
ance is not altered in case of renal dysfunction [64].
Conclusions and future prospects
Monoclonal gammopathy of undetermined signifi-
cance and SMM are asymptomatic plasma cell disor-
ders, which have different risks of progression toward
symptomatic MM. Importantly, the updated IMWG
criteria for MM recommend to start therapy in
REFERENCES Dispenzieri A, Kumar S, Clark RJ, Baris D,
Hoover R, Rajkumar SV Monoclonal gam-
1. Landgren O, Kyle RA, Pfeiffer RM, Katz- mopathy of undetermined significance
mann JA, Caporaso NE, Hayes RB, (MGUS) consistently precedes multiple
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM 119
patients before end-organ damage appear on the basis
of specific biomarkers such as BM plasma cell percent-
age ≥60%, FLC ratio ≥100, or ≥2 focal lesions on MRI
[18]. Patients with these myeloma-defining events
have a 2-year risk of progression of approximately
80%.
Monoclonal gammopathy of undetermined signifi-
cance patients have an average risk of progression to
MM or, to a lesser extent, other lymphoproliferative
disorders of 1% per year. MGUS patients should
receive follow-up according to their risk of progression
as well as their life expectancy based on age and pres-
ence of comorbidities (Figure 2). Similarly, patients
with SMM, who have a higher risk of progression
compared to MGUS patients (risk of progression of
approximately 10% per year for the first 5 years,
which decreases thereafter), should also be monitored
carefully or enrolled on clinical trials (Figure 2). In
this respect, several studies in high-risk SMM are
evaluating new therapeutic interventions to delay or
prevent disease progression or even eradicate the
plasma cell clone.
We expect that in the nearby future increased
knowledge of mechanisms underlying the progression
of MGUS or SMM to MM results in a further
improvement in the identification of patients at high
risk of progression, which will hopefully result in an
even more tailored follow-up with start of therapy
before serious complications develop.
AU T H O R C O N T R I B U T I O N S
N.W.C.J.v.d.D. performed literature searches and pre-
pared the first draft of the manuscript; and all other
authors reviewed and edited the draft of the report
and approved the final manuscript.
CONFLICT OF INTEREST
All authors declare no conflict of interest.
myeloma: a prospective study. Blood
2009;113:5412–7.
2. Weiss BM, Abadie J, Verma P, Howard RS,
Kuehl WM. A monoclonal gammopathy
120 N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM
precedes multiple myeloma in most
patients. Blood 2009;113:5418–22.
3. Walker BA, Wardell CP, Melchor L, Brioli A,
Johnson DC, Kaiser MF, Mirabella F, Lopez-
Corral L, Humphray S, Murray L, Ross M,
Bentley D, Gutierrez NC, Garcia-Sanz R, San
MJ, Davies FE, Gonzalez D, Morgan GJ Intr-
aclonal heterogeneity is a critical early event
in the development of myeloma and pre-
cedes the development of clinical symptoms.
Leukemia 2014;28:384–90.
4. van de Donk NW, Palumbo A, Johnsen HE,
Engelhardt M, Gay F, Gregersen H, Hajek
R, Kleber M, Ludwig H, Morgan G, Musto
P, Plesner T, Sezer O, Terpos E, Waage A,
Zweegman S, Einsele H, Sonneveld P,
Lokhorst HM The clinical relevance and
management of monoclonal gammopathy
of undetermined significance and related
disorders: recommendations from the Euro-
pean Myeloma Network. Haematologica
2014;99:984–96.
5. Lopez-Corral L, Sarasquete ME, Bea S, Gar-
cia-Sanz R, Mateos MV, Corchete LA, Saya-
gues JM, Garcia EM, Blade J, Oriol A,
Hernandez-Garcia MT, Giraldo P, Hernan-
dez J, Gonzalez M, Hernandez-Rivas JM,
San Miguel JF, Gutierrez NC SNP-based
mapping arrays reveal high genomic com-
plexity in monoclonal gammopathies, from
MGUS to myeloma status. Leukemia
2012;26:2521–9.
6. Ghobrial IM, Landgren O. How I treat
smoldering multiple myeloma. Blood
2014;124:3380–8.
7. Kyle RA, Therneau TM, Rajkumar SV,
Remstein ED, Offord JR, Larson DR, Plevak
MF, Melton LJ, III Long-term follow-up of
IgM monoclonal gammopathy of undeter-
mined significance. Blood 2003;102:3759–
64.
8. Dispenzieri A, Katzmann JA, Kyle RA, Lar-
son DR, Melton LJ III, Colby CL, Therneau
TM, Clark R, Kumar SK, Bradwell A, Fon-
seca R, Jelinek DF, Rajkumar SV Preva-
lence and risk of progression of light-chain
monoclonal gammopathy of undetermined
significance: a retrospective population-
based cohort study. Lancet 2010;375:1721–
8.
9. Weiss BM, Hebreo J, Cordaro DV,
Roschewski MJ, Baker TP, Abbott KC,
Olson SW Increased serum free light chains
precede the presentation of immunoglobu-
lin light chain amyloidosis. J Clin Oncol
2014;32:2699–704.
10. Eisele L, Durig J, Huttmann A, Duhrsen U,
Assert R, Bokhof B, Erbel R, Mann K,
Jockel KH, Moebus S Prevalence and pro-
gression of monoclonal gammopathy of
undetermined significance and light-chain
MGUS in Germany. Ann Hematol
2012;91:243–8.
11. Kyle RA, Therneau TM, Rajkumar SV,
Larson DR, Plevak MF, Offord JR,
Dispenzieri A, Katzmann JA, Melton LJ, III
Prevalence of monoclonal gammopathy of
undetermined significance. N Engl J Med
2006;354:1362–9.
12. Kyle RA, Therneau TM, Rajkumar SV,
Offord JR, Larson DR, Plevak MF, Melton
LJ, III A long-term study of prognosis in
monoclonal gammopathy of undetermined
significance. N Engl J Med 2002;346:564–
9.
13. Landgren O, Shim YK, Michalek J, Costello
R, Burton D, Ketchum N, Calvo KR, Capo-
raso N, Raveche E, Middleton D, Marti G,
Vogt RF, Jr Agent orange exposure and
monoclonal gammopathy of undetermined
significance: an operation ranch hand vet-
eran cohort study. JAMA Oncol
2015;1:1061–8.
14. Kyle RA, Greipp PR. Smoldering multiple
myeloma. N Engl J Med 1980;302:1347–
9.
15. Hillengass J, Fechtner K, Weber MA,
Bauerle T, Ayyaz S, Heiss C, Hielscher T,
Moehler TM, Egerer G, Neben K, Ho AD,
Kauczor HU, Delorme S, Goldschmidt H
Prognostic significance of focal lesions in
whole-body magnetic resonance imaging in
patients with asymptomatic multiple mye-
loma. J Clin Oncol 2010;28:1606–10.
16. Kastritis E, Moulopoulos LA, Terpos E,
Koutoulidis V, Dimopoulos MA. The prog-
nostic importance of the presence of more
than one focal lesion in spine MRI of
patients with asymptomatic (smoldering)
multiple myeloma. Leukemia
2014;28:2402–3.
17. Dimopoulos MA, Hillengass J, Usmani S,
Zamagni E, Lentzsch S, Davies FE, Raje N,
Sezer O, Zweegman S, Shah J, Badros A,
Shimizu K, Moreau P, Chim CS, Lahuerta
JJ, Hou J, Jurczyszyn A, Goldschmidt H,
Sonneveld P, Palumbo A, Ludwig H, Cavo
M, Barlogie B, Anderson K, Roodman GD,
Rajkumar SV, Durie BG, Terpos E Role of
magnetic resonance imaging in the man-
agement of patients with multiple mye-
loma: a consensus statement. J Clin Oncol
2015;33:657–64.
18. Rajkumar SV, Dimopoulos MA, Palumbo
A, Blade J, Merlini G, Mateos MV, Kumar
S, Hillengass J, Kastritis E, Richardson P,
Landgren O, Paiva B, Dispenzieri A, Weiss
B, Leleu X, Zweegman S, Lonial S, Rosinol
L, Zamagni E, Jagannath S, Sezer O, Kris-
tinsson SY, Caers J, Usmani SZ, Lahuerta
JJ, Johnsen HE, Beksac M, Cavo M, Gold-
schmidt H, Terpos E, Kyle RA, Anderson
KC, Durie BG, Miguel JF International
Myeloma Working Group updated criteria
for the diagnosis of multiple myeloma. Lan-
cet Oncol 2014;15:e538–48.
19. Waxman AJ, Mick R, Garfall AL, Cohen A,
Vogl DT, Stadtmauer EA, Weiss BM Classi-
fying ultra-high risk smoldering myeloma.
Leukemia 2015;29:751–3.
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
20. Sorrig R, Klausen TW, Salomo M, Vangsted
AJ, Ostergaard B, Gregersen H, Frolund
UC, Andersen NF, Helleberg C, Andersen
KT, Pedersen RS, Pedersen P, Abildgaard N,
Gimsing P Smoldering multiple myeloma
risk factors for progression: a Danish popu-
lation-based cohort study. Eur J Haematol
2015;29:10.
21. Larsen JT, Kumar SK, Dispenzieri A, Kyle
RA, Katzmann JA, Rajkumar SV. Serum
free light chain ratio as a biomarker for
high-risk smoldering multiple myeloma.
Leukemia 2013;27:941–6.
22. Kastritis E, Terpos E, Moulopoulos L, Spy-
ropoulou-Vlachou M, Kanellias N, Elefther-
akis-Papaiakovou E, Gkotzamanidou M,
Migkou M, Gavriatopoulou M, Roussou M,
Tasidou A, Dimopoulos MA Extensive bone
marrow infiltration and abnormal free light
chain ratio identifies patients with asymp-
tomatic myeloma at high risk for progres-
sion to symptomatic disease. Leukemia
2013;27:947–53.
23. Kyle RA, Larson DR, Therneau TM, Dis-
penzieri A, Melton LJ, III, Benson JT,
Kumar S, Rajkumar SV Clinical course of
light-chain smouldering multiple myeloma
(idiopathic Bence Jones proteinuria): a ret-
rospective cohort study. Lancet Haematol
2014;1:e28–36.
24. Rajkumar SV, Larson D, Kyle RA. Diagnosis
of smoldering multiple myeloma. N Engl J
Med 2011;365:474–5.
25. Cesana C, Klersy C, Barbarano L, Nosari
AM, Crugnola M, Pungolino E, Gargantini
L, Granata S, Valentini M, Morra E Prog-
nostic factors for malignant transformation
in monoclonal gammopathy of undeter-
mined significance and smoldering multiple
myeloma. J Clin Oncol 2002;20:1625–34.
26. Montoto S, Blade J, Montserrat E. Mono-
clonal gammopathy of undetermined sig-
nificance. N Engl J Med 2002;346:2087–8.
27. Perez-Persona E, Vidriales MB, Mateo G,
Garcia-Sanz R, Mateos MV, de Coca AG,
Galende J, Martin-Nunez G, Alonso JM, de
Las HN, Hernandez JM, Martin A, Lopez-
Berges C, Orfao A, San Miguel JF New cri-
teria to identify risk of progression in mon-
oclonal gammopathy of uncertain
significance and smoldering multiple mye-
loma based on multiparameter flow cytom-
etry analysis of bone marrow plasma cells.
Blood 2007;110:2586–92.
28. Rosinol L, Cibeira MT, Montoto S, Rozman
M, Esteve J, Filella X, Blade J Monoclonal
gammopathy of undetermined significance:
predictors of malignant transformation and
recognition of an evolving type character-
ized by a progressive increase in M protein
size. Mayo Clin Proc 2007;82:428–34.
29. Van De Donk N, De Weerdt O, Eurelings
M, Bloem A, Lokhorst H. Malignant trans-
formation of monoclonal gammopathy of
undetermined significance: cumulative

incidence and prognostic factors. Leuk
Lymphoma 2001;42:609–18.
30. Mian M, Franz I, Wasle I, Herold M, Gries-
macher A, Prokop W, Cortelazzo S, Gastl
G, Willenbacher W, Gunsilius E, Fiegl M
“Idiopathic Bence-Jones proteinuria”: a
new characterization of an old entity. Ann
Hematol 2013;92:1263–70.
31. Rajkumar SV, Kyle RA, Therneau TM,
Clark RJ, Bradwell AR, Melton LJ III, Lar-
son DR, Plevak MF, Katzmann JA Serum
free light chain ratio is an independent risk
factor for progression in monoclonal gam-
mopathy of undetermined significance.
Blood 2005;106:812–7.
32. Schaar CG, le Cessie S, Snijder S, Franck
PF, Wijermans PW, Ong C, Kluin-Nele-
mans H Long-term follow-up of a popula-
tion based cohort with monoclonal
proteinaemia. Br J Haematol
2009;144:176–84.
33. Kyle RA, Rajkumar SV, Therneau TM, Lar-
son DR, Plevak MF, Melton LJ III. Prognos-
tic factors and predictors of outcome of
immunoglobulin M monoclonal gammopa-
thy of undetermined significance. Clin
Lymphoma 2005;5:257–60.
34. Kumar S, Rajkumar SV, Kyle RA, Lacy
MQ, Dispenzieri A, Fonseca R, Lust JA,
Gertz MA, Greipp PR, Witzig TE Prognostic
value of circulating plasma cells in mono-
clonal gammopathy of undetermined sig-
nificance. J Clin Oncol 2005;23:5668–74.
35. Gregersen H, Mellemkjaer L, Ibsen JS, Dah-
lerup JF, Thomassen L, Sorensen HT. The
impact of M-component type and
immunoglobulin concentration on the risk
of malignant transformation in patients
with monoclonal gammopathy of undeter-
mined significance. Haematologica
2001;86:1172–9.
36. Hillengass J, Weber MA, Kilk K, Listl K,
Wagner-Gund B, Hillengass M, Hielscher T,
Farid A, Neben K, Delorme S, Landgren O,
Goldschmidt H. Prognostic significance of
whole-body MRI in patients with mono-
clonal gammopathy of undetermined sig-
nificance. Leukemia 2014 Jan;28(1):174–8.
37. Rossi F, Petrucci MT, Guffanti A, March-
eselli L, Rossi D, Callea V, Vincenzo F, De
MM, Baraldi A, Villani O, Musto P, Baci-
galupo A, Gaidano G, Avvisati G, Goldaniga
M, Depaoli L, Baldini L Proposal and vali-
dation of prognostic scoring systems for IgG
and IgA monoclonal gammopathies of
undetermined significance. Clin Cancer Res
2009;15:4439–45.
38. Blade J, Lopez-Guillermo A, Rozman C,
Cervantes F, Salgado C, Aguilar JL, Vives-
Corrons JL, Montserrat E Malignant trans-
formation and life expectancy in mono-
clonal gammopathy of undetermined
significance. Br J Haematol 1992;81:391–4.
39. Rajkumar SV, Kyle RA, Therneau TM,
Clark RJ, Bradwell AR, Melton LJ, III,
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM
Larson DR, Plevak MF, Katzmann JA Pres-
ence of monoclonal free light chains in the
serum predicts risk of progression in mono-
clonal gammopathy of undetermined sig-
nificance. Br J Haematol 2004;127:308–10.
40. Isaksson E, Bjorkholm M, Holm G, Johans-
son B, Nilsson B, Mellstedt H, Osterborg A
Blood clonal B-cell excess in patients with
monoclonal gammopathy of undetermined
significance (MGUS): association with
malignant transformation. Br J Haematol
1996;92:71–6.
41. Bataille R, Chappard D, Basle MF. Quan-
tifiable excess of bone resorption in mono-
clonal gammopathy is an early symptom of
malignancy: a prospective study of 87 bone
biopsies. Blood 1996;87:4762–9.
42. Papanikolaou X, Waheed S, Dhodapkar
MV, Usmani SZ, Heuck C, van Rhee F,
Epstein J, Barlogie B DNA flow cytometry
and metaphase cytogenetics can predict
progression of asymptomatic monoclonal
gammopathies (AMG) to symptomatic mul-
tiple myeloma (MM). ASH Annu Meeting
Abstr 2012;120:2915.
43. Dhodapkar MV, Sexton R, Waheed S,
Usmani S, Papanikolaou X, Nair B, Petty N,
Shaughnessy JD Jr, Hoering A, Crowley J,
Orlowski RZ, Barlogie B Clinical, genomic,
and imaging predictors of myeloma pro-
gression from asymptomatic monoclonal
gammopathies (SWOG S0120). Blood
2014;123:78–85.
44. Perez-Persona E, Mateo G, Garcia-Sanz R,
Mateos MV, de Las HN, de Coca AG, Her-
nandez JM, Galende J, Martin-Nunez G,
Barez A, Alonso JM, Martin A, Lopez-
Berges C, Orfao A, San Miguel JF, Vidriales
MB Risk of progression in smouldering
myeloma and monoclonal gammopathies
of unknown significance: comparative anal-
ysis of the evolution of monoclonal compo-
nent and multiparameter flow cytometry of
bone marrow plasma cells. Br J Haematol
2010;148:110–4.
45. Katzmann JA, Clark R, Kyle RA, Larson
DR, Therneau TM, Melton LJ III, Benson
JT, Colby CL, Dispenzieri A, Landgren O,
Kumar S, Bradwell AR, Cerhan JR, Rajku-
mar SV Suppression of uninvolved
immunoglobulins defined by heavy/light
chain pair suppression is a risk factor for
progression of MGUS. Leukemia
2013;27:208–12.
46. Heuck C, Sexton R, Dhodapkar M, Zhang
Q, Usmani S, Nair B, van Rhee F, Hoering
A, Crowley J, Shaughnessy JD Jr, Orlowski
RZ, Barlogie B SWOG S0120 observational
trial for MGUS and asymptomatic multiple
myeloma (AMM): imaging predictors of
progression for patients treated at UAMS.
ASH Annu Meeting Abstr 2011;118:3955.
47. Kyle RA, Remstein ED, Therneau TM, Dis-
penzieri A, Kurtin PJ, Hodnefield JM, Lar-
son DR, Plevak MF, Jelinek DF, Fonseca R,
121
Melton LJ III, Rajkumar SV Clinical course
and prognosis of smoldering (asymp-
tomatic) multiple myeloma. N Engl J Med
2007;356:2582–90.
48. Weber DM, Dimopoulos MA, Moulopoulos
LA, Delasalle KB, Smith T, Alexanian R.
Prognostic features of asymptomatic multi-
ple myeloma. Br J Haematol 1997;97:810–
4.
49. Dispenzieri A, Kyle RA, Katzmann JA,
Therneau TM, Larson D, Benson J, Clark
RJ, Melton LJ III, Gertz MA, Kumar SK,
Fonseca R, Jelinek DF, Rajkumar SV
Immunoglobulin free light chain ratio is an
independent risk factor for progression of
smoldering (asymptomatic) multiple mye-
loma. Blood 2008;111:785–9.
50. Bianchi G, Kyle RA, Larson DR, Witzig TE,
Kumar S, Dispenzieri A, Morice WG, Rajku-
mar SV High levels of peripheral blood circu-
lating plasma cells as a specific risk factor for
progression of smoldering multiple mye-
loma. Leukemia 2013;27:680–5.
51. Rosinol L, Blade J, Esteve J, Aymerich M,
Rozman M, Montoto S, Gine E, Nadal E,
Filella X, Queralt R, Carrio A, Montserrat E
Smoldering multiple myeloma: natural his-
tory and recognition of an evolving type.
Br J Haematol 2003;123:631–6.
52. Madan S, Kyle RA, Greipp PR. Plasma cell
labeling index in the evaluation of smol-
dering (asymptomatic) multiple myeloma.
Mayo Clin Proc 2010;85:300.
53. Merz M, Hielscher T, Wagner B, Sauer S,
Shah S, Raab MS, Jauch A, Neben K, Hose
D, Egerer G, Weber MA, Delorme S, Gold-
schmidt H, Hillengass J Predictive value of
longitudinal whole-body magnetic reso-
nance imaging in patients with smoldering
multiple myeloma. Leukemia
2014;28:1902–8.
54. Khan R, Dhodapkar M, Rosenthal A,
Heuck C, Papanikolaou X, Qu P, van RF,
Zangari M, Jethava Y, Epstein J, Yaccoby
S, Hoering A, Crowley J, Petty N, Bailey
C, Morgan G, Barlogie B Four genes pre-
dict high risk of progression from smol-
dering to symptomatic multiple myeloma
(SWOG S0120). Haematologica 2015;100:
1214–21.
55. Neben K, Jauch A, Hielscher T, Hillengass
J, Lehners N, Seckinger A, Granzow M,
Raab MS, Ho AD, Goldschmidt H, Hose D
Progression in smoldering myeloma is inde-
pendently determined by the chromosomal
abnormalities del(17p), t(4;14), gain 1q,
hyperdiploidy, and tumor load. J Clin
Oncol 2013;31:4325–32.
56. Rajkumar SV, Gupta V, Fonseca R, Dispen-
zieri A, Gonsalves WI, Larson D, Ketterling
RP, Lust JA, Kyle RA, Kumar SK Impact of
primary molecular cytogenetic abnormali-
ties and risk of progression in smoldering
multiple myeloma. Leukemia
2013;27:1738–44.
122 N. W. C. J. VAN DE DONK ET AL. | MGUS AND SMM
57. Siontis B, Kumar S, Dispenzieri A, Drake
MT, Lacy MQ, Buadi F, Dingli D, Kapoor P,
Gonsalves W, Gertz MA, Rajkumar SV
Positron emission tomography-computed
tomography in the diagnostic evaluation of
smoldering multiple myeloma: identifica-
tion of patients needing therapy. Blood
Cancer J 2015;23:e364.
58. Zamagni E, Nanni C, Gay F, Pezzi A, Patri-
arca F, Bello M, Rambaldi I, Tacchetti P,
Hillengass J, Gamberi B, Pantani L, Magar-
otto V, Versari A, Offidani M, Zannetti B,
Carobolante F, Balma M, Musto P, Rensi
M, Mancuso K, Dimitrakopoulou-Strauss
A, Chauvie S, Rocchi S, Fard N, Marzocchi
G, Storto G, Ghedini P, Palumbo A, Fanti
S, Cavo M 18F-FDG PET/CT focal, but not
osteolytic, lesions predict the progression of
smoldering myeloma to active disease. Leu-
kemia 2015;22:10.
59. Rossi D, De PL, Franceschetti S, Capello
D, Vendramin C, Lunghi M, Conconi A,
Magnani C, Gaidano G Prevalence and
clinical characteristics of immune throm-
bocytopenic purpura in a cohort of mono-
clonal gammopathy of uncertain
significance. Br J Haematol 2007;138:249–
52.
60. Ojeda-Uribe M, Caron C, Itzhar-Baikian N,
Debliquis A. Bortezomib effectiveness in
one patient with acquired von Willebrand
syndrome associated to monoclonal gam-
mopathy of undetermined significance. Am
J Hematol 2010;85:396.
61. Taher A, Abiad R, Uthman I. Coexistence
of lupus anticoagulant and acquired hae-
mophilia in a patient with monoclonal
gammopathy of unknown significance.
Lupus 2003;12:854–6.
62. Leung N, Bridoux F, Hutchison CA, Nasr
SH, Cockwell P, Fermand JP, Dispenzieri A,
Song KW, Kyle RA Monoclonal gammopa-
thy of renal significance: when MGUS is no
longer undetermined or insignificant. Blood
2012;120:4292–5.
63. Gertz M, Buadi FK. Case vignettes and
other brain teasers of monoclonal gam-
mopathies. Hematology Am Soc Hematol
Educ Program 2012;2012:582–5.
64. Fermand JP, Bridoux F, Kyle RA, Kastritis
E, Weiss BM, Cook MA, Drayson MT, Dis-
penzieri A, Leung N. International Kidney
and Monoclonal Gammopathy Research
Group. Blood 2013;122:3583–90.
65. Merlini G, Stone MJ. Dangerous small B-
cell clones. Blood 2006;108:2520–30.
66. Mangiacavalli S, Cocito F, Pochintesta L,
Pascutto C, Ferretti V, Varettoni M, Zappa-
sodi P, Pompa A, Landini B, Cazzola M,
Corso A Monoclonal gammopathy of unde-
termined significance: a new proposal of
workup. Eur J Haematol 2013;17:10.
67. Mateos MV, San Miguel JF. Smoldering
multiple myeloma: when to observe and
when to treat? Am Soc Clin Oncol Educ
Book. 2015;e484–92.
68. Go RS, Gundrum JD, Neuner JM. Deter-
mining the clinical significance of mono-
clonal gammopathy of undetermined
significance: a SEER-Medicare population
analysis. Clin Lymphoma Myeloma Leuk
2015;15:177–86.
69. Sigurdardottir EE, Turesson I, Lund SH,
Lindqvist EK, Mailankody S, Korde N,
Bjorkholm M, Landgren O, Kristinsson SY
The role of diagnosis and clinical follow-up
of monoclonal gammopathy of undeter-
mined significance on survival in multiple
myeloma. JAMA Oncol 2015;1:168–74.
70. Bianchi G, Kyle RA, Colby CL, Larson
DR, Kumar S, Katzmann JA, Dispenzieri
A, Therneau TM, Cerhan JR, Melton
LJ III, Rajkumar SV Impact of optimal
follow-up of monoclonal gammopathy
of undetermined significance on early
diagnosis and prevention of myeloma-
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38 (Suppl. 1), 110–122
related complications. Blood 2010;116:
2019–25.
71. Rajkumar SV, Landgren O, Mateos MV.
Smoldering multiple myeloma. Blood
2015;125:3069–75.
72. Mateos MV, Hernandez MT, Giraldo P, de
la Rubia J, de AF, Lopez CL, Rosinol L,
Paiva B, Palomera L, Bargay J, Oriol A,
Prosper F, Lopez J, Olavarria E, Quintana
N, Garcia JL, Blade J, Lahuerta JJ, San
Miguel JF Lenalidomide plus dexametha-
sone for high-risk smoldering multiple
myeloma. N Engl J Med 2013;369:438–
47.
73. Korde N, Roschewski M, Zingone A, Kwok
M, Manasanch EE, Bhutani M, Tageja N,
Kazandjian D, Mailankody S, Wu P, Mor-
rison C, Costello R, Zhang Y, Burton D,
Mulquin M, Zuchlinski D, Lamping L, Car-
penter A, Wall Y, Carter G, Cunningham
SC, Gounden V, Sissung TM, Peer C, Maric
I, Calvo KR, Braylan R, Yuan C, Stetler-
Stevenson M, Arthur DC, Kong KA, Weng
L, Faham M, Lindenberg L, Kurdziel K,
Choyke P, Steinberg SM, Figg W, Landgren
O Treatment with carfilzomib-lenalido-
mide-dexamethasone with lenalidomide
extension in patients with smoldering or
newly diagnosed multiple myeloma. JAMA
Oncol 2015;1:746–54.
74. van de Donk NW, Moreau P, Plesner T,
Palumbo A, Gay F, Laubach JP, Malavasi F,
Avet-Loiseau H, Mateos MV, Sonneveld P,
Lokhorst HM, Richardson PG Clinical effi-
cacy and management of monoclonal anti-
bodies targeting CD38 and SLAMF7 in
multiple myeloma. 2016 Feb 11;127(6):
681–95.
75. Merlini G, Palladini G. Differential diagno-
sis of monoclonal gammopathy of undeter-
mined significance. Hematology Am Soc
Hematol Educ Program 2012;2012:595–
603.