www.thelancet.com/oncology Vol 15 November 2014
e538
Review
International Myeloma Working Group updated criteria for
the diagnosis of multiple myeloma
S Vincent Rajkumar, Meletios A Dimopoulos, Antonio Palumbo, Joan Blade, Giampaolo Merlini, María-Victoria Mateos, Shaji Kumar, Jens Hillengass,
Efstathios Kastritis, Paul Richardson, Ola Landgren, Bruno Paiva, Angela Dispenzieri, Brendan Weiss, Xavier LeLeu, Sonja Zweegman, Sagar Lonial,
Laura Rosinol, Elena Zamagni, Sundar Jagannath, Orhan Sezer, Sigurdur Y Kristinsson, Jo Caers, Saad Z Usmani, Juan José Lahuerta, Hans Erik Johnsen,
Meral Beksac, Michele Cavo, Hartmut Goldschmidt, Evangelos Terpos, Robert A Kyle, Kenneth C Anderson, Brian G M Durie, Jesus F San Miguel
This International Myeloma Working Group consensus updates the disease defi nition of multiple myeloma to include
validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal
failure, anaemia, and bone lesions). These changes are based on the identifi cation of biomarkers associated with near
inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering
multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be
detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and
radiographic variables that fulfi l the criteria for the presence of myeloma-defi ning CRAB features, and the histological
and monoclonal protein requirements for the disease diagnosis. Finally, we provide specifi c metrics that new
biomarkers should meet for inclusion in the disease defi nition. The International Myeloma Working Group
recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends
that future studies analyse any diff erences in outcome that might occur as a result of the new disease defi nition.
Introduction
Multiple myeloma is a cytogenetically heterogeneous
clonal plasma cell proliferative disorder
1,2
and is almost
always preceded by an asymptomatic premalignant stage
termed monoclonal gammopathy of undetermined
signifi cance (MGUS).
3,4
MGUS is present in roughly
3–4% of the population over the age of 50 years.
5–9
The
diagnosis of MGUS requires the absence of hyper-
calcaemia, renal failure, anaemia, and bone lesions
(referred to as CRAB features) that can be attributed to
the underlying plasma cell disorder (all features must be
absent; table 1).
10–20
About 80% of multiple myeloma
originates from non-IgM immunoglobulin MGUS (non-
IgM MGUS), and 20% from light-chain immunoglobulin
MGUS (LC-MGUS). In the event of progression, IgM
immunoglobulin MGUS (IgM MGUS) usually evolves
into Waldenström macroglobulinaemia, but in rare
instances IgM MGUS can progress to multiple myeloma
(IgM myeloma).
18,21–24
The rate of progression of MGUS to
multiple myeloma is 0·5–1% per year, but the precise
risk is aff ected by the concentration of the monoclonal
protein, type of monoclonal protein, serum free light-
chain ratio, bone marrow plasmacytosis, proportion of
phenotypically clonal plasma cells, and presence of
immunoparesis.
24–29
Smouldering multiple myeloma is an intermediate
clinical stage between MGUS and multiple myeloma in
which the risk of progression to malignant disease in the
fi rst 5 years after diagnosis is much higher, at about 10%
per year.
30
Prognostic models have been proposed to
predict risk of progression, but lack con cordance and
need additional studies for verifi cation.
31
According to a
population-based study from Scandinavia, smouldering
multiple myeloma accounts for about 14% of all patients
with multiple myeloma.
32
As with MGUS, the diagnosis
needs the absence of CRAB features attributable to the
clonal plasma cell proliferative disorder, but the
thresholds for monoclonal protein level and bone-
marrow plasma cell (BMPC) percentage are diff erent.
Smouldering multiple myeloma is a biologically
heterogeneous, clinically defi ned entity consisting of a
subset of patients with biological premalignancy (ie,
MGUS) and a subset with CRAB-negative malignancy
(ie, multiple myeloma).
33
It includes patients similar to
those with MGUS, with a very low rate of progression, as
well as patients who develop clinical symptoms and end-
organ damage within the fi rst 2 years of diagnosis.
34,35
Unfortunately, no single pathological or molecular
feature can be used to distinguish patients with
smouldering multiple myeloma who have only clonal
premalignant plasma cells from those with clonal
malignant myeloma cells. A biomarker-based defi nition
that accurately identifi es the subset of patients with
smouldering multiple myeloma and biological
malignancy, who are at imminent risk of developing
CRAB features (and should therefore be considered for
therapy), is needed.
34
Rationale for updating of diagnostic criteria
The present disease defi nitions of smouldering multiple
myeloma and multiple myeloma were reported by the
International Myeloma Working Group (IMWG) in
2003.
10
With minor clarifi cations,
11
these criteria have
been used in clinical practice as well as in research
studies and trials in the past decade.
36,37
One of the major
diffi culties in multiple myeloma is that, unlike other
malignancies, the disease defi nition is clinicopathological;
it needs overt clinical manifestations of serious end-
organ damage, such as osteolytic bone lesions and renal
failure, before the diagnosis can be made. This
conundrum has ensured that patients cannot get early
therapy to prevent organ damage, and has prevented any
Lancet Oncol 2014; 15: e538–48
See Online for a podcast
interview with
S Vincent Rajkumar
Division of Hematology, Mayo
Clinic, Rochester
, MN, USA
(Prof S V Rajkumar MD,
Prof S Kumar MD,
Prof A Dispenzieri MD,
Prof R A Kyle MD); Department
of Clinical Therapeutics,
University of Athens, School of
Medicine, Athens, Greece
(Prof M A Dimopoulos MD,
E Kastritis MD, E Terpos MD);
Myeloma Unit, Division of
Hematology, University of
Torino, Azienda Ospedaliero-
Universitaria Città della Salute
e della Scienza di Torino,
Torino, Italy
(Prof A Palumbo MD); Hospital
Clinic, Barcelona, Spain
(J Blade MD, L Rosinol MD);
Amyloidosis Center, University
Hospital Policlinico San
Matteo, Pavia, Italy
(Prof G Merlini MD); University
Hospital of Salamanca/IBSAL,
Salamanca, Spain
(M V Mateos MD); Department
of Hematology, Oncology and
Rheumatology, University of
Heidelberg, Heidelberg,
Germany (J Hillengass MD,
Prof H Goldschmidt MD); Dana-
Farber Cancer Institute,
Boston, MA, USA
(Prof P Richardson MD,
Prof K C Anderson MD);
Memorial Sloan Kettering
Cancer Center, New York, NY,
USA (O Landgren MD); Clinica
Universidad de Navarra, Centro
de Investigacion Medica
Aplicada (CIMA), Pamplona,
Spain (B Paiva MD,
Prof J F San Miguel MD);
Abramson Cancer Center,
University of Pennsylvania,
Philadelphia, PA, USA
(B Weiss MD); University
Hospital of Lille, Lille, France
(X Leleu MD); Department of
Hematology , VU University
Medical Center, Amsterdam,
Netherlands
(Prof S Zweegman MD);
Department of Hematology
e539
www.thelancet.com/oncology Vol 15 November 2014
Review
attempts at cancer treatment at a stage when it is in its
most susceptible microenvironment-dependent state.
These criteria were acceptable in an era of restricted
treatment options that had substantial toxic eff ects and
did not show any apparent clinical benefi t from early
intervention. However, this defi nition can no longer be
justifi ed because treatment options have greatly
improved, and data show early intervention in high-risk
asymptomatic patients can extend survival.
38
Moreover,
advances in laboratory and imaging techniques call for
an update on the specifi c variables that should be
regarded as meeting the criteria for CRAB features.
39
and Medical Oncology, Winship
Cancer Institute, Emory
University, Atlanta, GA, USA
(Prof S Lonial MD); Seràgnoli
Institute of Hematology,
Bologna University School of
Medicine, Bologna, Italy
Defi nition
††
Progression rate Primary progression events
Non-IgM monoclonal
gammopathy of
undetermined signifi cance
10
Serum monoclonal protein (non-IgM type) <30 g/L
Clonal bone marrow plasma cells <10%*
Absence of end-organ damage such as hypercalcaemia, renal insuffi ciency, anaemia, and bone lesions
(CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
1% per year Multiple myeloma, solitary
plasmacytoma, immunoglobulin-
related amyloidosis (AL, AHL, AH)
IgM monoclonal
gammopathy of
undetermined signifi cance
11
Serum IgM monoclonal protein <30 g/L
Bone marrow lymphoplasmacytic infi ltration <10%
No evidence of anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy,
hepatosplenomegaly, or other end-organ damage that can be attributed to the underlying
lymphoproliferative disorder
1·5% per year Waldenström
macroglobulinaemia,
immunoglobulin-related
amyloidosis (AL, AHL, AH)
Light-chain monoclonal
gammopathy of
undetermined
signifi cance
8,12
Abnormal FLC ratio (<0·26 or >1·65)
Increased level of the appropriate involved light chain (increased κ FLC in patients with ratio >1·65 and
increased λ FLC in patients with ratio <0·26)
No immunoglobulin heavy chain expression on immunofi xation
Absence of end-organ damage such as hypercalcaemia, renal insuffi ciency, anaemia, and bone lesions
(CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
Clonal bone marrow plasma cells <10%
Urinary monoclonal protein <500 mg/24 h
0·3% per year Light chain multiple myeloma,
immunoglobulin light-chain
amyloidosis
Solitary plasmacytoma
13–16
Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
Normal bone marrow with no evidence of clonal plasma cells
Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
Absence of end-organ damage such as hypercalcaemia, renal insuffi ciency, anaemia, or bone lesions
(CRAB) that can be attributed to a lymphoplasma cell proliferative disorder
About 10% within
3 years
Multiple myeloma
Solitary plasmacytoma
with minimal marrow
involvement†
13–16
Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
Clonal bone marrow plasma cells <10%
Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
Absence of end-organ damage such as hypercalcaemia, renal insuffi ciency, anaemia, or bone lesions
(CRAB) that can be attributed to a lymphoplasma cell proliferative disorder
60% (bone) or 20%
(soft tissue) within
3 years
Multiple myeloma
POEMS syndrome‡
11,17
Polyneuropathy
Monoclonal plasma cell proliferative disorder (almost always λ)
Any one of the following three other major criteria:
Sclerotic bone lesions
Castleman’s disease
Elevated levels of VEGFA§
Any one of the following six minor criteria:
Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
Extravascular volume overload (oedema, pleural eff usion, or ascites)
Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)¶
Skin changes (hyperpigmentation, hypertrichosis, glomeruloid haemangiomata, plethora,
acrocyanosis, fl ushing, white nails)
Papilloedema
Thrombocytosis/polycythaemia
NA NA
Systemic AL
amyloidosis||**
11,18
Presence of an amyloid-related systemic syndrome (eg, renal, liver, heart, gastrointestinal tract, or
peripheral nerve involvement)
Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow, or organ biopsy)
Evidence that amyloid is light-chain-related established by direct examination of the amyloid using mass
spectrometry-based proteomic analysis, or immunoelectronmicroscopy, and
Evidence of a monoclonal plasma cell proliferative disorder (serum or urine monoclonal protein,
abnormal free light-chain ratio, or clonal plasma cells in the bone marrow)
NA Some patients might develop
multiple myeloma
IgM=immunoglobulin M. AL=immunoglobulin light-chain amyloidosis. AHL=immunoglobulin heavy and light-chain amyloidosis. AH=immunoglobulin heavy chain amyloidosis. FLC=free light chain. *Bone
marrow can be deferred in patients with low-risk monoclonal gammopathy of undetermined signifi cance (IgG type, monoclonal protein <15 g/L, normal free light-chain ratio) in whom there are no clinical
features concerning for myeloma. †Solitary plasmacytoma with 10% or more clonal plasma cells is regarded as multiple myeloma. ‡Not every patient meeting these criteria will have POEMS syndrome; the
features should have a temporal association with each other and no other attributable cause. Anaemia or thrombocytopenia are distinctively unusual in this syndrome unless Castleman’s disease is present. §The
source data do not define an optimal cutoff value for considering elevated VEGFA level as a major criterion. We suggest that VEGFA measured in the serum or plasma should be at least three to four times higher
than the normal reference range for the laboratory that is doing the testing to be regarded as a major criterion. ¶To regard endocrinopathy as a minor criterion, an endocrine disorder other than diabetes or
hypothyroidism is required because these two disorders are common in the general population. ||Patients with AL amyloidosis who also meet criteria for multiple myeloma are considered to have both diseases.
**About 2–3% of patients with AL amyloidosis will not meet the requirement for evidence of a monoclonal plasma cell disorder listed; the diagnosis of AL amyloidosis must be made with caution in these
patients. ††All presented criteria must be met for the disease to be diagnosed.
Table 1: International Myeloma Working Group diagnostic criteria and classifi cation for monoclonal gammopathy of undetermined signifi cance and related plasma-cell disorders
www.thelancet.com/oncology Vol 15 November 2014
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(E Zamagni MD,
Prof M Cavo MD); Mount Sinai
Cancer Institute, New York, NY,
USA (Prof S Jagannath MD);
Memorial Hospital, Istanbul,
Turkey (Prof O Sezer MD);
Karolinska University Hospital,
Karolinska Institutet,
Stockholm, Sweden
(S Y Kristinsson MD);
Department of Hematology,
CHU de Liege, Liege, Belgium
(J Caers MD); Levine Cancer
Institute, Carolinas HealthCare
System, Charlotte, NC, USA
(S Z Usmani MD); Servicio de
Hematología, Hospital
Universitario 12 de Octubre,
Madrid, Spain (J J Lahuerta MD);
Department of Haematology,
Aalborg University Hospital,
Aalborg, Denmark
(Prof H E Johnsen MD); Ankara
University School of Medicine,
Ankara, Turkey
(Prof M Beksac MD); and Cedars-
Sinai Comprehensive Cancer
Center, Los Angeles, CA, USA
(Prof B G M Durie MD)
Correspondence to:
Prof S Vincent Rajkumar, Division
of Hematology, Mayo Clinic,
200 First St SW, Rochester,
MN 55905, USA
rajkumar.vincent@mayo.edu
Finally, some revisions to the monoclonal protein and
bone marrow plasma cell requirements are also needed.
Myeloma-defi ning biomarkers
To intervene before the development of end-organ
damage in multiple myeloma, biomarkers are needed
that accurately identify the subset of patients with
smouldering multiple myeloma who have biological
malignancy and are at imminent risk of progression.
35,40–44
A Mayo Clinic study
45
of patients with smouldering
multiple myeloma reported that having a BMPC of at
least 60% can be used as a marker to identify patients
with a notably high risk (about 90%) of progression
within 2 years of diagnosis. In 2011 at a summit in
London, UK, the IMWG reached a consensus that, if
reliable biomarkers associated with roughly an 80%
probability of progression to multiple myeloma within
2 years were identifi ed, such patients should be regarded
as having multiple myeloma and off ered therapy. This
threshold would identify a small cohort of smouldering
multiple myeloma with a median time to development of
end-organ damage of about 12 months, for whom a delay
of therapy would be unreasonable. The IMWG consensus
was driven by the following considerations. First, this
very high-risk cohort is not representative of most
patients with smouldering multiple myeloma, in view of
the 40% per year risk of progression (based on the
prespecifi ed defi nition), compared with the 10% per year
risk of progression with smouldering multiple myeloma.
Second, one of the reasons to delay therapy in
smouldering multiple myeloma is based on the fact that
a substantial proportion of patients can remain free of
progression for long periods of time. For example, 50%
of patients with smouldering multiple myeloma do not
progress in the fi rst 5 years, and roughly 30% are free of
progression after 10 years.
30
Such con siderations do not
apply to this ultra-high risk subgroup in which few, if
any, patients are free of progression beyond 3 years.
Third, the proportion of patients who do not progress
within 2 years (up to 20%) was regarded to be reasonable,
because these patients are probably not very diff erent
from some patients with multiple myeloma who have
minimal CRAB features for whom prompt treatment is
widely accepted (eg, patients with one or two lytic lesions,
or mild anaemia), yet who can remain stable without
therapy. Fourth, the results of end-organ damage,
especially acute renal failure or pathological fracture,
were judged to be unacceptably severe, with risk of
substantial long-term morbidity. Therefore, we believed
that persisting with a disease defi
nition that demanded
such damage occur before the disease is called multiple
myeloma was unreasonable for patients. Finally, we
believed that major advances have been made in the
treatment of multiple myeloma, and although watchful
waiting was appropriate in an era of only alkylating
agents and corticosteroids, it was not justifi able for ultra-
high-risk patients in view of the availability of several
safer and more eff ective treat ments.
46–51
Trials with
alkylators that did not show an increase in overall survival
with early treatment for smouldering multiple myeloma
were underpowered, and did not focus on high-risk
patients.
52,53
A randomised trial
38
done in 2013 reported
that early therapy for smouldering multiple myeloma
can extend overall survival, greatly diminishing concerns
that treatment of patients with a very high-risk of
smouldering multiple myeloma as multiple myeloma
will lead to overtreatment or unnecessary therapy
.
Revisions to laboratory and imaging criteria for CRAB
In addition to the previous discussion on incorporation
of additional biomarker-defi ned myeloma-defi ning
events to the standard CRAB features, updates are also
needed that take into account the substantial changes to
laboratory testing and imaging used in the diagnosis of
multiple myeloma that have happened since the initial
publication of the IMWG diagnostic criteria. These
include better methods of detecting bone and
extramedullary disease using CT (including low-dose
whole body CT), MRI, ¹⁸F-fl uorodeoxyglucose (FDG)
PET, and FDG-PET with CT (PET-CT).
54–56
They also
include better estimation of renal damage by use of
creatinine clearance in addition to serum creatinine
measurements, and the criteria for clonal bone marrow
plasma cells needed on bone marrow examination have
been revised.
Other revisions
Other minor clarifi cations to the disease defi nition are
needed to account for patients with non-secretory
multiple myeloma (where there is no monoclonal protein
in any tests), and patients with normal or scarcely
involved (<10% clonal plasma cells) bone marrow
examinations who have multiple lytic lesions, plasma-
cytomas (bony or extramedullary), or other CRAB
features without diff use infi ltration of the marrow.
Revised IMWG criteria for diagnosis of myeloma
The updated IMWG criteria for diagnosis of multiple
myeloma are given in the panel; the supporting data for
each of the changes are discussed below. The term
multiple myeloma refers to multiple myeloma requiring
therapy.
Bone marrow plasma cells of 60% or greater
In 2011, a re-analysis of the original Mayo Clinic cohort of
smouldering multiple myeloma noted that only six (2%)
of 276 patients had a BMPC of 60% or greater (defi ned as
the highest percentage noted on an aspirate or trephine
biopsy sections). The median progression-free survival
was 7·7 months (95% CI 0·4–14·9), and fi ve of the six
patients (83%) patients had progressed or died by
14 months.
45
To validate this fi nding, a study was done in a new
group of 651 patients with smouldering multiple
e541
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Review
myeloma diagnosed at the Mayo Clinic between
January, 1996, and June, 2010.
45
Only 21 (3%) patients
had a BMPC of 60% or greater, and 95% of these
patients progressed to multiple myeloma within 2 years
of diagnosis (median time to progression 7·0 months
[95% CI 1·0–12·9]). These studies showed that extreme
plasmacytosis was uncommon in smouldering multiple
myeloma, because at that level of plasmacytosis, CRAB
features—especially anaemia—almost always occur,
which results in a diagnosis of multiple myeloma. The
investigators recommended that in view of the clinical
course noted, patients with 60% or greater plasma cell
involvement on marrow examination should be
regarded as having multiple myeloma requiring therapy
irrespective of the presence or absence of CRAB
features. This fi nding was subsequently validated in an
investi gation of 96 patients with smouldering multiple
myeloma by Kastritis and colleagues from the Greek
Myeloma Group, who showed that BMPC of 60% of
greater was associated with a high risk of progression
(median time to progression of 15·0 months, hazard
ratio [HR] 13·7 [95% CI 4·44–42·50]; p<0·001).
57
Six
(5%) of 121 patients with smouldering multiple
myeloma in a third study were reported to have BMPC
60% or greater, and all progressed to multiple myeloma
within 2 years.
58
BMPC estimation for diagnosis is based on either
conventional bone marrow aspirate or biopsy
examination. BMPC estimation should not be based on
the proportion of plasma cells reported by fl ow cytometry;
studies are ongoing to determine whether fl ow-based
enumeration is feasible.
59
If a discrepancy exists between
BMPC estimation in the biopsy sample and aspirate, the
higher of the two values should be used.
60
Serum free light chain ratio of 100 or greater
The free light chain (FLC) assay is an automated
nephelometric assay that identifi es and measures κ and λ
light immunoglobulin chains that circulate unbound to
heavy chains in the serum.
61–63
The normal ratio for FLC-
κ/λ is 0·26–1·65. In clonal plasma cell disorders, excess
production of one FLC type (the clonal component
referred to as the involved light chain) often results in an
abnormal FLC ratio.
64
About a third of patients with
MGUS, 70% of patients with smouldering multiple
myeloma, and more than 90% of patients with multiple
myeloma have altered FLC ratios that indicate excess
production of a clonal FLC by the proliferating plasma
cell population.
27,44,65,66
The presence of an abnormal FLC
ratio, and the extent to which the FLC ratio is abnormal,
predict risk of progression in MGUS, smouldering
multiple myeloma, amyloid light-chain (AL) amyloidosis,
and solitary plasmacytoma.
27,44,67
Dispenzieri and colleagues
44
reported that in patients
with smouldering multiple myeloma, an involved to
uninvolved FLC ratio of 8 or more is associated with
about a 40% risk of progression within the fi rst 2 years
from diagnosis. Subsequently, Larsen and colleagues
68
studied 586 patients with smouldering multiple myeloma
to determine the threshold at which the FLC ratio is
associated with an 80% probability of progression to
multiple myeloma or related malignant disease within
2 years. A serum involved to uninvolved FLC ratio of at
least 100 was noted in 90 (15%) patients of the total
cohort; the involved FLC level was higher than the
normal range in all. The risk of progression to multiple
myeloma within the fi rst 2 years in patients with an FLC
ratio of at least 100 was 72%; the risk of progression to
multiple myeloma or AL amyloidosis in 2 years was 79%.
The risk of progression to multiple myeloma or AL
amyloidosis for patients with an FLC ratio of at least 100
and an involved FLC level at least 1000 mg/L was 82% at
2 years, and 93% at 3 years. Taking an absolute FLC level
threshold into account improved positive predictive value
of the FLC assay, but lowered sensitivity. Importantly,
27% of patients with a FLC ratio of at least 100 had acute
renal failure as the myeloma-defi ning event. The
researchers concluded that a FLC ratio of at least 100 is a
predictor of imminent progression in smouldering
Panel: Revised International Myeloma Working Group diagnostic criteria for multiple
myeloma and smouldering multiple myeloma
Defi nition of multiple myeloma
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary
plasmacytoma* and any
one or more of the following myeloma defi ning events:
• Myeloma defi ning events:
• Evidence of end organ damage that can be attributed to the underlying plasma cell
proliferative disorder, specifi cally:
• Hypercalcaemia: 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 insuffi ciency: creatinine clearance <40 mL per min† or serum creatinine
>177 μmol/L (>2 mg/dL)
• Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a
haemoglobin value <100 g/L
• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or
PET-CT‡
• 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 on MRI studies¶
Defi nition of smouldering multiple myeloma
Both criteria must be met:
• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg
per 24 h and/or clonal bone marrow plasma cells 10–60%
• Absence of myeloma defi ning events or amyloidosis
PET-CT=¹⁸F-fl uorodeoxyglucose PET with CT. *Clonality should be established by showing κ/λ-light-chain restriction on fl ow
cytometry, immunohistochemistry, or immunofl uorescence. Bone marrow plasma cell percentage should preferably be
estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be
used. †Measured or estimated by validated equations. ‡If bone marrow has less than 10% clonal plasma cells, more than one
bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement. §These values are based
on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L. ¶Each
focal lesion must be 5 mm or more in size.
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e542
Review
multiple myeloma, and that such patients should be
regarded as having multiple myeloma requiring therapy.
Similar results were obtained in work by Kastritis and
colleagues
57
from the Greek Myeloma Group. In their
investigation of 96 patients with smouldering multiple
myeloma, seven (7%) had an involved to uninvolved
FLC ratio of at least 100, and almost all progressed
within 18 months (HR 9·0 [95% CI 2·15–39·00],
p=0·003). In a third study,
58
the risk of patients with
smouldering multiple myeloma with an involved to
uninvolved FLC ratio of at least 100 progressing within
2 years was 64%. Although these studies did not need a
minimum involved FLC level, to reduce possibility of
error the new criteria require a minimum involved FLC
level of at least 100 mg/L.
MRI with more than one focal lesion
MRI is benefi cial in evaluating patients with smouldering
multiple myeloma, and is recommended as part of the
initial assessment.
54
Abnormal MRI imaging features in
smouldering multiple myeloma include both focal
lesions (involving bone or bone marrow), and diff use
bone marrow abnormalities. These abnormalities have
been associated with increased risk of progression in
smouldering multiple myeloma.
69–71
However, only within
the past 5 years have investigators precisely determined
the level of abnormality that is associated with a high
probability of progression within 2 years. Hillengass and
colleagues
72
studied 149 patients with smouldering
multiple myeloma with whole-body MRI. Focal lesions
were detected in 42 (28%) patients; more than one focal
lesion was identifi ed in 23 (15%) patients of the total
cohort. The presence of more than one focal lesion was
associated with a substantial increase in risk of
progression (HR 4·05, p<0·001; univariate analysis). The
median time to progression was 13 months, and 70% of
patients had progressed at 2 years. On multivariate
analysis, presence of more than one focal lesion
remained a signifi cant predictor of progression. In
patients with more than one focal lesion on MRI, if such
lesions are small (<5 mm) or equivocal, additional
imaging with CT or PET-CT should be considered before
making the diagnosis of multiple myeloma.
Kastritis and colleagues
73
analysed data from the Greek
Myeloma Database and identifi ed 65 patients with
smouldering multiple myeloma who underwent spinal
MRI and were followed up for a minimum of 2·5 years.
In this cohort, nine (14%) patients had more than one
focal lesion. The median time to progression to multiple
myeloma for patients with more than one focal lesion
was 15 months (95% CI 6–26). At 2 years, 69% of patients
had progressed, as had 85% at 3 years. By contrast, the
median time to progression for patients with one or no
focal lesions was over 5 years (p<0·001).
A diff use marrow infi ltration pattern is associated with
an increased risk of progression, but is not recommended
as adequate to establish the diagnosis of multiple
myeloma. Additional data are needed on the specifi c risk
of progression in the fi rst 2 years in the absence of focal
lesions and extreme bone marrow plasmacytosis.
74,75
In
the study by Hillengass,
72
diff use MRI infi ltration was
associated with a HR of 3·5 (p<0·001). A 2014 analysis
76
shows that the increase in number or size of focal lesions
in follow-up MRI of patients with smouldering multiple
myeloma has additional predictive value, including
information on growth dynamics of the plasma cell
tumours in bone marrow. Therefore, in patients with
diff use infi ltration, solitary focal lesion, or in the presence
of equivocal fi ndings, follow-up examinations in
3–6 months are strongly recommended.
Defi nition of myeloma bone disease
Bone disease in multiple myeloma, to meet the CRAB
criteria, has been defi ned as the presence of osteolytic
bone lesions or the presence of osteoporosis with
compression fractures attributable to the underlying
clonal plasma cell disorder.
10,11
Traditionally, bone disease
has been identifi ed on the basis of conventional skeletal
radiography. The 2003 IMWG criteria for the diagnosis
of multiple myeloma concluded that MRI and CT can be
used to clarify the presence of bone disease.
10
Although
the criteria did not explicitly state that these modalities
can be used in isolation to fulfi l the CRAB criteria in the
absence of bone disease on skeletal radiography, it was
the intent of the investigators that a defi nite osteolytic
lesion detected on CT should be regarded as fulfi lling
CRAB criteria even if it was not visible on conventional
skeletal radiography (RAK, unpublished data). In the
past 10 years substantial advances have been made in
imaging technology, as well as more widespread use of
MRI, low-dose whole-body CT, and FDG-PET to assess
bone disease and bone marrow infi ltration in multiple
myeloma.
54,55,77–81
A 2013 systematic review
56
compared
modern imaging methods including MRI, FDG-PET,
PET-CT, and whole-body CT with conventional whole-
body skeletal radiography. Newer imaging techniques
had greater sensitivity than radiographic bone survey for
detection of multiple myeloma bone lesions, with as
many as 80% or more lesions detected by the newer
imaging techniques. CT and MRI were equally sensitive,
and thus either test can be used, depending on availability
and access. Furthermore, the IMWG recommended the
use of these techniques during the diagnostic assessment
of patients with smouldering multiple myeloma and
solitary plasmacytoma.
21
The IMWG recommends that
one of PET-CT, low-dose whole-body CT, or MRI of the
whole-body or spine be done in all patients with
suspected smouldering multiple myeloma, with the exact
imaging modality determined by availability and
resources.
In this updated IMWG criteria, we now clarify that
clear evidence of one or more sites of osteolytic bone
destruction (≥5 mm in size) seen on CT (including low-
dose whole-body CT) or PET-CT does fulfi l the criteria for