Review

Role of ¹⁸F-FDG PET/CT in the diagnosis and management

of multiple myeloma and other plasma cell disorders:
a consensus statement by the International Myeloma
Working Group
Michele Cavo, Evangelos Terpos, Cristina Nanni, Philippe Moreau, Suzanne Lentzsch, Sonja Zweegman, Jens Hillengass, Monika Engelhardt,
Saad Z Usmani, David H Vesole, Jesus San-Miguel, Shaji K Kumar, Paul G Richardson, Joseph R Mikhael, Fernando Leal da Costa,
Meletios-Athanassios Dimopoulos, Chiara Zingaretti, Niels Abildgaard, Hartmut Goldschmidt, Robert Z Orlowski, Wee Joo Chng, Hermann Einsele,
Sagar Lonial, Bart Barlogie, Kenneth C Anderson, S Vincent Rajkumar, Brian G M Durie, Elena Zamagni

The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of Lancet Oncol 2017; 18: e206–17
¹⁸fluorodeoxyglucose (¹⁸F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including Seràgnoli Institute of
smouldering multiple myeloma and solitary plasmacytoma. ¹⁸F-FDG PET/CT can be considered a valuable tool for Hematology, Bologna
University School of Medicine,
the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses
Bologna, Italy (Prof M Cavo MD,
bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal E Zamagni MD); Department of
plasma cells while providing important prognostic information. The use of ¹⁸F-FDG PET/CT is mandatory to confirm Clinical Therapeutics, School of
a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to Medicine, National and
Kapodistrian University of
distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-
Athens, Athens, Greece
body MRI is unavailable. Based on the ability of ¹⁸F-FDG PET/CT to distinguish between metabolically active and (Prof E Terpos MD); Nuclear
inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect Medicine, Azienda
of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to Ospedaliero-Universitaria di
Bologna, Bologna, Italy
therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive (C Nanni MD); Haematology
autologous stem-cell transplantation. ¹⁸F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques Department, University
to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who Hospital of Nantes, Nantes,
are defined as having imaging MRD negativity. France (Prof P Moreau MD);
Columbia University Medical
Center, New York, NY, USA
Introduction criteria, and of interobserver reproducibility in interpreting (S Lentzsch MD); Department of
Bone disease, the hallmark of multiple myeloma, occurs results. Consistent with previous experiences in solid Hematology, VU University
in virtually all patients during the course of the disease, tumours and lymphomas, ensuring reproducibility and Medical Center, Amsterdam,
Netherlands
frequently impairing their quality of life, and represents a establishing imaging definitions for assessing the burden (Prof S Zweegman MD);
major cause of morbidity and mortality.1 Skeletal damage and activity of the disease is warranted before ¹⁸F-FDG Department of Internal
assessed by whole-body x-ray (WBXR) has for a long time PET/CT can be introduced into everyday clinical practice Medicine V, University Hospital
been one of the major criteria defining the need to start outside the setting of major academic centres.8,9 On the Heidelberg, Heidelberg,
Germany (Prof J Hillengass MD,
anti-multiple myeloma therapy. The International basis of these considerations, we aimed to review published Prof H Goldschmidt MD);
Myeloma Working Group (IMWG) has clarified that data for the use of ¹⁸F-FDG PET/CT in patients with Department of Medicine,
more than one focal lesion on MRI and one or more lytic multiple myeloma and other plasma cell disorders, such as Hematology, Oncology & Stem
bone lesions detected on CT scan, including whole-body smouldering multiple myeloma and solitary Cell Transplantation, Medical
Center, Faculty of Medicine,
low-dose CT or PET/CT, fulfill the criteria for bone plasmacytoma, to provide practical recommendations for University of Freiburg,
damage requiring therapy.2 Additionally, emerging data its optimal use. Herein is the outline of those Freiburg, Germany
support the role of new functional imaging techniques to recommendations. (Prof M Engelhardt MD); Levine
Cancer Institute, Carolinas
predict outcomes and evaluate response to therapy.3
HealthCare System, Charlotte,
¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT combines Techniques for use in multiple myeloma and NC, USA (Prof S Z Usmani MD);
functional imaging assessed by PET with morphological solitary plasmacytoma John Theurer Cancer Center at
evaluation provided by CT. It has become a standard ¹⁸F-FDG PET/CT enables a whole body evaluation to be Hackensack UMC, Hackensack,
NJ, USA (Prof D H Vesole MD);
technique in the diagnosis and management of several done in one session and in a reasonable timeframe while
Clínica Universidad de Navarra,
types of tumour, particularly for FDG-avid lymphomas.4 assuring a relatively high sensitivity and reasonable CIMA, IDISNA, Pamplona,
Although, over the past decade, ¹⁸F-FDG PET/CT has specificity for detection of both medullary and extra­ Spain (Prof J San-Miguel MD);
increasingly been used in the prognosis of multiple medullary disease (EMD).10,11 However, the most significant Division of Hematology,
Department of Medicine, Mayo
myeloma and other clonal proliferative plasma cell advantage of ¹⁸F-FDG PET/CT is its ability to assess with
Clinic, Rochester, MN, USA
disorders, its routine use is still hampered by several good accuracy the burden of the disease and to distinguish (Prof S K Kumar MD,
factors, including high cost, differences in reimbursement between metabolically active and inactive lesions. Prof S V Rajkumar MD); Jerome
between countries, lack of cost-effectiveness studies, and Minimum technical requirements for the use of ¹⁸F-FDG Lipper Multiple Myeloma
Center, Dana-Farber Cancer
limited availability.5–7 However, the major limitation of PET/CT in patients with multiple myeloma are
Institute, Boston, MA, USA
¹⁸F-FDG PET/CT is the lack of standardised imaging summarised in the appendix (p 2).

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 Review

needed before this value can be accepted as a standard.

Tracer Features
However, because SUVmax depends on the uptake time and
Cassou-Mounat et al, ¹⁸F-FCH vs ¹⁸F-FDG More sensitive than ¹⁸F-FDG in relapsed or refractory multiple might be influenced by several factors, obtaining a more
201620 myeloma
reproducible parameter by indexing it to a background is
Nanni et al, 200721 11
C-choline Allows specific evaluation of cell membrane proliferation; more
reasonable. A background on L1/L2, if healthy, or the liver
sensitive than ¹⁸F-FDG, especially in detecting skull lesions
or the mediastinal blood pool, could be considered and
Luckerath et al, 201522 11
C-methionine Highly concentrated in sites of myeloma bone disease;
Dankerl et al, 2007;23 correlates with bone marrow involvement and clinical calculated as the SUV mean of a standard volume of
Lapa et al, 201624 parameters interest, although no standard methods have been
Agool et al, 200625 ¹⁸F-fluorothymidine Uptake correlates with DNA synthesis and high proliferation accepted so far for scan evaluation in multiple myeloma.
Ak et al, 201526 ¹⁸F-NaF Uptake is a function of bone blood flow and reflects bone Additional volumetric parameters of interest for
remodelling. ¹⁸F-FDG better than ¹⁸F-NaF for the detection of prognostication in multiple myeloma include the total
myeloma focal lesions, but ¹⁸F-NaF better than ¹⁸F-FDG for the
assessment of rib fractures or degenerative changes
metabolic tumour volume, representing the total volume
of active disease in the PET field of view, and total lesion
Ho et al, 201427 11
C-acetate Uptake depends both on the tri-carboxylic acid cycle and cell
Lin et al, 201428 membrane lipid synthesis. Possible advantages over ¹⁸F-FDG glycolysis, which accurately reflects the glycolytic pheno­
suggested in the staging of patients with newly diagnosed type of focal lesions.16,17
multiple myeloma When evaluating ¹⁸F-FDG PET/CT scans, the possibility
Okasaki et al, 201529 C-4-thiothymidine
11
More sensitive than ¹⁸F-FDG for the detection of active lesions of false positive and false negative results should be
and more closely related to bone marrow plasma-cell
infiltration considered.12,18 False positives might occur due to artifacts,
Herrmann et al, 68
Ga-pentixafor Excellent PET imaging characteristics and favourable human
such as the presence of bone metallic implants and
201630 dosimetry accumulation of the tracer in physiological regions
(including joint surfaces, kidneys, ureters, bladder, crura
¹⁸F-FDG=¹⁸F-fluorodeoxyglucose. ¹⁸F-FCH=¹⁸F-fluorochloride. ¹⁸F-NaF=sodium fluoride.
of the diaphragm, and deposits of metabolically active
Table 1: Studies investigating tracers other than ¹⁸F-FDG for PET/CT imaging in patients with brown fat). Additional conditions leading to false positive
multiple myeloma results include inflammation or infection, post-surgical or
biopsy area(s), bone remodelling, fractures, and recent use
of chemotherapy, radiotherapy, or growth factors inducing
(Prof P G Richardson MD, Although the administered dose of ¹⁸F-FDG is variable a false diffuse bone marrow pattern. False negative scans,
Prof K C Anderson MD); Division and depends on the tomograph and the patient’s weight, on the other hand, are associated with hyperglycaemia,
of Hematology and Oncology,
Mayo Clinic, Phoenix, AZ, USA
the procedure for image acquisition and reconstruction is recent administration of high-dose steroids leading to a
(J R Mikhael MD); Myeloma standard.12,13 Appropriate patient preparation includes transient metabolic suppression (a finding that requires
Clinic, Hematology fasting for at least 6 h, discontinuation of oral antidiabetic steroid discontinuation before ¹⁸F-FDG PET/CT), or the
Department, Instituto therapy according to published recommendations,9 a fully presence of small sub-centimetre lytic lesions in the skull,
Português de Oncologia
Francisco Gentil, Lisboa,
intravenous injection of the tracer, and a waited uptake close to the brain. To our knowledge, no influence of
Portugal (F L da Costa MD); time of about 50–70 min. Supine decubitus under the bisphosphonate therapy on ¹⁸F-FDG distribution has been
Department of Clinical scanner is the preferred position for optimal image reading reported. Moreover, in a variable though not yet well
Therapeutics, National and and interpretation, but it is not mandatory. Analgesic defined proportion of patients, plasma cells might not be
Kapodistrian University of
Athens, School of Medicine,
drugs do not interfere with ¹⁸F-FDG distribution and can ¹⁸F-FDG-avid11,14,15,19 or do not overexpress glucose
Athens, Greece be administered to improve patient comfort. The total transporter (GLUT-1). As a result, non-hypermetabolic lytic
(Prof M-A Dimopoulos MD); duration of the procedure takes about 80–90 min. The field lesion(s) can be detected on ¹⁸F-FDG PET/CT scans, and it
Biostatistics and Clinical trial
of view of ¹⁸F-FDG PET/CT should include at least the might be difficult to distinguish between a low metabolic
Unit, IRST-IRCCS, Meldola, Italy
(C Zingaretti PhD); Department skull, upper limbs, and femurs; however, under particular lesion related to multiple myeloma and a benign one.
of Hematology, Odense circumstances, lower limbs can also be included in the In addition to ¹⁸F-FDG, new PET/CT tracers targeting
University Hospital, Odense, PET field of view. Low-dose CT (120 kV, 80 mA) is necessary different metabolic pathways or receptors expressed by
Denmark
for attenuation, correction, and image interpretation. multiple myeloma cells and acting as molecular imaging
(Prof N Abildgaard MD);
The University of Texas MD Hypermetabolic bone lesions, irrespective of underlying biomarkers have been preliminarily investigated in
Anderson Cancer Center, lytic lesions at CT, are identified with a PET standard several limited series of patients with multiple myeloma
Houston, TX, USA spatial resolution limit of about 5 mm. Renal failure and (table 1).20–30 No available data consistently support the
(Prof R Z Orlowski MD); National
metallic bone implants are not a contraindication to superiority of any of these tracers over ¹⁸F-FDG in terms
University Cancer Institute,
National University Health ¹⁸F-FDG PET/CT use. Once reconstructed, images must of accuracy of detection of bone lesion(s) and of
System, Singapore be interpreted on a dedicated workstation, providing image prognostication. As such, identification of potentially
(Prof WJ Chng MD); Department fusion and multiplanar cuts. The maximum standardised more sensitive tracers that could overcome some of the
of Internal Medicine II,
uptake value (SUVmax) based on body weight is the standard limitations of ¹⁸F-FDG would be of great interest,
University Hospital Würzburg,
Würzburg, Germany (Prof semi-quantitative index that can be considered for image including the lack of sensitivity for the assessment
H Einsele MD); Department of interpretation, particularly when evaluating response to of diffuse bone marrow plasma-cell infiltration, and
Hematology and Medical therapy. An average cut-off value of four for SUVmax has of specificity to multiple myeloma-associated lesions.
Oncology, Winship Cancer
Institute, Emory University,
been found to distinguish between active and inactive Hybrid systems integrating MRI with PET/CT platforms,
disease after therapy,14,15 but confirmatory analyses are combination of protons to monoclonal antibodies, and

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 Review

attempts at targeting antigens expressed on plasma
cells for radioimmunotherapy are currently under
investigation, and might provide advancements in
molecular imaging and precision medicine therapy
for multiple myeloma in the near future. For example,
⁶⁸Ga-pentixafor, which targets chemokine receptor-4 and
is labeled with α-emitters and β-emitters is currently
being explored in pilot studies as endo­radiotherapy in
patients with extensive EMD.30
Assessment of bone damage in multiple
myeloma
Several studies have shown the usefulness of ¹⁸F-FDG
PET/CT as part of the work-up done at diagnosis of multiple
myeloma, reporting a sensitivity and specificity in detecting
bone damage in the range of 80–100% (table 2).6,7,10,11,31–39
In one study11 designed to prospectively compare ¹⁸F-FDG
PET/CT with WBXR and MRI of the spine and pelvis,
¹⁸F-FDG PET/CT was superior to WBXR for the detection
of bone lesions, while MRI was more sensitive than
¹⁸F-FDG PET/CT for the detection of diffuse bone marrow
plasma-cell infiltration. However, in a third of patients,
¹⁸F-FDG PET/CT demonstrated bone changes in sites out
of the MRI field of view. In an additional study,33 ¹⁸F-FDG
PET/CT and MRI of the spine were equally effective for the
detection of focal lesions. Another study32 evaluated the
value of dynamic ¹⁸F-FDG PET/CT examination based on
estimates of SUV values and kinetics of the tracer in
multiple myeloma lesions. The results showed a correlation Atlanta, GA, USA
between ¹⁸F-FDG PET/CT parameters and the percentage (Prof S Lonial MD); Tisch Cancer
Institute/Multiple Myeloma
of bone marrow plasma cells. In particular, patients with Program, Mt. Sinai Cancer
negative ¹⁸F-FDG PET/CT scans had the lowest bone Institute, New York, NY, USA
marrow plasma-cell infiltration, whereas the highest (Prof B Barlogie MD); and
infiltration rate was observed in patients with a mixed focal Cedars-Sinai Comprehensive
Cancer Center, Los Angeles, CA,
or diffuse pattern of tracer uptake.32 A systematic review10 of USA (B G M Durie MD)
18 studies comparing ¹⁸F-FDG PET/CT with WBXR, or
Correspondence to:
MRI, or both, confirmed that MRI is the gold standard Prof Michele Cavo, Seràgnoli
technique for the assessment of diffuse bone marrow Institute of Hematology,
involvement of the spine, while ¹⁸F-FDG PET/CT is more Department of Experimental,
Diagnostic and Specialty
sensitive than WBXR for the detection of bone lesions. Medicine, Bologna University
In another review40 using data from 32 studies, the bone School of Medicine,
detection rate using PET, ¹⁸F-FDG PET/CT, MRI, and S Orsola-Malpighi Hospital,
whole-body CT, was superior to that of WBXR; however, Bologna 40138, Italy
michele.cavo@unibo.it
WBXR had a higher sensitivity to depict lesions in the skull
and ribs. No differences between ¹⁸F-FDG PET/CT and See Online for appendix
MRI in terms of sensitivity and specificity to detect bone
damage in patients with multiple myeloma were found in
additional systematic reviews41,42 of published studies.
Although whole-body low-dose CT has been proposed as
the standard technique for the assessment of lytic bone
lesions in multiple myeloma in a recent set of guidelines
for the management of multiple myeloma-associated
complications from the European Myeloma Network43 and
in the 2016 updated version of the European Society of
Medical Oncology guidelines (P Moreau, personal
communication) for the management of multiple

Study design Patients Imaging techniques Results

(n)
Zamagni et al, 200711 Prospective 46 PET/CT vs WBXR vs MRI WBXR and PET/CT concordant in 46% of patients; PET/CT>WBXR in 46% of
patients; MRI and PET/CT concordant in 70% of patients, MRI > PET/CT in 30%
of patients; PET/CT and MRI spine sensitivity 92%
Fonti et al, 200831 Prospective 33 PET/CT vs MRI vs MIBI PET/CT sensitivity 97%; PET/CT spine and pelvis sensitivity was 63%; MRI
sensitivity 81%
Sachpekidis et al, 201532 Prospective 40 PET/CT Lowest bone marrow plasma-cell infiltration associated with PET negativity;
highest bone marrow plasma-cell infiltration associated with a mixed pattern
of tracer uptake
Moreau et al, 201533 Prospective 134 PET/CT vs axial MRI MRI positivity in 95% of patients and PET/CT positivity in 91%
Bredella et al, 20055 Retrospective 13 PET/CT vs WBXR, MRI PET/CT sensitivity 85%, specificity 92%; PET/CT and WBXR concordant in 50%
spine, CT of patients
Nanni et al, 200634 Retrospective 28 PET/CT vs WBXR vs MRI PET/CT > WBXR for the detection of small lytic bone lesions; PET/CT concordant
to MRI in detecting bone disease of the spine and pelvis; MRI > PET/CT in
detecting an infiltrative bone marrow pattern in the spine
Breyer et al, 200635 Retrospective 16 PET/CT vs WBXR vs MRI PET/CT > WBXR in 63% of patients; PET/CT > MRI in 69% of patients
Hur et al, 200836 Retrospective 22 PET/CT vs MRI of the Stage 1 and 2, PET/CT concordant to MRI (78% vs 86% of patients); stage 3,
spine PET/CT < MRI (80% vs 92% of patients)
Shortt et al, 200912 Retrospective 24 PET/CT vs whole-body MRI and PET/CT concordant in 62% of patients; in discordant cases, MRI > PET/
MRI CT in eight of 13 cases
Sager et al, 201137 Retrospective 42 PET/CT vs WBXR PET/CT vs conventional techniques sensitivity: 90% vs 84%
Spinnato et al, 201238 Retrospective 191 PET/CT vs axial MRI At diagnosis PET/CT failed to detect diffuse bone marrow involvement in 14%
of patients; PET/CT detected focal lesions out of MRI field of view in 37% of
patients
Waheed et al, 201339 Retrospective 270 WBXR vs PET/CT vs MRI PET/CT and MRI almost concordant and >WBXR

¹⁸F-FDG=¹⁸F-fluorodeoxyglucose. WBXR=whole-body x-ray. MIBI=Sestamibi Technetium-99m bone marrow scanning.

Table 2: Studies of ¹⁸F-FDG PET/CT as part of initial work-up in patients with multiple myeloma

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 Review

myeloma, there is a lack of studies aimed at prospectively detect bone damage at an earlier phase than WBXR
comparing ¹⁸F-FDG PET/CT with whole-body low-dose CT. (evidence level 1, grade A). Several guidelines2,43 have
A large study44 conducted by the National Oncologic PET established whole-body low-dose CT as the preferred
Registry in patients with 18 different types of cancer method for the detection of lytic bone lesions in multiple
revealed that PET findings had the greatest impact on myeloma. ¹⁸F-FDG PET/CT should be considered as a
physicians’ intended management of patients with multiple valuable option, because of its ability to identify lytic
myeloma, as reflected by an overall 49% probability of lesions and extramedullary masses, while also being able
changes in management decisions and 42% changes from to provide reliable prognostic information (evidence
non­treatment to treatment.44 level 2, grade B). We recommend ¹⁸F-FDG PET/CT to
distinguish active from smouldering multiple myeloma, if
Consensus statement WBXR is negative and whole-body MRI is unavailable
We recommend incorporating these novel imaging (evidence level 1, grade A). In the current era of highly
techniques into the diagnostic work-up of multiple active novel agents, availability of ¹⁸F-FDG PET/CT scans
myeloma because of their higher sensitivity and ability to at baseline allows the comparison of pre-treatment images
with post-treatment images, and to identify patients who
Study design Patients (n) PFS or TTP OS are now considered as having imaging minimal residual
disease (MRD) negativity (evidence level 2, grade B).
At diagnosis, ASCT-eligible patients
Bartel et al, 200915 Prospective 239
Prediction of prognosis in multiple myeloma
Focal lesions PFS: 66% vs 87% at 73% vs 90% at
>three vs ≤three 30 months (p<0·0001) 30 months (p=0·0002)
In newly diagnosed patients eligible or ineligible for
EMD vs no EMD PFS: 50% vs 82% at 50% vs 87% at
autologous stem-cell transplantation
30 months (p=0·0002) 30 months (p=0·002) ¹⁸F-FDG PET/CT can be used to determine prognosis in
Zamagni et al, 201114 Prospective 192 patients with newly diagnosed and relapsed or refractory
SUV >4·2 vs ≤4·2 PFS: 42% vs 66% at 76% vs 92% at multiple myeloma (table 3).14–16,45–48
48 months (p=0·003) 48 months (p=0·02) The independent effect of more than three focal lesions
EMD vs no EMD PFS: 22% vs 63% at 64% vs 90% at at baseline, a PET image that is frequently linked to adverse
48 months (p<0·0001) 48 months (p=0·02) prognostic factors—such as high β-2 microglobulin, lactate
Focal lesions PFS: 50% vs 69% at ·· dehydrogenase, C-reactive protein levels and a high-risk
>three vs ≤three 4 years (p=0·006)
gene expression profile—and shortened progression-free
Haznedar et al, 201045 Retrospective 61
survival and overall survival, was first shown in a series of
EMD vs no EMD ·· 62% vs not reached at
5 years (p=0·01)
patients treated upfront with novel agents and double
autologous stem-cell transplantation.15 In an updated
At diagnosis, ASCT-ineligible patients
report49 by the same group, the number of focal lesions
Zamagni et al, 201546 Retrospective 76
identified by ¹⁸F-FDG PET/CT (>three) and axial MRI
Presence vs absence PFS: worse with SUV Worse with SUV >4·2,
SUV >4·2, EMD, >4·2, EMD, and focal EMD, and focal lesions (>seven) was confirmed to be associated with a high-risk
and focal lesions >three lesions >three >three gene expression profile that in turn was more frequently
Before allo-SCT observed in patients with EMD. Additionally, a comparison
Patriarca et al, 2015,47 Retrospective 54 between the gene expression profile and whole-exome
SUV >4·2 vs ≤4·2 PFS: 42% vs 72% at 16% vs 51% at sequencing done on paired random bone marrow and focal
24 months (p=0·013) 24 months (p=0·031) lesion aspirates showed different risk signatures,
EMD vs no EMD PFS: 50% vs 62%at 12% vs 33% at supporting the hypothesis that spatial clonal heterogeneity
24 months (p=0·016) 24 months (p=0·010)
might contribute to disease progression.50 In an
Focal lesions PFS: 49% vs 72% at 21% vs 56% at independent series of patients prospectively treated with a
>one vs ≤one 24 months (p=0·075) 24 months (p=0·033)
combination of thalidomide and dexamethasone
At relapse or progression
incorporated into a double autologous stem-cell trans­
Lapa et al, 201448 Retrospective 37
plantation, the number of focal lesions (>three), the SUVmax
Focal lesions >10 vs ≤10 TTP: 4·1 vs 7·0 months vs not
10·0 months (p=0·003) reached (p=0·023)
value (>4·2), and presence of EMD at baseline, were
EMD vs no EMD TTP: 3·2 vs 8·8 months vs not
significantly associated with shorter progression-free
29·3 months (p=0·049) reached (p=0·172) survival and overall survival when compared with a lower
Fonti et al, 201216 Retrospective 47 number of focal lesions (three or less), a lower SUVmax value
Lower vs higher MTV PFS: better with lower Better with lower MTV (≤4.2) and absence of EMD.14 Of these parameters, both
MTV (p=0·046) (p<0·0001) EMD and increased ¹⁸F-FDG avidity retained independent
prognostic relevance in a multivariate regression analysis.
¹⁸F-FDG=¹⁸F-fluorodeoxyglucose. PFS=progression-free survival. TTP=time to progression. OS=overall survival.
ASCT=autologous stem-cell transplantation. EMD=extramedullary disease. SUV=standardised uptake value. Several independent studies provided confirmatory results
allo-SCT=allogeneic stem-cell transplantation. MTV=metabolic tumour volume. of the poor prognosis imparted by high ¹⁸F-FDG uptake51
and presence of EMD45 that in turn was detected by ¹⁸F-FDG
Table 3: Studies of ¹⁸F-FDG PET/CT as a predictor of prognosis in patients with multiple myeloma
PET/CT as part of initial work-up.52

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Consistent with the findings reported in autologous
stem cell transplantation (ASCT)-eligible patients, the
number of focal lesions, the SUVmax value, and the
presence of EMD, were strong predictors of adverse
progression-free survival and overall survival in ASCT-
ineligible patients.46
In patients receiving allogeneic stem-cell
transplantation
The effect of ¹⁸F-FDG PET/CT findings on the outcomes
of patients who received an allogeneic-stem cell
transplantation (allo-SCT), either upfront or as salvage
treatment, has been evaluated in a single study.47 ¹⁸F-FDG
PET/CT scans were carried out within 30 days before
allo-SCT and were positive in 32 (59%) of cases, revealing
the presence of EMD in 6 (11%) patients, and an SUVmax
of more than 4·2 in 21 (39%) patients. In a multivariate
regression analysis, EMD and a high SUVmax were
independent predictors of poor progression-free survival
and overall survival. Despite the retrospective nature of
the analysis and the small number of patients, this study
suggests that ¹⁸F-FDG PET/CT might be of help in
predicting the outcomes of patients who are planned to
receive an allo-SCT, and provides the basis for the design
of future prospective trials in this setting.
In patients with relapsed or progressive disease
An analysis48 of the prognostic value of ¹⁸F-FDG PET/CT
done at the time of relapse or progression after previous
ASCT or allo-SCT confirmed the favourable prognosis
associated with negative ¹⁸F-FDG PET/CT scans. On the
contrary, the number of focal lesions (>ten), particularly
those located in the appendicular skeleton and the
presence of EMD adversely affected both time to
progression and overall survival. Shorter time to
progression was also associated with a SUVmax value of
more than 18·6. ¹⁸F-FDG PET/CT findings influenced
treatment strategies in 11 (30%) patients, more frequently
revealing occult sites of EMD. An additional study53
underscored the value of ¹⁸F-FDG PET/CT in detecting
sites of active disease at the time of relapse or progression,
with an overall sensitivity of 80%. When ¹⁸F-FDG
PET/CT findings were combined with laboratory data,
the specificity in predicting relapse or progression
was 100%.53 In another study16 of patients at different
stages of multiple myeloma, direct measurement of the
tumour burden obtained by calculating the metabolic
tumour volume from ¹⁸F-FDG PET/CT images was used
to predict progression-free survival and overall survival.
Progression-free survival and overall survival for patients
with a metabolic tumour volume below an identified cut-
off value were significantly better than those of patients
with a value above the threshold value. These data, taken
in aggregate, suggest that the evaluation of metabolic
activity provided by ¹⁸F-FDG PET/CT allows earlier
detection of relapse, distinction between progressive and
stable or non-viable multiple myeloma, and confirmation
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Review
of relapse or progression in equivocal cases, thus
contributing to a more careful prognostic identification
of patients with multiple myeloma.
Consensus statement
¹⁸F-FDG PET/CT done at the onset of multiple myeloma
is a reliable tool as a predictor of prognosis (evidence
level 1, grade A). More robust data from studies in newly
diagnosed patients treated with ASCT are available
compared with those done in patients who were not
eligible for ASCT or who have relapsed or who have
refractory multiple myeloma. We encourage studies in
such patients to further explore the role of ¹⁸F-FDG PET/CT
as a prognostic indicator. Consistencies between
independent studies confirm the negative prognostic
value of EMD and the presence of more than three focal
lesions, particularly after upfront ASCT, while the
prognostic role of SUVmax is more conflicting (evidence
level 3, grade C). A high number of focal lesions or the
presence of EMD more frequently correlates with adverse
prognostic factors associated with the burden or the
biology of multiple myeloma (evidence level 3).
Assessment of response to therapy in multiple
myeloma
¹⁸F-FDG PET/CT is an excellent tool to evaluate and
monitor response to treatment because of its ability to
distinguish between metabolically active and inactive sites
of clonal proliferating plasma cells.14,15,33,55–58 Additionally,
negative ¹⁸F-FDG PET/CT images correlate well with high
quality response to therapy (table 4).14,15 In two studies,15,55
¹⁸F-FDG PET/CT was evaluated either on day 7 after
induction treatment or before the first ASCT. Persistence of
more than three focal lesions at day 7 was an early predictor
of significantly shorter progression-free survival and overall
survival, especially in the subgroup of patients with a high-
risk gene expression profile.55 By contrast, complete
suppression of ¹⁸F-FDG avidity in focal lesions before an
ASCT was associated with significantly longer progression-
free survival and overall survival. Negative ¹⁸F-FDG PET/
CT scans showed complete response 12 months before
more conventionally defined methods, while resolution of
focal lesions using MRI was observed later on (18 month
probability of negative images was 92% with ¹⁸F-FDG PET/
CT vs 29% with MRI). In an additional study,14 persistence
of high tumour metabolism after induction treatment
predicted shorter progression-free survival after ASCT,
while post-ASCT ¹⁸F-FDG PET/CT negativity (observed in
124 [65%] of patients) was an independent factor associated
with durable disease control and prolonged overall survival.
Negative ¹⁸F-FDG PET/CT scans after ASCT were
associated with prolonged time to progression;14 by contrast,
a short time to progression could be anticipated in patients
in whom increased metabolic activity still persisted after
therapy.19 In another series of patients33 who were randomly
assigned to receive upfront ASCT or standard dose
intensification therapy to be followed by 1 year of
e210
 Review

Study design Patients Treatment Time of Parameter Endpoint

(n) assessment

Bartel et al, Prospective 239 Chemotherapy plus novel Before ASCT Normalisation PFS 89% vs 63% at 30 months from
200915 agents plus double ASCT vs persistence of first ASCT (p=0·003)
FDG uptake
Dimitrakopoulou- Prospective 19 Chemotherapy After first cycle of SUV > 4 vs ≤4 PFS: worse at 18 months (p<0·05)
Strauss et al, chemotherapy
200956
Zamagni et al, Prospective 192 Thalidomide plus After TD induction SUV >4·2 vs ≤4·2 PFS: 44% vs 69% at48 months
201114 dexamethasone plus double therapy (p=0·007)
ASCT
Zamagni et al, Prospective 192 Thalidomide plus After double ASCT SUV >4·2 vs ≤4·2 PFS: 32% vs 47% at 48 months
201114 dexamethasone plus double (p=0·02); OS: 66% vs 79% at 48
ASCT months (p=0·02)
Usmani et al, Prospective 302 Chemotherapy plus novel At day 7 of Focal lesions 0 PFS: 84% vs 78% vs 56% at 36 months
201355 agents plus double ASCT induction therapy vs 1–3 vs >3 (p<0·0003); OS: 87% vs 82% vs 63%
at 36 months (p<0·0001)
Nanni et al, Prospective 107 ASCT After ASCT PET/CT negative Median TTP: 27·6 vs 18 months,
201319 vs positive p=0·05
Beksac et al, Prospective 139 Chemotherapy plus ASCT Before and after SUV >4·2 vs ≤4·2 PFS: 25·6% vs 45·8% at 36 months,
201557 ASCT p=0·05
Beksac et al, Prospective 139 Chemotherapy plus ASCT Before and after SUV >3·35 vs OS: 79·5% vs 94·9% at 36 months
201557 ASCT ≤3·35 (p=0·037)
Moreau et al, Prospective 134 Bortezomib, lenalidomide, After bortezomib, PET/CT positive vs PFS: 60% vs 79% at 30 months
201533 and dexamethasone with or lenalidomide, and negative (p=0·04)
without ASCT dexamethasone
induction therapy
Moreau et al, Prospective 134 Bortezomib, lenalidomide, Before PET/CT positive vs PFS: 76% vs 54% at 30 months
201533 and dexamethasone with or maintenance negative (p=0·0004)
without ASCT therapy
Korde et al, Prospective 45 Carfilzomib, lenalidomide, After carfilzomib, PET/CT positive or PFS: 82% vs 89% at 18 months
201558 and dexamethasone lenalidomide, and partial vs negative (p=0·54)
dexamethasone or improved
Elliott et al, Retrospective 56 Chemotherapy plus ASCT After therapy PET/CT negative PFS: better at 12 months with PET/CT
201154 plus novel agents vs positive (p=0·0005)
Fonti et al, Retrospective 47 Novel agents plus ASCT (in After induction Persistence of PFS: worse with high MTV
201216 19 patients) therapy high vs low MTV (p=0·0465); OS: worse (p<0·0001)
Patriarca et al, Retrospective 54 Allo-SCT At 6 months after PET/CT positive vs PFS: 25% vs 51% at 24 months
201547 allo-SCT negative (p=0·03); OS: 47%
vs 81% at 24 months (p=0·001)
Zamagni et al, Retrospective 189 Chemotherapy, novel agents At 3 months after PET/CT positive vs PFS: median 38 vs 52 months,
201546 with or without ASCT therapy negative (p=0·0319); OS: 71% vs 90% at 60
months (p=0·00014)

¹⁸F-FDG=¹⁸F-fluorodeoxyglucose. ASCT=autologous stem-cell transplantation. PFS=progression-free survival. SUV=standardised uptake value. OS=overall survival. TTP=time
to progression. allo-SCT=allogeneic stem-cell transplantation. MTV=metabolic tumour volume.

Table 4: Studies of 18F-FDG PET/CT as a tool to evaluate metabolic response to treatment in patients with multiple myeloma

maintenance therapy, ¹⁸F-FDG PET/CT was evaluated after
induction therapy and before maintenance. Normalisation
of ¹⁸F-FDG PET/CT scans after induction therapy (43 [32%]
patients) was associated with improved progression-free
survival when compared with persistent ¹⁸F-FDG uptake,
while ¹⁸F-FDG PET/CT negativity before starting
maintenance therapy (83 [62%] patients) predicted longer
progression-free survival and overall survival than did
¹⁸F-FDG PET/CT-positivity. Additional studies55–58
confirmed the value of ¹⁸F-FDG PET/CT combined with
laboratory data in predicting the risk of progression after
high-dose or conventional-dose therapy with or without any
novel agents. A prospective evaluation57 of ¹⁸F-FDG PET/CT
scans before and after ASCT showed that the absence of
¹⁸F-FDG metabolic activity or an improvement in metabolic
response after high-dose therapy had a favourable impact
on progression-free survival. In a similar study47 of ¹⁸F-FDG
PET/CT done before and after allo-SCT, EMD persistence
after therapy was an independent variable predicting
shorter progression-free survival and overall survival, while
significantly improved outcomes were observed for patients
who maintained or achieved PET negativity compared with
those with persistent PET positivity. A dynamic prospective
study56 of ¹⁸F-FDG PET/CT before and after the first cycle of

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chemotherapy revealed that a kinetic analysis of SUV and
other imaging-associated variables was helpful for
predicting progression-free survival and identifying
patients who mostly benefited from therapy. By comparison
with contrast-enhanced MRI, ¹⁸F-FDG PET/CT was
associated with faster normalisation of imaging findings in
patients who had achieved a complete response or who had
achieved a very good partial response after therapy.38
¹⁸F-FDG PET/CT and whole-body MRI were concordant in
detecting residual lesions after therapy in 62% of cases (21
of 34 pairs of images), with positive predictive values of
81% for ¹⁸F-FDG PET/CT and 88% for whole-body MRI.12
Results of prospective studies aimed at evaluating the
performance of diffusion-weighted imaging whole-body
MRI in assessing response to therapy are still limited. An
overview59 of six prospective and four retrospective studies
including 690 patients with multiple myeloma or solitary
plasmacytoma, confirmed the value of ¹⁸F-FDG PET/CT to
assess the extent of response to treatment and to detect
sites of disease recurrence early.
Detection of minimal residual disease in
multiple myeloma
Advances with the introduction of highly effective novel
drugs for the treatment of multiple myeloma have led to
the definition of new response categories that reflect
deeper degrees of tumour reduction than those identified
in the past as conventional complete response.60 Interest
in detecting and monitoring MRD has progressively
grown over the past years. Cell-based and molecular-based
methods to assess MRD in the bone marrow include
multiparametric flow cytometry immuno­ phenotyping,
and either allele-specific oligo­nucleotide-PCR or multiplex
PCR, using standard primers recognising all V and J
segments within a given immunoglobulin locus, followed
by high-throughput next-generation sequencing.
However, owing to the patchy pattern of bone marrow
plasma-cell infiltration in multiple myeloma and the
increasing frequency of EMD, the probability of a false-
negative assessment of MRD is relatively high. To establish
that the tumour clone has been completely eradicated,
sensitive bone marrow-based assays as part of MRD
detection should be coupled with functional imaging
techniques that detect MRD outside the bone marrow. In
this context, ¹⁸F-FDG PET/CT is a powerful tool for
evaluating tumour activity and its metabolic response to a
given therapy.
Several independent studies14,33 and a meta-analysis61
consistently showed that among those patients who
achieved a complete response after an ASCT, ¹⁸F-FDG
PET-CT negativity was a predictor of better outcomes than
persistent metabolic activity, possibly reflecting different
levels of MRD. In a retrospective study46 of both ASCT-
eligible and ASCT-ineligible patients, ¹⁸F-FDG PET/CT
was evaluated at diagnosis and after treatment. 100 (53%)
of 189 patients achieved a complete response, but in 29
(29%) of these 100 cases the ¹⁸F-FDG PET/CT images
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Review
remained positive. For these patients, the median
progression-free survival and overall survival were
significantly shorter than those with normalised ¹⁸F-FDG
PET/CT scans (median progression-free survival 44 vs 84
months [p=0·0009], overall survival at 5 years 70% vs 90%
[p= 0·003]). On multivariate analysis, post-treatment
¹⁸F-FDG PET/CT negativity was an independent factor
that predicted prolonged progression-free survival and
overall survival. In an additional study,57 ¹⁸F-FDG PET/CT
negativity in patients achieving a very good partial
response after ASCT was associated with significantly
improved progression-free survival and overall survival.
By contrast, in a series58 of patients treated upfront with a
three drug regimen including the next-generation
proteasome inhibitor, carfilzomib, no association was
evidenced between ¹⁸F-FDG PET/CT scans, clinical
response, and MRD status. Whether or not the value of
¹⁸F-FDG PET/CT in detecting MRD will be retained with
the use of highly effective therapies that target the tumour
clone via different mechanisms of action remains an open
question that should be addressed in future clinical trials.
Finally, recognition that both false positive and false
negative results might occur with the use of ¹⁸F-FDG PET/
CT to detect and monitor MRD is important. Importantly,
the low sensitivity of ¹⁸F-FDG PET/CT in patients with
diffuse bone marrow plasma-cell infiltration can be
outweighed by coupling this technique with either
multiparametric flow cytometry or next-generation
sequencing as part of MRD evaluation.
Several studies have assessed ¹⁸F-FDG PET/CT as a
tool to evaluate response to therapy in multiple myeloma
(table 4) and its use in symptomatic multiple myeloma
has advantages and disadvantages (panel).
Consensus statement
We recommend that ¹⁸F-FDG PET/CT should be
considered the preferred imaging technique to evaluate
and monitor metabolic response to therapy in multiple
myeloma (evidence level 1, grade A). Changes in ¹⁸F-FDG
avidity provide an earlier evaluation of response compared
with MRI; data for diffusion-weighted imaging whole-
body MRI are still limited. ¹⁸F-FDG PET/CT negativity
before ASCT is an early predictor of favourable post-ASCT
outcomes (evidence level 3, grade B). For patients with
conventionally defined complete response after treatment,
in particular after ASCT, persistent ¹⁸F-FDG PET/CT-
positive scans after 3–6 months predict worse outcomes
(evidence level 3, grade B). In view of the ability of
¹⁸F-FDG PET/CT to detect the presence of EMD, this
technique should be coupled with sensitive bone marrow-
based assays as part of MRD assessment to confirm MRD
negativity both inside and outside the bone marrow. The
combination of negative multiparametric flow cytometry
or next-generation sequencing, negative ¹⁸F-FDG PET/CT
scans and a normal heavy/light chain ratio might
ultimately reflect the complete eradication of myeloma
cells from all compartments.60
e212
 Review
Panel: Use of ¹⁸F-FDG PET/CT at diagnosis and after treatment in multiple myeloma
At diagnosis
Advantages
• Provides a whole body evaluation at one session while
detecting with relatively high sensitivity and specificity
myeloma bone disease
• Optimal to detect extramedullary sites of the disease
• Detects lytic bone lesions (diameter of >5 mm)
• Optimal to assess the burden and metabolism of the tumour
• Valuable tool for predicting prognosis (particularly, absence
or presence of focal lesions, and of extramedullary disease)
• Mandatory to confirm the diagnosis of solitary plasmacytoma
Disadvantages
• Suboptimal for detecting diffuse bone marrow plasma-cell
infiltration and lytic lesions in the skull
• Higher costs compared with MRI and whole-body MRI
• Radiation dose is greater than that given for whole-body
X-ray, whole-body low-dose CT
• Poor availability
• False positivity due to bone metallic implants, accumulation
of the tracer in physiological districts, inflammation,
¹⁸F-FDG PET/CT use in smouldering multiple
myeloma
Smouldering multiple myeloma is a biologically hetero­
geneous plasma cell disorder in which the probability of
progression to multiple myeloma ranges from about
10–40% per year, and is driven by the absence or presence
of several biomarkers of malignancy, including focal
lesions at MRI.62,63
Data for the role of ¹⁸F-FDG PET/CT in predicting the
risk of progression of smouldering multiple myeloma to
multiple myeloma are limited. In a series64 of patients with
smouldering multiple myeloma and for whom ¹⁸F-FDG
PET/CT scans at baseline were available, the 2-year risk of
progression to active multiple myeloma was 75% for those
with increased ¹⁸F-FDG uptake, with or without underlying
lytic lesions, and 61% for the small subgroup of patients
with abnormal tumour metabolism but without underlying
osteolysis. One study65 aimed to prospectively evaluate the
impact of focal lesions without underlying osteolysis on
the risk of progression of smouldering multiple myeloma
to multiple myeloma using PET. With a median follow-up
of 2·2 years, patients with positive ¹⁸F-FDG PET/CT
images (19 [16%] of 120 patients) had a higher risk of
progression to active multiple myeloma (58% at 2 years)
and a shorter time to progression (median of 1·1 years)
than those with negative ¹⁸F-FDG PET/CT scans, for
whom the risk of progression at 2 years was 33% and
median time to progression was 4·5 years. PET positivity
might become a new potential biomarker to identify
patients with high-risk smouldering multiple myeloma
who need to be considered for future clinical trials to test
early therapy.62,66 Further studies using a larger series of
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infections, post-surgical areas, concomitant tumours, or
recent chemotherapy or radiotherapy or use of growth
factors inducing a false diffuse bone marrow pattern
• False negativity due to hyperglycaemia, recent use of
high-dose steroids inducing a transient metabolic
suppression, presence of sub-centimetre lytic lesions in
the skull, or close to the brain
After treatment
Advantages
• Powerful tool for evaluating metabolic response to therapy
• Provides earlier assessment of response compared with MRI
• Identifies those patients who are imaging MRD-negative
• Correlates well with biochemical markers of response
Disadvantages
• Lack of standardisation
• Only applicable in 75% of patients
• Poor availability
• High costs
¹⁸F-FDG=¹⁸F-fluorodeoxyglucose.
patients are needed to identify the optimal cut-off value for
the number of focal lesions and cut-off value for SUVmax
that might predict the highest risk of imminent (eg, within
2 years or less) progression to active multiple myeloma in
at least 80% of patients. Furthermore, the possible
combination of ¹⁸F-FDG PET/CT with other biomarkers of
malignancy should be exploited to more carefully predict
the risk of progression of smouldering multiple myeloma
to multiple myeloma.
Consensus statement
Patients who meet the criteria for smouldering multiple
myeloma but have one or more lytic lesions on ¹⁸F-FDG
PET/CT should be defined as having multiple myeloma
that requires therapy (evidence level 1, grade A). ¹⁸F-FDG
PET/CT is required to distinguish active from
smouldering multiple myeloma, if WBXR is negative and
whole-body MRI is unavailable (evidence level 1, grade A).
Early data suggest that focal lesions without underlying
bone changes on ¹⁸F-FDG PET/CT predict for a higher
risk of early progression from smouldering multiple
myeloma to active multiple myeloma, but further
confirmation is warranted (evidence level 3, grade B).
We encourage the incorporation of ¹⁸F-FDG PET/CT into
prospective studies of patients with newly diagnosed
smouldering multiple myeloma.
¹⁸F-FDG PET/CT use in solitary plasmacytoma
Historically, solitary plasmacytoma diagnosis relied on
biopsy-proven presence of clonal plasma cells in a single
lytic bone lesion or a soft tissue mass, either in the
absence of bone marrow plasma-cell infiltration or with a
www.thelancet.com/oncology Vol 18 April 2017

minimal bone marrow involvement (eg, <10% plasma
cells), without evidence of end-organ damage according
to the CRAB criteria (hypercalcaemia, renal failure,
anaemia, lytic bone lesions). Negative MRI of the spine
and pelvis or no additional MRI findings other than a
single area of bone involvement is required to confirm
diagnosis. According to the site in which solitary
plasmacytoma develops, two different entities are
recognised, namely solitary bone plasmacytoma, which
represents about two thirds of all solitary plasmacytomas
and extramedullary plasmacytoma.
When diagnosing solitary plasmacytoma, it is of
particular importance to carefully evaluate the bone
marrow by coupling standard techniques with more
sensitive tools to reveal the presence of cytologically
undetectable plasma cells, as well as to exclude the
possible coexistence of additional occult sites of the
disease, because the prognosis varies consistently.
Modern imaging techniques offer a major contribution to
the detection of occult lesions not visualised by WBXR.67
In this setting, MRI of the axial skeleton has been shown
to be superior to WBXR68,69 and is recommended in
patients with solitary bone plasmacytoma of the spine
and suspected cord or nerve root compression.68,70
¹⁸F-FDG PET/CT is of high value in this field, due to the
combination of its metabolic properties with anatomic
reliability. In a systematic review and meta-analysis of
14 studies,71 ¹⁸F-FDG PET/CT was identified as the
imaging technique with the highest reliability in terms of
sensitivity, specificity, and positive and negative likelihood
ratios for the detection of sites of clonal plasma cells,
particularly outside the bone marrow. In a retrospective
analysis72 of patients with a suspected diagnosis of solitary
plasmacytoma based on WBXR, the presence at baseline
of at least two hypermetabolic lesions on ¹⁸F-FDG PET/
CT scans and an abnormal serum free light chain ratio
were the leading independent predictors of early evolution
to multiple myeloma. In several other studies73–75 of
patients suspected of having solitary plasmacytoma,
¹⁸F-FDG PET/CT revealed occult osteolysis, or soft tissue
masses, or both, not assessed by WBXR or out of the field
of view of MRI of the spine in 30–50% of cases, but failed
to detect bone marrow involvement of the spine or pelvis
in about 30% of patients when compared with axial MRI.11
Consensus statement
We think integration of the novel functional imaging
techniques into the diagnostic procedures in patients
with suspected solitary plasmacytoma is warranted to
more carefully assess the extent of the tumour and to
confirm the diagnosis by ruling out the presence of
additional occult sites of proliferating clonal plasma cells
(evidence level 1, grade A). On the basis of the limited
availability of whole-body MRI, we recommend ¹⁸F-FDG
PET/CT as part of the initial investigations in patients
with a suspicion of either extramedullary plasmacytoma
or solitary bone plasmacytoma.
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Review
Open issues
Several questions regarding the use of ¹⁸F-FDG PET/CT
and other novel imaging techniques in the diagnosis and
management of plasma cell disorders remain currently
unanswered and need to be properly addressed in well
designed clinical trials. Of these, the most relevant are
associated with the assessment of MRD and the impact of
metabolic response to treatment strategies. Regarding
MRD evaluation, it will be important to establish the
relationship between complete metabolic response and
MRD negativity at the bone marrow level. Another
important question is the potential effect of imaging
results on treatment decisions, in particular, the need to
tailor treatment according to image response. Additionally,
the specificity of additional multiple myeloma-specific
tracers other than ¹⁸F-FDG is an exploratory field of
interest. Upcoming prospective trials including novel
imaging techniques will help to address these issues.
Standardisation of ¹⁸F-FDG PET/CT interpretation
criteria
¹⁸F-FDG PET/CT might be equivocal and difficult to
interpret in multiple myeloma. False positive and false
negative results might occur. Additionally, the lack of
established criteria for image interpretation makes it
challenging to correctly assess response to therapy.
In several studies, semi-quantitative criteria, such as
Grade
Active multiple myeloma
¹⁸F-FDG PET/CT should be considered as part of the initial investigations in patients with newly B
diagnosed multiple myeloma because it provides information useful for prognostication and allows
to more carefully assess the bulk of the disease, particularly in patients with extramedullary sites of the
disease; assessing the bulk of the disease with ¹⁸F-FDG PET/CT also applies to patients with relapsed or
refractory multiple myeloma
In patients with newly diagnosed multiple myeloma, with or without EMD, and more than three B
focal lesions, ¹⁸F-FDG PET/CT identifies subgroups of patients with unfavourable outcomes;
controversies exist about the prognostic role of SUVmax
¹⁸F-FDG PET/CT is now the preferred technique for evaluating and monitoring response to therapy; A
metabolic changes assessed by ¹⁸F-FDG PET/CT provide an earlier evaluation of response compared
with MRI
¹⁸F-FDG PET/CT should be coupled with sensitive bone marrow-based assays as part of minimal B
residual disease detection inside and outside the bone marrow
Smouldering multiple myeloma
Patients who meet the diagnostic criteria for smouldering multiple myeloma and have one or A
more lytic lesions on ¹⁸F-FDG PET/CT should be defined as having multiple myeloma that requires
immediate therapy
¹⁸F-FDG PET/CT is recommended to distinguish smouldering multiple myeloma from active A
multiple myeloma if whole-body X-ray is negative and whole-body MRI is unavailable
Solitary plasmacytoma
Patients with focal lesions on PET but without underlying lytic lesions on the CT part of ¹⁸F-FDG PET/ B
CT are at high risk of progression to active multiple myeloma
Patients with suspected solitary plasmacytoma, either extramedullary plasmacytoma or solitary bone A
plasmacytoma without symptoms or signs suggestive of cord compression, should receive ¹⁸F-FDG
PET/CT to unequivocally confirm the diagnosis, provided whole-body MRI is unavailable
¹⁸F-FDG= ¹⁸F-fluorodeoxyglucose. EMD=extramedullary disease. ASCT=autologous stem-cell transplantation.
SUV=standardised uptake value.
Table 5: Recommendations for the use of ¹⁸F-FDG PET/CT in patients with multiple myeloma and other
plasma cell disorders
e214
 Review
SUVmax, were applied, while in others visual criteria or both
of these approaches were used. No consensus has been
reached regarding an appropriate SUVmax cut-off value to
distinguish between PET-positive and PET-negative scans.
These discrepancies prevented data reproducibility and
represent a challenge not only for routine evaluation of
PET images, but also for harmonisation of results across
different centres and multicentre trials.
Several recommendations for the interpretation of
¹⁸F-FDG PET/CT scans for multiple myeloma have been
proposed6 (appendix p 3). A group of experienced nuclear
medicine physicians and haematologists defined new
visual interpretation criteria (Italian Myeloma criteria for
PET Use [IMPeTUs]) in an attempt to standardise
¹⁸F-FDG PET/CT scans in multiple myeloma.70 These
criteria are based on the standard Deauville 5-point
system and include bone marrow metabolic state, focal
bone lesions (eg, site, number, and ¹⁸F-FDG uptake) with
or without an underlying osteolysis, paramedullary or
extramedullary disease, and fractures (appendix p 4).
These criteria, which are merely descriptive, warrant
validation by future analyses aimed at evaluating their
impact on clinical outcomes and might represent the
backbone for new proposals of image interpretation.
Except for the interpretation of ¹⁸F-FDG PET/CT
images at onset or relapse of multiple myeloma, no
consensus exists on what criteria should be used to
evaluate metabolic response to therapy. Complete
resolution of every area of increased ¹⁸F-FDG uptake
found before the start of therapy can be accepted as a
criterion to define PET-defined complete response,
although preliminary data seem to indicate that
persistence of a minimal increase in ¹⁸F-FDG uptake
does not significantly affect prognosis.14 To overcome
these challenges in image interpretation, a group of
European haematologists, nuclear medicine physicians,
and physicists have set up a standardisation project of
Search strategy and selection criteria
We describe the different methods used to perform ¹⁸F-FDG PET/CT in multiple myeloma
and other plasma cell disorders and the role of ¹⁸F-FDG PET/CT in the evaluation of bone
disease, assessment of response to therapy, and prognostication in different phases of
multiple myeloma, as well as introducing a proposal to standardise image interpretation
criteria. To inform our Review, we searched PubMed for articles published in English between
Jan 1, 1980, and April 30, 2016. References were identified using the search terms “positron
emission tomography”, “computed tomography”, “18F fluorodeoxyglucose”, “imaging”,
“multiple myeloma”, “smouldering myeloma”, and “solitary plasmacytoma”. Articles were
also identified through search of the authors’ own files. The final reference list was generated
on the basis of originality and relevance to the broad scope of this Review. This Review and
the recommendations on the use of ¹⁸F-FDG PET/CT were developed by an interdisciplinary
panel of experts on ¹⁸F-FDG PET/CT and bone disease in multiple myeloma. Expert consensus
was used to propose recommendations in the absence of sufficiently robust data. Levels of
evidence and grades of recommendations were attributed to the different indications
according to published criteria (appendix p 1). The paper was drafted and circulated among
all panel members followed by subsequent rounds of revisions until consensus was achieved.
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PET/CT scan interpretation criteria built on the pivotal
IMPeTUs proposal.76
Conclusion
¹⁸F-FDG PET/CT combines functional imaging provided
by PET with morphological evaluation assessed by CT,
thus enabling the detection of the presence of sites of
metabolically active plasma cells both inside and outside
the bone marrow to define the anatomical localisation,
size, and metabolic properties of focal lesions, or EMD, or
both, to predict patients’ clinical outcomes, and to assess
therapy-induced changes in tumour-cell metabolism. On
the basis of these attributes, ¹⁸F-FDG PET/CT can be
considered as a valuable tool in the initial work-up of
patients with newly diagnosed and relapsed or refractory
multiple myeloma, in particular for the detection of
paramedullary and extramedullary soft tissue masses or
solid organ involvement and for the assessment of the risk
imparted by the number of focal lesions and presence of
EMD. In patients with suspected solitary plasmacytoma
and if whole-body MRI is unavailable, ¹⁸F-FDG PET/CT is
mandatory to confirm diagnosis. However, the major
strength of ¹⁸F-FDG PET/CT is the ability to distinguish
between metabolically active and inactive sites of the
disease, a finding that makes this technique the gold
standard for evaluating and monitoring response to
therapy. Changes in ¹⁸F-FDG avidity provide an earlier
evaluation of response compared with MRI and can predict
outcomes, particularly in patients who are candidates to
receive ASCT. ¹⁸F-FDG PET/CT can be coupled with
sensitive bone marrow tools to detect MRD inside and
outside the bone marrow, contributing to the identification
of patients who are defined as having imaging MRD
negativity. We recommend the use of ¹⁸F-FDG PET/CT in
patients with active multiple myeloma, smouldering
multiple myeloma, and solitary plasmacytoma (table 5).
Contributors
MC and EZ wrote the first draft of the manuscript after reviewing the
scientific literature and after discussion with members of the IMWG. All
authors reviewed the draft, provided detailed comments and input, and
contributed to the final report.
Declaration of interests
MC reports personal fees from Janssen, Celgene, Takeda, Amgen, and
BMS, outside the submitted work. ET reports grants, personal fees, and
non-financial support from Amgen, Celgene, and Janssen-Cilag; personal
fees and non-financial support from Takeda; and personal fees from
Novartis, Roche, and BMS, outside the submitted work. PM reports
personal fees from Celgene, Janssen, Amgen, Novartis, Takeda, and BMS,
outside the submitted work. SL reports an advisory role for Celgene, BMS,
Novartis, and Janssen, outside the submitted work. SZ reports grants
from Celgene, Takeda, and Janssen, outside the submitted work. JH
reports personal fees from Celgene, Janssen, Takeda, Amgen, BMS,
Sanofi, and Novartis, outside the submitted work. ME reports financial
support from Celgene, Novartis, Janssen, and MSD, outside the submitted
work. JS-M reports advisory role for Millennium, Celgene, Novartis, Onyx,
Janssen, BMS, MSD, Amgen, outside the submitted work. SKK reports
personal fees from Kesios, Noxxon, Skyline Diagnostics, financial support
to the institution for which he works from R01, Merck, Takeda, Celgene,
Sanofi, Amgen, Janssen, Glycomimetics, outside the submitted work.
PGR reports an advisory role for Celgene and Takeda, outside the
submitted work. M-AD reports personal fees from and advisory role for
www.thelancet.com/oncology Vol 18 April 2017

Amgen, Celgene, Janssen, Novartis, and Takeda outside the submitted
work. HG reports honoraria, advisory role, speakers bureau, and research
funding from Janssen-Cilag, Celgene, Janssen, Novartis, Bristol-Myers
Squibb, Millennium, Amgen, Takeda, Mundipharma, and Johnson &
Johnson, outside the submitted work. Prof. Orlowski reports grants from,
and advisory roles for Takeda Oncology, Celgene Corporation, Bristol-
Myers Squibb, Incyte, Amgen, grants from Spectrum Pharmaceuticals,
and an advisory role for Forma Therapeutics, and Janssen, outside the
submitted work. HE reports grants from Janssen, Celgene, Amgen, and
Novartis, outside the submitted work. SL reports personal fees from
Millennium, Celgene, Novartis, BMS, Janssen, and Onyx, outside the
submitted work. KCA reports personal fees from Celgene, Millennium,
Gilead, and BMS outside the submitted work. CZ, CN, FLDC, SZU, DHV,
JRM, NA, WJC, BB, SVR, BGMD, EZ declare no competing interests.
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