1. The place of newer imaging techniques in multiple myeloma
Dr Andrew Chantry
Senior Clinical Lecturer and Honorary Consultant in Haematology
University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust
UKMF Autumn Educational Day ‘The evolving management of multiple myeloma and related plasma cell disorders’
Brunei Gallery, School of Oriental and African Studies

2. Devastating consequences of myeloma bone disease
Treating physicians must keep foremost in mind that myeloma bone disease is often the cause of the most disabling problems that pts face and, therefore, careful baseline and serial radiographic assessments are essential to maintaining and improving their pts quality of life.
Dimopoulos MA et al Leukemia 2009 ‘IMWG consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma’

3. A 60 year old male with Durie-Salmon IIIA, presenting a multi-focal MRI pattern on saggital T2 sequence with mildly increased signal intensity of FL throughout the vertebral column (A), more intense STIR signal (B). Corresponding PET/CT image shows a high degree of FDG avidity with a multi-focal uptake pattern (C).
Mesguich C, et al. State of the art imaging of multiple myeloma: Comparative review of FDG PET/CT imaging in various clinical settings. Eur J Radiol (2014),

4. A 42 year old female with IgM kappa restricted MM, ISS stage I Durie-Salmon IIB. T2 STIR-sagittal MR image shows normal signal of the vertebral bodies (A) and T1 sagittal MR image shows diffusely hypointense signal of the vertebral bodies (B). Involvement (20-50%) of the BM is evidenced by only a moderate signal reduction on T1 sequence, which can pose challenges for the diagnosis. PET/CT shows a diffuse homogenously increased FDG uptake of BM that exceeds the liver uptake, which is consistent with diffuse BM involvement (C).
Mesguich C, et al. State of the art imaging of multiple myeloma: Comparative review of FDG PET/CT imaging in various clinical settings. Eur J Radiol (2014),

5. The role of imaging in myeloma
Bone disease is the most frequent feature of multiple myeloma, occurring in approximately two-thirds of patients at diagnosis and in nearly all patients during the course of the disease.
Despite recent advances, the consequences of skeletal involvement remain clinically troublesome; bone disease in myeloma substantially impairs quality of life and is a major cause of morbidity and mortality (Kyle et al 2003; Terpos & Dimopoulos, 2005).
Various imaging techniques are available to date for the detection and monitoring of myeloma bone disease and the optimal use of these techniques supports clinical decision making specifically
Bone disease denotes myeloma-related organ damage, which calls for an immediate start of systemic therapy.
Sensitive imaging techniques are required to distinguish solitary plasmacytoma, which may be treated with radiotherapy alone and multiple plasmacytomata or multiple myeloma which require systemic therapy.
During the course of the disease, imaging is required to identify painful bone lesions or sites of bone disease at potential risk of pathological fractures or neurological complications eg spinal cord compression.
Newer imaging tools, such as MRI, allow one to better predict the risk of early progression from asymptomatic or smouldering myeloma to symptomatic disease.
PET/CT and whole body MRI are predictors of clinical outcomes at diagnosis and after treatment.
In addition, these functional imaging methods could more accurately assess the depth of response to novel-agent-based therapies, thus refining the definition of complete response (CR), and are useful tools in the follow-up of treated patients.
Newer imaging modalities (eg MRI and PET/CT) play a role in monitoring non-secretory disease.
Zamagni et al, 2012, British Journal of Haematology ‘’The role of imaging techniques in the management of multiple myeloma.”

6. Skeletal survey
Skeletal survey has long been the screening technique of choice in diagnosis.
Widely available, simple, low cost and low radiation dose
The presence of lytic lesions on conventional radiographs is a criterion defining symptomatic myeloma which requires immediate treatment
Lytic lesions only become evident at WBXR when more than 30-50% of the BMD has been lost (Terpos et al, 2011); thus, we know that skeletal survey underestimates the presence of lytic bone disease in a significant proportion of patients.
Focal lesions are more easily seen in cortical bone, but often invisible inside the spongiosa eg within vertebral bodies.
A 2013 systematic review (Regelink et al, 2013) compared modern imaging methods including MRI, WBCT and PET/CT with conventional radiography; newer imaging techniques had greater sensitivity than skeletal survey, with as many as 80% or more lesions detected by the newer imaging techniques.
CT and MRI were equally sensitive.
Skeletal survey cannot distinguish myeloma related osteoporosis form post-menopausal or steroid induced osteoporosis.
Neither is skeletal survey useful in the assessment of response to treatment or during the follow-up phase, because healing of lytic lesions is a rare event even in those who achieve a CR.

7. False negative radiograph
False negative radiograph. Focal osteolytic lesions of MM are seen well with 18-FDG PET-CT compared with corresponding radiographs. Radiograph of lateral view of lumbar spine (far left) demonstrates no obvious lytic lesions or tumour involvement. 18-FDG PET-CT (second from left) reveals diffuse myeloma marrow infiltration (shorter arrows) and focal lytic bone lesions (longer arrows) of L3 and L4. 18-FDG PET-CT fused images (far right), and corresponding CT-only images (second from right).
Walker et al 2012 The journal of Nuclear medicine ‘Imaging of Multiple Myeloma and Related Plasma Cell Dyscrasias’

8. Computerised tomography (CT)
CT has a higher sensitivity than plain radiographs in detecting small lytic lesions, especially in areas that are hard to visualise by plain X-rays such as the sternum, ribs or scapulae.
CT is hence primarily indicated for the detection of early sites of bone destruction not depicted by plain X-rays.
Anatomical sites of unexplained pain can guide when to request CT clarification.
Moreover, CT can accurately reveal the presence and size of myelomatous soft tissue masses, providing an optimal guide for focal needle biopsy and accurately identifies spinal cord and/or nerve root compression.
CT is useful when evaluating the stability of collapsed vertebrae, estimating the risk of fractures, in particular in the spine and pelvis and planning radiotherapy or surgical fields.
CT is, however, unable to evaluate osteoporosis or assess response to therapy.
Caution also needed in the use of iv iodine-containing contrast agents in patients with renal impairment.
Major disadvantage of CT over skeletal survey is the higher radiation exposure (up to three times higher).
Consequently, whole body multi-detector low dose CT (WBMDLDCT) has been explored and should be considered in patients with bone pain and lack of evidence of osteolysis on the skeletal survey and/or in patients in whom MRI is contra-indicated.

9. Whole body computerised tomography (WBCT)
‘Whole body, low dose MDCT has substituted conventional radiography in some centres (IMWG 2009) – higher sensitivity for the detection of osseous lesions and its ability to diagnose extra osseous lesions.’ Thirty nine patients were evaluated. WBLDCT identified more osteolytic lesions than skeletal survey with a greater degree of diagnostic confidence and led to restaging in 18 instances (16 upstaged, 2 down staged) Gleeson et al 2009
Finding on WBLDCT not identified on SS. a. Conventional lateral radiograph of the thoracic spine – no focal lytic lesion identifiable. b. WBLDCT sagittal view of the spine showing a focal lytic lesion eroding through the cortex of the anterior wall of the spinal canal at T10 c. WBLDCT axial image showing extension into the canal at high risk of cord compression. The patient was referred for emergency radiotherapy.
(Gleeson, T.G. et al 2009 ‘Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions and correlation of disease with whole body MRI (WBMRI)’

10. ‘morphological’ vs ‘functional’ imaging techniques
Both WBXR and CT are referred to as ‘morphological’ imaging techniques, because they assess the damage to mineralised bone induced by the tumour clone, but not the activity or viability of tumour cells.
By contrast, MRI and PET/CT are ‘functional’ imaging methods, because they evaluate the micro- circulation within the bone marrow and the diffusion of interstitial water molecules or glucose uptake, which are surrogate markers for tumour activity.

11. MRI is the gold standard technique for assessment of the spine
Accurately shows the presence of any spinal cord lesion and/or nerve root compression and enables the recognition of soft tissue masses
MRI can predict the risk of vertebral fracture even though it does not help in predicting the level of fracture. It has been reported that the risk of vertebral collapse is 6 to 10 fold higher in patients with >10 focal lesions on MRI (Lecouvet et al 1997)
Good tool for distinguishing between benign and malignant induced vertebral fractures ie benign and malignant osteoporosis.
MRI can accurately evaluate the percentage of vertebral height loss before percutaneous vertebroplasty or kyphoplasty.
MRI detects amyloid deposition
Can identify avascular necrosis of the femoral head.
- Spinal cord compression up to 5% of all pts with myeloma at some stage (Kyle et al 2003)

12. MRI in the assessment of patients with presumed asymptomatic myeloma
About 15-20% of myeloma patients are defined as having asymptomatic or smouldering myeloma, based on the lack of organ damage related to the tumour clone (IMWG 2003).
In these patients, bone disease has traditionally been evaluated by means of WBXR and the presence of at least one lytic lesion was associated with a shorter time to progression.
The recent introduction of more sensitive imaging and laboratory techniques, such as MRI, serum free light chains and multiparametric flow cytometry, has helped to identify different sub-groups of patients who have different risk of progression.
Moulopoulos et al (1995) reported that patients with conventionally defined asymptomatic myeloma and abnormal MRI findings progressed to symptomatic disease more quickly than those with normal MRI.
In a recent report on 149 patients with smouldering myeloma, the presence of focal lesions on whole body MRI was the strongest adverse prognostic adverse prognostic factor for subsequent progression to symptomatic myeloma (Hillengrass et al, 2010).
There is, therefore, a case for whole body MRI (or PET/CT) in patients with presumed asymptomatic myeloma, as it may help assess the risk of progression and lead to a better definition of symptomatic disease.

13. MRI has been proposed as a staging modality for symptomatic myeloma
MRI should also be considered for the staging of symptomatic myeloma due to its higher sensitivity in detecting lytic bone lesions than skeletal survey.
Several studies clearly show the superiority of MRI over conventional radiography in detecting lytic lesions (Tertti et al, 1995; Lecouvet et al, 1999; Zamagni et al, 2007)
Both MRI and PET/CT have been successfully incorporated into the Durie-Salmon plus staging system, to identify bone involvement by the presence of focal lesions and a diffuse bone marrow pattern.
Brian G.M. Durie 2006 ejca ‘’The role of anatomic and functional staging in myeloma: Description of Durie/Salmon plus staging system.’

14. Different patterns of bone marrow infiltration seen on MRI
By using MRI in myeloma, it is possible to distinguish five different patterns of marrow involvement
Normal, typical of MGUS and detectable at diagnosis in 50-75% of patients with smouldering/Durie-Salmon stage 1 myeloma
Focal (30% of patients)
Diffuse, seen in nearly 80% of patients with advanced disease or high tumour burden
Variegated or ‘salt and pepper’, which reflects non-homogenous composition of bone marrow with fatty islands
low-grade interstitial infiltration by plasma cells (usually <20%), found in 3-5% of patients typically with early stage disease
Delorme, S. and Baur-Melnyk, A. European Journal of Radiology, 2009 ‘Imaging in Multiple Myeloma’

15. Different patterns of bone marrow infiltration seen on MRI
Variegated or ‘salt and pepper’
Focal
Diffusely integrated
Hanrahan, C.J. et al Radiographics 2010 ‘Current Concepts in the Evaluation of Multiple Myeloma with MR Imaging and FDG PET/CT’

16. Different patterns of marrow involvement seen on MRI as an outcome predictor and in the evaluation of treatment response in symptomatic myeloma
Both focal and diffuse patterns were associated with a higher tumour burden and reduced overall survival in symptomatic myeloma (Stabler et al, 1996; Lecouvet et al, 1998; Moulopoulos et al, 2005).
In patients with advanced disease receiving conventional chemotherapy, a normal MRI pattern significantly correlated with a higher rate of response and prolonged OS, in comparison with focal or diffuse abnormalities (Lecouvet et al, 1998).
In 142 patients with newly diagnosed symptomatic myeloma receiving chemotherapy or ASCT, the presence of a diffuse MRI pattern, despite not influencing the rate of response, predicted for shorter OS as compared to focal, variegated or normal patterns, regardless of exposure (or not) to high dose therapy (Moulopoulos et al, 2005).
In a large series of patients treated up-front with chemotherapy, thalidomide and double ASCT, the number of FLs on MRI of the spine (cut-off number: 7) had independent prognostic value (Walker et al, 2007). MRI-FLs correlated with several known prognostic factors, such as albumin, C-reactive protein (CRP) and lactate dehydrogenase (LDH), but not with beta-2 microglobulin (beta-2m) and the presence of cytogenetic abnormalities (CA). MRI-FLs and CA were combined into a single model, predicting for OS.
The prognostic impact of different patterns of marrow involvement on MRI, as evaluated at different phases of the disease has been evaluated in several studies.

17. Changes in MRI patterns may correlate with response to therapy and may be used to assess the effects of anti-myeloma treatment
It has been reported that patients achieving CR after treatment usually present complete resolution of the preceding bone marrow abnormality, while patients with partial response more frequently convert from a diffuse to a focal or variegated pattern (Moulopoulos et al,1994).
Lecouvet et al (2001) developed an index for the assessment of spine MRI changes after ASCT, which combines the number and size of lesions, the contrast enhancement and the marrow background; a significant correlation between the index and treatment response was evident.
In another study, resolution of FLs (MRI-CR) conferred superior OS, with particular benefit to patients with more than seven FLs at baseline (Walker et al, 2007). Of note, the time to conventionally defined CR was similar among patients with different numbers of FLs, while the time to MRI-CR was shorter for patients with <7 FLs.
A retrospective study of 100 patients who received up-front single or double ASCT and were studied with WB-MRI before and after treatment, showed that post-ASCT number of FLs predicted for OS (P = 0001) (Hillengass et al, 2012).
However, FLs may remain hyper-intense in both responder and non-responder patients for several months after therapy, due to treatment induced necrosis and inflammation (Hartman et al, 2004).
Moreover, a ‘false’ diffuse bone marrow pattern may appear, due to the use of growth factors.
For these reasons, a routine gap of 1–3 months after the end of treatment is suggested before MRI monitoring.

18. Sagittal views of short-tau inversion recovery-weighted MRI series demonstrating baseline diffuse and focal disease, treatment response and relapse. (A) At time of diagnosis, diffuse tumour infiltration and focal lesions are seen (arrows). (B) Complete response is seen 240 days later, with normal MRI appearances. © Relapse is seed 610 days later, with slight increase in diffuse, heterogenous marrow signal, recurrent focal lesion at L4 (bottom arrow), and new lesion at L2 (top arrow).
Walker et al 2012 The journal of Nuclear medicine ‘Imaging of Multiple Myeloma and Related Plasma Cell Dyscrasias’

19. Whole body MRI
The main limitations of MRI are the prolonged acquisition time (requiring about 45–60 min), high cost, limiting patient factors, such as claustrophobia or metal devices in the body, and, particularly, the limited FOV.
In addition, MRI is not a reliable tool for investigating several bones, such as skull, clavicle or ribs, because of false-negative results (Lutje et al, 2009).
To overcome these disadvantages, WB-MRI was introduced. This technique is based on T1, T1 non-fat-saturated and short T1 inversion recovery (STIR) sequences, usually not requiring contrast infusion; the total scan time for a whole-body image is generally <20 min.
WB-MRI proved more sensitive than WBXR and MDCT for the detection of bone lesions and both focal and diffuse marrow involvement, respectively (Ghanem et al, 2005; Baur-Melnyk et al, 2008; Gleeson et al, 2009; Lutje et al, 2009; Shortt et al, 2009).
Preliminary results seemed to suggest a possible role for WB-MRI with diffusion-weighted images in the assessment of short-term response to treatment (Lin et al, 2010; Horger et al, 2011).

20. Positron emission tomography-computerised tomography (PET/CT)
PET/CT is a nuclear imaging procedure that uses positrons as radiolabels; the combination of functional imaging with PET and morphological assessment with CT makes it possible to detect hypermetabolic lesions, both intramedullary and extramedullary, and their exact anatomic localization.
A low dose of radiopharmaceutical, labelled with a positron emitter, is injected into the patient, who is scanned by a multidetector tomographic system, usually with a low-dose CT component, to minimize radiation exposure, which is anyway of some concern; the scan takes 20–40 min to perform.
The most widely used radiopharmaceutical is FDG, which is taken up, phosphorylated and then stored by metabolically active cells with high glucose demand, thus allowing tumour cells to be distinguished from normal cells.

21. Solitary plasmacytoma
Diagnosis of solitary plasmacytoma requires the presence of a solitary osteolytic bone lesion or a single extra-medullary soft tissue mass, with histologically proven presence of clonal plasma cells, in the absence of bone marrow plasma cell infiltration.
MRI and PET/CT are useful tools to establish a correct diagnosis of solitary plasmacytoma in patients with the confirmed presence of a single lesion/mass as well as in the subsequent follow-up of such patients.
Bartel, T.B. et al, Blood 2009 ‘F18-FDG positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma.’

22. FDG PET/CT reveals extra-osseous disease
Left – axial unenhanced CT image shows faint hypodense lesions in the liver; right – axial PET image shows multiple foci of intense FDG uptake within the liver.
Hall et al, 2010, American Journal of Roentgenology ‘Imaging of Extraosseous Myeloma: CT, PET-CT and MRI Features’

23. FDG PET/CT in the staging of plasma cell dyscrasias
There is limited experience regarding MGUS and smouldering MM, which usually appear negative for both diffuse FDG marrow uptake and FLs; one small study showed that negative FDG-PET reliably predicts stable MGUS with only one out of 14 patients developing MM after 8 months (Durie et al, 2002).
In future it could be interesting to plan prospective trials to see if FDG-PET/CT plays a role in the identification of patients with smouldering MM and higher risk of progression to symptomatic MM.
Due to its ability to identify extra-medullary sites of active disease, PET/CT is increasingly being used in patients with a suspected diagnosis of SP. In several studies, FDG-PET/CT allowed detection of occult sites of bone disease and/or soft tissue masses, not previously assessed by WBXR and MRI of the spine, in 30–50% of patients with a suspected SP, a finding that changed the ultimate diagnosis and significantly affected therapeutic decisions (Schirrmeister et al, 2003; Nanni et al, 2008; Salaun et al, 2008).

24. 18-F FDG PET/CT has prognostic value in newly diagnosed patients with myeloma
Presence at baseline of at least 3 focal lesions (FLs; 44% of cases), a standardised uptake value (SUV) >4.2, and extramedullary disease (EMD; 6%) adversely affected 4-year estimates of progression free survival (PFS; at least 3 FLs:50%, SUV>4.2:43%; presence of EMD: 28%)
SUV>4.2 and EMD were also correlated with shorter overall survival (OS; 4-year rates: 77% and 66% respectively).
Persistance of SUV >4.2 after TD induction was an early predictor for shorter PFS. Three months after ASCT, PET/CT was negative in 65% of patients whose 4-year rates of PFS and OS were superior to those of PET-positive patients (PFS: 66% and OS:89%).
In a multivariate analysis, both EMD and SUV>4.2 at baseline and persistance of FDG uptake after ASCT were independent variables adversely affecting PFS.
PET/CT involvement at diagnosis and after novel agent-based induction and subsequent ASCT is a reliable predictor of prognosis in myeloma patients.
Hence, the serial use of PET-CT after induction treatment and subsequent ASCT could contribute to the design of individualised patient therapies, justifying changes to alternative treatments in those individuals with persistent PET positivity before and after transplantation.
Although attainment of CR according to conventionally
defined criteria and durable sustainment of CR5 remain important
prognostic factors and primary endpoints of ongoing clinical trials,
more sensitive techniques than negative immunofixation are needed
to better evaluate the increasing depth of response afforded by
novel agent-based therapies. In this context, elimination of minimal
residual disease (MRD), as detected at the BM level by multiparametric
flow cytometry or PCR, has been shown to more carefully
prognosticate for improved clinical outcomes in comparison with
standard CR.6 In addition, imaging techniques, such as magnetic
resonance imaging (MRI) to detect the absence of focal lesions
(FLs) potentially harboring viable monoclonal plasma cells7 have
been proposed as an additional tool to increase the definition level
of CR and its impact on prognosis.
Positron emission tomography (PET) integrated with computed
tomography (PET/CT) using the positron-emitting radionuclide
18F labeled with fluorodeoxyglucose (18F-FDG) is a careful
technique to detect, with high sensitivity and specificity, the
presence of myeloma bone lesions and/or BM involvement at the
onset of the disease.8-10 Moreover, FDG-PET has the advantage of
demonstrating the presence of active or inactive disease and has
thus been explored as a means to monitor response and to predict
the outcome in various tumors, most extensively in lymphoma.
Zamagni et al, 2011, Blood ‘prognostic relevance of 18-FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation’

25. Presence of more than 3 PET focal lesions after day 7 first cycle of induction chemotherapy can predict for inferior overall survival and progression free survival (Total therapy 3 cohort)
According to multivariate analysis, more than 3 focal lesions detected by 18-FDG PET-CT on day 7 imparted inferior overall survival and progression free survival, overall and in the subset with gene expression profiling (GEP) data.
GEP high risk designation retained independent significance for all 3 end points examined.
Thus the presence of >3 focal lesions as detected by 18-FDG PET-CT on day 7 follow-up may be exploited toward early therapy change, especially for the 15% of patients with GEP-defined high-risk disease with a median survival expectation of 2 years.
Usmani et al, 2013, Blood ‘Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3.’

26. FDG PET/CT is an excellent imaging tool to monitor response to treatment owing to its ability to distinguish between active disease and fibrotic lesions
Normalization of PET/CT correlated well with the achievement of high-quality responses to therapy (Zamagni et al, 2007; Bartel et al, 2009)
In one study, PET/CT was evaluated before the first ASCT and complete FDG suppression in FLs conferred significantly better PFS and OS. PET-negativity preceded the achievement of conventionally defined CR, while a normal MRI pattern was reached later on (Bartel et al, 2009).
In another study, permanence of high tumour metabolism after induction treatment was an early predictor of worse PFS after ASCT, while postautotransplantation PET/CT-negativity was a favourable independent prognostic factor for durable disease control and prolonged OS.
For such reasons PET/CT has been explored as a means of monitoring response and predicting outcome (Cerci et al, 2010; Terasawa et al, 2010).

27. Fig. 4 Whole-body 18F-FDG PET/CT in the assessment of the
response to therapy. A 64-year-old male patient who received eight
cycles of a bortezomib/melphalan/prednisone regimen following a
diagnosis of lambda light chain micromolecular MM. a–d Images
before the start of therapy: a whole-body sagittal PET; b axial PET
image of the pelvis; c axial CT image of the pelvis; d axial fused PET/
CT image of the pelvis. Multiple lesions are seen in several skeletal
areas, especially along the rachis and in the pelvis. e–h PET/CT
images following therapy: e whole-body sagittal PET; f axial PET
image of the pelvis; g axial CT image of the pelvis; h axial fused
PET/CT image of the pelvis. A diffuse increase in glucose metabolic
uptake is visible in the dorso-lumbar district of the spine, but the
extensive lesions revealed prior to therapy appear remarkably reduced
in size, indicating a considerable response to therapy
18F-FDG PET/CT used to track response to treatment in a 64 year old man pre- and post treatment with 8xVMP
(Dammacco, F. et al, 2014 Clin Exp Med ‘18F-FDG PET/CT: a review of diagnostic and prognostic features in multiple myeloma and related disorders’)

28. IMWG updated criteria for the diagnosis of multiple myeloma - Rajkumar, S.V. et al, The Lancet, A paradigm shift with significant implications for the assessment of smouldering myeloma
Progression of smouldering myeloma – when to treat?
Changes proposed by IMWG ‘are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering myeloma’
A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients resulting in substantial, yet preventable end organ damage eg significant skeletal damage and renal failure.
Smouldering myeloma is a biologically heterogeneous, clinically defined entity consisting of
a subset of patients with biological premalignancy (ie MGUS) and low risk of progression and
a subset with CRAB negative malignancy (ie multiple myeloma) and a high risk of progression
One of the major difficulties in multiple myeloma is that, unlike other malignancies, the disease definition is clinicopathological; it needs overt clinical manifestations of serious endorgan 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 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 benefit from early intervention. However, this definition 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.

29. IMWG updated criteria for the diagnosis of multiple myeloma - Rajkumar, S.V. et al, The Lancet, A paradigm shift?
No single pathological or molecular feature can be used to distinguish patients with smouldering myeloma who have only clonal premalignant plasma cells from those with clonal malignant plasma cells.
IMWG propose a number of ‘Myeloma defining biomarkers’ that accurately predict an 80% progression rate to overt CRAB positive myeloma within two years, and, when present these should confirm the diagnosis of multiple myeloma that requires treatment.
Myeloma defining biomarkers
Bone marrow plasmacytosis of 60% or greater
Serum free light chain ratio of 100 or greater
MRI with more than one focal bone lesion

30. MRI with more than one focal lesion is proposed as a myeloma defining biomarker warranting commencement of chemotherapy
MRI (whole body or spine and pelvis) is beneficial in evaluating patients with smouldering myeloma and is recommended as part of initial assessment.
Abnormal MRI imaging features in smouldering myeloma include both focal (involving bone or bone marrow), and diffuse bone marrow abnormalities.
These abnormalities have been associated with increased risk of progression in smouldering myeloma but only recently have investigators determined the level of abnormality that is associated with a high risk of progression within 2 years.
Specifically, the presence of more than one focal lesion was associated with a substantial risk of progression (>70% within 2 years).
If lesions are small <5mm, or equivocal, additional imaging with CT or PET/CT should be considered.
Diffuse marrow infiltration is associated with an increased risk of progression, but is not recommended as adequate to justify treatment.
Therefore, in patients with diffuse infiltration, solitary focal lesion, or in the presence of equivocal findings, follow-up examinations in 3-6 months are strongly recommended.

31. 2014 IMWG revised definition of myeloma bone disease
Traditionally, bone disease has been identified 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.
Now, in 2014, the IMWG recommend the use of these techniques during the assessment of patients with smouldering myeloma and solitary plasmacytoma.
Also, IMWG now (2014) recommend that one of PET/CT, LDWBCT, 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.

32. 2014 IMWG revised definition of myeloma bone disease - caveats
Increased uptake on PET/CT alone is not adequate for the diagnosis of multiple myeloma; evidence of underlying bone destruction is needed on the CT portion of the examination.
Care should be taken to avoid over-interpretation of equivocal or tiny lucencies seen only on CT or PET/CT; as with skeletal surveys, if there are doubts about the nature of these lesions, a repeat study in 3-6 months should be performed.
Furthermore, if the diagnosis is in doubt, biopsy should be considered.
Interestingly, IMWG no longer recommend the presence of osteoporosis plus or minus the presence of vertebral compression fractures alone, in the absence of lytic lesions as being sufficient evidence of bone disease thus avoiding overdiagnosis in older patients.
When only one osteolytic bone lesion is seen in the presence of 10% or more clonal plasma cells, no clear indication is present for systemic therapy if no other criteria are met for active myeloma, and further thought is needed. This circumstance is rare, and we recommend that patients could be given radiation therapy and observed.

33. Tailoring treatment
Newer imaging modalities can identify patients, who would have previously been considered as having smouldering myeloma, as patients with a high risk of progression and vital end organ damage, who would clearly benefit from commencement of chemotherapy.
Given that recent incorporation of novel agents into newer treatment strategies for MM has enabled unprecedented rates of CR to be achieved, interest has progressively grown in the evaluation of the depth of response beyond the conventionally defined CR level.
For this purpose, PET/CT scanning and/or WB-MRI could become complementary investigation tools aimed at detecting minimal residual disease after treatment, due to their ability to identify the persistence of focal lesions, potentially harbouring non-secretory MM cells, or sites of active disease outside the medullary cavity of the bone.
These findings might ultimately lead to tailoring different treatment strategies based on the absence or presence of sites of active residual disease.
Zamagni et al, 2012, British Journal of Haematology ‘’The role of imaging techniques in the management of multiple myeloma.”

34. Overall conclusions
Increasing evidence to justify the use of more sophisticated imaging techniques including CT, WBCT, MRI and PET/CT.
Skeletal survey is likely to remain a reasonable screening procedure.
But it is for equivocal cases where the newer techniques have proved their worth, are rapidly becoming validated with strong evidence and should now enter into routine clinical practice.
Choice of modality depends in part on the nature of the problem and in part on local availability.
‘Treating physicians must keep foremost in mind that myeloma bone disease is often the cause of the most disabling problems that patients face and, therefore, careful baseline and serial radiographic assessments are essential to maintaining and improving quality of life.’
Dimopoulos MA et al Leukemia 2009 ‘IMWG consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma’

35. Acknowledgements
Dr Nichola Mullholland, Consultant Radiologist, King’s College London
Dr Sally Barrington, Consultant Radiologist, PET Imaging Centre, King’s College London, St Thomas’ Hospital, London
Professor Vicky Goh, Consultant Radiologist, Department of Cancer Imaging, King’s College London
Dr Majid Kazmi, Consultant Haematologist, Guy’s and St Thomas’ NHS Foundation Trust
Dr Matthew Streetly, Consultant Haematologist, Guy’s and St Thomas’ NHS Foundation Trust
Dr Guy Pratt, Senior Lecturer in Haematology, University of Birmingham and Honorary Consultant Haematologist, Birmingham Heartlands Hospital

36. Bibliography Bird et al UK MM Guidelines
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Walker et al 2012 The journal of Nuclear medicine ‘Imaging of Multiple Myeloma and Related Plasma Cell Dyscrasias’
Gleeson, T.G. et al 2009 ‘Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions and correlation of disease with whole body MRI (WBMRI)
Dammacco, F. et al, 2014 Clin Exp Med ‘18F-FDG PET/CT: a review of diagnostic and prognostic features in multiple myeloma and related disorders’
Brian G.M. Durie 2006 ejca ‘’The role of anatomic and functional staging in myeloma: Description of Durie/Salmon plus staging system.’
Hall et al, 2010, American Journal of Roentgenology ‘Imaging of Extraosseous Myeloma: CT, PET-CT and MRI Features’
Bartel, T.B. et al, Blood 2009 ‘F18-FDG positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma.’
Zamagni et al, 2011, Blood ‘Prognostic relevance of 18-FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation.’
Usmani et al, 2013, Blood ‘Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3.’
Thorsten Derlin, Peter Bannas, World Journal of Orthopaedices 2014 July 18; 5(3);
D’Sa et al 2007 Br J of Haematol ‘Guidelines for the use of imaging in the management of multiple myeloma.’
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Mesguich C, et al. State of the art imaging of multiple myeloma: Comparative review of FDG PET/CT imaging in various clinical settings. Eur J Radiol (2014)

37. Current BCSH Myeloma Guidelines concerning Imaging
• The skeletal survey remains the screening technique of choice at diagnosis. (Grade B1)
• The skeletal survey should include a postero-anterior (PA) view of the chest, antero-posterior (AP) and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view of the pelvis; other symptomatic areas should be specifically visualized with appropriate views (Grade B1)
• Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) should be used to clarify the significance of ambiguous plain radiographic findings, such as equivocal lytic lesions, especially in parts of the skeleton that are difficult to visualize on plain radiographs, such as ribs, sternum and scapulae (Grade A1)
• Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in myeloma patients with or without vertebral collapse. Urgent CT scanning is an alternative, when MRI is unavailable, intolerable or contraindicated.
• CT or MRI is indicated to delineate the nature and extent of soft tissue masses and where appropriate, tissue biopsy may be guided by CT scanning (Grade A1)
• There is insufficient evidence to recommend the routine use of positron-emission tomography (PET) or 99mTechnetium sestamibi (MIBI) imaging. Either technique may be useful in selected cases for clarification of previous imaging findings preferably within the context of a clinical trial (Grade C2)
• Bone scintigraphy has no place in the routine staging of myeloma (Grade A1)
• Routine assessment of bone mineral density cannot be recommended, owing to the methodological difficulties of the technique and the universal use of bisphosphonates in all symptomatic myeloma patients (Grade A1).

38. IMWG Consensus guidelines on Imaging in MM 2009
As part of the staging procedure of newly diagnosed myeloma, the skeletal survey is mandatory
In addition, symptomatic areas should be specifically visualised
Whole body, low dose MDCT has substituted conventional radiography in some centres
Whole body MRI can give complimentary information to the skeletal survey and is recommended in pts with normal conventional radiography
MRI of the whole spine should be performed in addition to the skeletal survey as part of staging in all patients with an apparently solitary plasmacytoma of bone irrespective of site of index lesion
Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression even in the absence of vertebral collapse
Urgent CT may be used to establish the presence of suspected cord compression in cases where MRI is unavailable or contra-indicated, for example, by intraorbital metallic foreign bodies or cardiac pacemakers.
CT of the spine or other areas of the skeleton may be considered to clarify the presence or absence of bone destruction in areas of clinical concern.
CT is indicated to clarify the nature and extent of soft tissue disease and, where appropriate, to guide tissue biopsy.
MRI should be used to clarify the significance of ambiguous CT findings, as these two imaging techniques can give complimentary information, whereas both can be used for assessment before vertebroplasty or kyphoplasty.
Bone scintigraphy has no place in the routine staging of myeloma.
Sequential DEXA scans are not recommended.
Based on the currently available evidence, neither PET nor MIBI imaging can be recommended for routine use in the management of myeloma, although both techniques may be useful in selected cases that warrant clarification of previous imaging findings, but ideally within the context of a clinical trial.
In the event of disease progression, the skeletal survey should be repeated as part of the re-staging process; any newly symptomatic areas should be specifically targeted; MRI should be performed in all pts with negative skeletal survey.
MRI or CT can be used for monitoring the response of soft tissue masses to therapy.
The usefulness of PET/CT and MIBI on the follow-up of myeloma has not been confirmed and further trials are needed.
Treating physicians must keep foremost in mind that myeloma bone disease is often the cause of the most disabling problems that pts face and, therefore, careful baseline and serial radiographic assessments are essential to maintaining and improving their pts quality of life.
Dimopoulos MA et al Leukemia 2009 ‘IMWG consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma’