Updates in Clinical Practice: New Bone Assessment Criteria
Evangelos Terpos, MD, PhD
Associate Professor of Hematology, Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece
Clinical experience with advanced imaging techniques in the management of multiple myeloma (MM) has sufficiently progressed to the point that they are now recommended for expanded use outside of the clinical trial setting for the diagnosis of MM requiring treatment, as well as to assess response to treatment where imaging has the potential to provide valuable prognostic information. However, not all advanced imaging strategies provide equivalent value under all circumstances, but rather have demonstrable intrinsic and extrinsic value, as well as limitations, depending upon the specific circumstances in which they are being used. This discussion focuses on the various expanded uses of imaging strategies in community MM practice today, while noting the strengths and limitations of each.
Updated and Novel Criteria for the Definition of Multiple Myeloma Requiring Treatment
The 2014 updated criteria for the diagnosis of multiple myeloma (MM) which requires treatment, formerly referred to as symptomatic MM, but now more appropriately referred to as just MM or overt MM,  represents one of the most significant changes to how this malignancy is diagnosed since the International Myeloma Working Group (IMWG) first introduced a consensus definition of this malignancy in 2003.  For many years, patients who may not yet have progressed sufficiently through the lifecycle of the disease so as to exhibit measurable MM-defining CRAB (hypercalcemia, renal impairment, anemia, and bone disease) events have traditionally been considered smoldering myeloma patients. The changes made in the IMWG 2014 update are a result of many years of dedicated research by the IMWG clinical community to determine criteria that will reliably identify patients who would have been considered smoldering myeloma patients by this definition but who will, due to discreet, measurable, clinically validated ultra-high risk features, nevertheless inevitably progress to having one or more CRAB events, if left untreated within a short time. In other words, the goal has been to identify patients who may benefit from early treatment intervention, while their prognosis is still at its most favorable, rather than limiting intervention to expectant management until progressive disease results in measurable end organ damage – when MM becomes more difficult to treat and manage, and when survival outcomes become adversely affected. The changes to myeloma‑defining events (MDEs) are two-fold and include clarifications to the CRAB criteria as well as the expansion of MDEs to include three new criteria called “biomarkers of malignancy,” which can be also be remembered by the acronym SLiM [Figure 1]. The modifications to the myeloma-defining CRAB features include:
- The addition of creatinine clearance (<40 mL/min) into the definition of renal impairment; and
- The presence of lytic lesions detected not only by conventional radiography but also by computed tomography (CT), whole-body low-dose CT (WBLDCT) or positron-emission tomography/CT (PET-CT)
The three newly introduced myeloma-defining biomarkers of malignancy or SLiM events are:
- The presence of ≥60% clonal plasma cells in bone marrow
- An involved to uninvolved serum free light chain ratio of ≥100; and
- The presence of >1 focal lesions on magnetic resonance imaging (MRI) studies which are ≥5 mm each 
The presence of any one or more myeloma‑defining CRAB-SLIM events serve to identify MM requiring treatment, as long as other differential diagnostic conditions for MGUS/smoldering myeloma are met [Figure 1]. Based on the updates as shown above, it is highly evident that there are now expanded myeloma-defining bone assessment criteria, and thus the role of imaging has become even more crucial to the task of identifying patients whose disease should be treated, rather than left to be observed.
Whole-body Low-dose CT [WBLDCT] for the Diagnosis of Symptomatic Myeloma
Myeloma-related bone disease is the main complication of this malignancy and the presence of osteolytic lesions defines MM which requires treatment. What is the best method for the diagnosis of lytic bone disease in a MM patient? It has been suggested by the European Myeloma Network that WBLDCT substitute for conventional radiography as the standard technique for the evaluation of bone disease in MM.  Several studies have demonstrated the superiority of WBLDCT over conventional radiography in the depiction of osteolysis in MM, where 20-60% of patients with normal skeletal radiography by standard X-rays have detectable osteolytic lesions by WBLDCT. [3-6] This is due to the main limitation of plain X-ray, which is the depiction of lytic disease only when over 20-30% of the trabecular bone has been lost; thus, approximately 30% of MM patients at diagnosis have normal skeletal survey. Other limitations of the conventional radiography include:
- Lack of accurate visualization and thus depiction of lytic lesions in some areas, including the spine and the pelvis
- Reduced sensitivity and specificity for the differential diagnosis of malignant versus benign causes of osteopenia or osteoporotic fractures (mainly new fractures; problems in defining disease progression in the absence of any other criteria of progression)
- Difficulty in assessing response to therapy due to reduced ability to identify evidence of healing of osteolytic lesions
- Observer dependency
- Lengthy period of the test, which is poorly tolerated by patients with severe pain due to extended lytic disease 
In contrast, WBLDCT allows the accurate visualization of bone lytic lesions of the whole skeleton, in a short period of time for the examination (less than 2-3 minutes in the machine), in the absence of any contrast agent and using low radiation dose (2- to 3-fold lower administered radiation dose compared to conventional CT).  Figure 2 shows WBLDCT and conventional radiography of a myeloma patient.
Figure 2. A patient with multiple myeloma and subtle lucencies in the bony pelvis on whole body X-ray (WBXR) that may be easily missed or mistaken for bowel loops (A). WBLDCT images (B–D) show multiple bony lytic lesions in the pelvis indicated by white arrows. 
PET/CT for the Diagnosis of Overt Multiple Myeloma
Fluorodeoxyglucose-PET/CT (18F-FDG-PET/CT) is a functional imaging method in which the uptake of 18F-FDG by cells reflects the tissue uptake of glucose, and thus specific types of tissue metabolism can be revealed. After the intravenous administration of 18F-FDG into a cancer patient, the PET scanner can create two- or three-dimensional images showing the distribution of 18F-FDG into the different body organs and tissues, revealing areas where cancer has invaded.  In MM, the combination of PET with CT shows the hypermetabolic activity of intramedullary and extramedullary myeloma sites (PET part of the method) along with the depiction of bone lytic lesions (CT part of the technique). Several studies and a large meta-analysis have supported the higher sensitivity of PET/CT over conventional radiography for the detection of osteolyses in MM. [10-14] In one of the largest studies in the field, 16% of 120 patients with normal conventional radiography of the skeleton had positive PET/CT results.  In such patients, the median time to progression (TTP) is expected to be approximately one year versus 4.5 years for patients who have negative PET/CT, and the probability of 2-year progression-free survival is 42%.  In a study from the Mayo Clinic involving 188 patients with suspected asymptomatic MM, the PET/CT was positive in almost 40% of patients. More importantly, the probability of progression was more than 85% at two years for patients who had a positive PET/CT, compared to 30% for patients who had a negative PET/CT, and the median TTP was 21 and 60 months, respectively. 
Although PET/CT is more accurate compared to conventional radiography in depicting osteolytic lesions, its major limitations include its high cost, the lack of availability in many centers and countries, and the false positive results due to inflammation of other underlying pathology. Furthermore, the standardization of the method seems to be rather problematic, and almost every center uses different limits for defining positivity of PET. Very recently, there was an attempt to improve reporting of PET/CT by an Italian committee of experts both in PET and in MM. In Table 1 the suggested reporting is fully described, along with a representational FDG-PET/CT imaging in a patient with MM in Figure 3. 
Table 1. Summary of the Novel IMPeTUs Criteria for the PET/CT Standardization for MM
*“A” if hypermetabolism in limbs and ribs
**For nodal disease: cervical; supraclavicular; mediastinal; axillary; retroperitoneal; mesenteric; inguinal
*** For extranodal disease: liver; muscle; spleen; skin; other
Deauville five-point scale:
1 No uptake at all
2 ≤ mediastinal blood pool uptake (SUVmax)
3 > mediastinal blood pool uptake, ≤ liver uptake
4 > liver uptake +10 %
5 >> liver uptake (twice) 
Figure 3. FDG-PET/CT imaging in a patient with MM. a) The whole body image; b-c) Transaxial fused images (red arrows extramedullary lesion (liver), filled and unfilled arrows extraspinal bone lesions). In this patient the descriptive criteria (IMPeTUs) are: BM3, F2 ExtraSp (5), L, EM EN (5), where BM3 indicates bone marrow uptake is < liver but > mediastinum, F2 indicates one to three lesions, ExtraSp indicates outside the spine with (5) indicating reference lesion uptake >> liver, L indicates at least one lesion is also lytic, EM indicates at least one extramedullary lesion, EN indicates the extramedullary lesion is extranodal (liver) with (5) indicating extramedullary lesion uptake >> liver. 
MRI for the Diagnosis of Overt Myeloma
Every myeloma patient who does not exhibit a measurable CRAB event should have a whole-body MRI evaluation (or spine and pelvic MRI, if WB-MRI is not available). According to novel criteria, if they have at least two focal lesions of a diameter of more than 5 mm, they should be considered as having overt disease that requires therapy. [1,18] This recommendation is based on two studies that showed that, for myeloma patients with more than one focal lesion on MRI evaluation and no other criteria defining symptomatic disease, the median TTP to symptomatic myeloma is between 13 -15 months and the 2-year probability of progression is approximately 70%. [19,20] Furthermore, MRI depicts bone involvement in MM more often compared to conventional radiography [Figure 4]. [18,21] In this context, it is crucial to mention that MRI depicts the bone marrow infiltration pattern by malignant plasma cells and does not reveal osteolytic lesions that are depicted only by conventional X-rays or CT technology. Thus, MRI can reveal focal, diffuse, variegated, and normal patterns of marrow infiltration.  In cases of equivocal small focal lesions (below 5 mm) in a patient with otherwise asymptomatic disease, a second MRI should be performed after 3-6 months, and if there is progression in MRI at that time, then the patient should be treated as a symptomatic myeloma patient. 
|Figure 4. Comparison of MRI and conventional X‑ray examinations over time in a representative myeloma patient:
(A) Focal lesions recurring at previously involved sites and developing at new sites;
(B) Skeletal survey over a comparable time frame demonstrates lateral lumbar spine images that appear normal throughout the disease course.
BL=baseline; da=days. 
What is the Best Imaging Technique for the Diagnosis of Bone Involvement in Myeloma?
According to the previously described novel criteria for symptomatic myeloma, if a patient has negative WBLDCT or PET/CT, he/she needs an MRI evaluation for the depiction of possible focal lesions. But, do we have any evidence that MRI is superior over WBLDCT or PET/CT? In two small studies, with 41 and 46 newly-diagnosed MM patients, respectively, WB-MRI was able to detect a higher number of patients with bone marrow involvement compared to WBLDCT or PET/CT. The superiority of MRI over PET/CT was mainly due to the higher sensitivity of MRI for the detection of diffuse disease. [12,22] However, in the largest comparison to-date, in 303 myeloma patients, there was no superiority of MRI over PET/CT for the detection of focal lesions; however, a diffuse MRI pattern of bone marrow involvement was not included in this comparison.  Finally, in a retrospective study of 210 MRI and 210 PET/CT studies in MM patients, MRI achieved better results than PET/CT for the detection of myeloma at diagnosis and at progression; however, PET/CT detected findings of response to anti-myeloma therapy earlier than MRI.  In general, MRI and PET/CT are more sensitive in revealing bone involvement compared to conventional X-rays. It seems that MRI offers similar information with PET/CT regarding focal lesions at diagnosis. However, MRI is superior compared to PET/CT for the detection of diffuse pattern of marrow infiltration. Although diffuse pattern correlates with inferior survival,  more data are needed for the evaluation of this information at the time of myeloma diagnosis.
Bone Imaging Criteria for the Evaluation of Minimal Residual Disease
The role of modern imaging seems to be very important for the follow-up of myeloma patients and an improved definition of response. Both MRI and PET/CT have shown that their results have independent prognostic value for survival at diagnosis in different studies. However, PET/CT seems to be superior compared to MRI regarding the results of follow-up. In 192 newly-diagnosed patients who underwent autologous stem cell transplantation (ASCT), the persistence of FDG uptake post-ASCT has independent adverse prognostic value.  More importantly, in a recent study which has been reported only in abstract form, 134 patients who were eligible for treatment with ASCT were randomized to receive 8 cycles of bortezomib-lenalidomide-dexamethasone (VRD) followed by one-year maintenance with lenalidomide, or 3 cycles of VRD followed by ASCT plus 2 cycles of VRD consolidation and one-year lenalidomide maintenance. PET/CT and WB-MRI were performed after induction and before maintenance. Both techniques were positive at diagnosis in more than 90% of patients. After induction therapy and before maintenance, more patients continued to have positive MRI than PET/CT (93% versus 55%, and 83% versus 21%, respectively), possibly due to earlier reduction of activity of PET/CT lesions. Both after induction and before maintenance, normalization of PET/CT and not of MRI could predict for PFS, while only normalization of PET/CT before maintenance could predict for OS (30-month OS rate: 70% in PET/CT positive patients versus 94.6% in patients with negative PET/CT negative; P=.01). 
Figure 5. Untreated myeloma patient with time-concordant MBS, MRI, and FDG-PET/CT studies. Baseline imaging studies (top row) showed no osteolysis on MBS (top left), several foci on STIR-weighted MRI images with the largest in the left ischium (top middle), and 2 foci on FDG-PET/CT imaging (top right) with the largest again in the left ischium with a maximum SUV of 4.1. The patient was in near-complete remission 168 days later, with a significant decrease in focal activity in the left ischial lesion on PET (bottom right). 
WBLDCT appears to be suitable for the detection of osteolytic bone disease in MM patients at diagnosis, replacing WBXR. WB-MRI (or at least MRI of the spine and pelvis if WB-MRI is not available) should be performed in all smoldering myeloma patients with no lytic lesions, to look for occult disease which may justify treatment. PET/CT seems to be inferior to MRI regarding the detection of marrow involvement in MM, but it is probably the best technique for optimal definition of complete response and follow-up of myeloma patients.
- Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-548.
- International Myeloma Working Group. Criteria for the classiﬁcation of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749–757.
- Horger M, Claussen CD, Bross-Bach U, et al. Whole-body low-dose multidetector row-CT in the diagnosis of multiple myeloma: an alternative to conventional radiography. Eur J Radiol. 2005;54:289-297.
- Kropil P, Fenk R, Fritz LB, et al. Comparison of whole- body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma. Eur Radiol. 2008;18:51-58.
- Gleeson TG, Moriarty J, Shortt CP, et al. Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions, and correlation of disease distribution with whole-body MRI (WBMRI). Skeletal Radiol. 2009;38:225-236.
- Ippolito D, Besostri V, Bonaffini PA, et al. Diagnostic value of whole-body low-dose computed tomography (WBLDCT) in bone lesions detection in patients with multiple myeloma (MM). Eur J Radiol. 2013;82:2322-2327.
- Dimopoulos M, Terpos E, Comenzo RL, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia. 2009;23:1545-1556.
- Pianko MJ, Terpos E, Roodman GD, et al. Whole-body low-dose computed tomography and advanced imaging techniques for multiple myeloma bone disease. Clin Cancer Res. 2014;20:5888-5897.
- Som P, Atkins HL, Bandoypadhyay D, et al. A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection. J Nucl Med. 1980;21:670-675.
- Bredella MA, Steinbach L, Caputo G, et al. Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J Roentgenol. 2005;184:1199-1204.
- Breyer RJ 3rd, Mulligan ME, Smith SE, et al. Comparison of imaging with FDG PET/CT with other imaging modalities in myeloma. Skeletal Radiol. 2006;35:632-640.
- Zamagni E, Nanni C, Patriarca F, et al. A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica. 2007;92:50-55.
- Bartel TB, Haessler J, Brown TL, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068-2076.
- Regelink JC, Minnema MC, Terpos E, et al. Comparison of modern and conventional imaging techniques in establishing multiple myeloma-related bone disease: a systematic review. Br J Haematol. 2013;162:50-61.
- Zamagni E, Nanni C, Gay F, et al. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia. 2016;30:417-422.
- Siontis B, Kumar S, Dispenzieri A, et al. Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy. Blood Cancer J. 2015;5:e364.
- Nanni C, Zamagni E, Versari A, et al. Image interpretation criteria for FDG PET/CT in multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging. 2016;43:414-421.
- Dimopoulos MA, Hillengass J, Usmani S, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol. 2015;33:657-664.
- Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606-1610.
- Kastritis E, Moulopoulos LA, Terpos E, et al. The prognostic importance of the presence of more than one focal lesion in spine MRI of patients with asymptomatic (smoldering) multiple myeloma. Leukemia. 2014;28:2402-2403.
- Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol. 2007;25:1121-1128.
- Baur-Melnyk A, Buhmann S, Becker C, et al. Whole-body MRI versus whole-body MDCT for staging of multiple myeloma. AJR Am J Roentgenol. 2008;190:1097-1104.
- Waheed S, Mitchell A, Usmani S, et al. Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica. 2013;98:71-78.
- Spinnato P, Bazzocchi A, Brioli A, et al. Contrast enhanced MRI and 18-F-FDG PET-CT in the assessment of multiple myeloma: a comparison of results in different phases of the disease. Eur J Radiol. 2012;81:4013-4018.
- Moulopoulos LA, Dimopoulos MA, Christoulas D, et al. Diffuse MRI marrow pattern correlates with increased angiogenesis, advanced disease features and poor prognosis in newly diagnosed myeloma treated with novel agents. Leukemia. 2010;24:1206-1212.
- Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118:5989-5995.
- Moreau P, Attal M, Karlin L, et al. Prospective evaluation of MRI and PET-CT at diagnosis and before maintenance therapy in symptomatic patients with Multiple Myeloma included in the IFM/DFCI 2009 trial. Blood. 2015;126:395 (ASH abstract).