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Bone marrow involvement is a myeloma-defining event, and the extent and pattern of myeloma infiltration impact treatment decisions following updated diagnostic criteria by the International Myeloma Working Group (IMWG).
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Whole-body MR imaging is recognized as the gold standard for the imaging diagnosis of bone marrow involvement in myeloma.
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Whole-body MR imaging is particularly recommended for the workup of patients with smoldering or asymptomatic myeloma or those with solitary plasmacytoma.
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The IMWG classifies MR imaging bone involvement as greater than 1 focal lesion with a diameter greater than 5 mm.
Introduction
Myeloma is the most common primary malignancy affecting the skeleton, with an incidence of approximately 10 per 100,000.
It is a clinically and biologically heterogeneous cancer arising from bone marrow plasma cells that evolves from a premalignant precursor condition (monoclonal gammopathy of undetermined significance) into asymptomatic myeloma and, finally, symptomatic disease.
Uncontrolled myeloma frequently causes significant morbidity, which typically includes immunosuppression, kidney impairment, and lytic bone destruction. The pathogenesis of myeloma bone disease starts with expansion of malignant myeloma cells in the bone marrow where they interact with stromal cells and shift the balance toward an excess of osteoclast-activating factors and suppression of osteoblast activity. Unchecked osteoclastic activity promotes the production of various cytokines from stromal cells, which leads directly or indirectly to further multiple myeloma clone proliferation. A vicious cycle is set in motion, with bone destruction feeding tumor growth and multiple myeloma cells promoting bone destruction.
Modern therapies can disrupt this vicious cycle and limit other disease morbidity, increasingly mandating sensitive and specific diagnostic tools to identify patients who will benefit from treatment.
Definition and role of imaging in myeloma
The International Myeloma Working Group’s (IMWG) updated criteria for the diagnosis of multiple myeloma include
Clonal bone marrow plasma cells greater than 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma-defining events:
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Evidence of end-organ damage
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Hypercalcemia
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Renal insufficiency
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Anemia
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Bone lesions
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Any one or more of the following biomarkers of malignancy:
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Clonal bone marrow plasma cell percentage of 60% or greater
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Involved: uninvolved serum free light chain ratio of 100 or greater
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Greater than 1 focal lesions on MR imaging studies greater than 5 mm
In light of the diagnostic criteria, the major indication for imaging is establishing bone involvement as a myeloma-defining event. However, skeletal complications, such as fractures and spinal cord compression, are highly morbid and imaging is critical for risk assessment, detection, and management guidance. As the therapeutic options for patients with myeloma become more sophisticated, the role of imaging in risk stratification, restaging, and detecting minimal residual disease is also evolving.
Myeloma is primarily a disease of bone marrow that can occur anywhere in the skeleton; therefore, wide skeletal coverage is mandatory. Until very recently, bone destruction was necessary to confirm a diagnosis of bone involvement; thus, cheap and readily available skeletal surveys served as the most commonly used imaging tool. However, plain films offer limited sensitivity; up to 50% of bone demineralization can occur before lesions become evident.
Whole-body computed tomography (CT) techniques have been used as a more sensitive alternative and can lead to therapy change in between 18% and 61% of the patients compared with skeletal surveys (Fig. 1).
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).
Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.
Radiation doses can be minimized using dedicated low-dose CT protocols, but they remain 2 to 4 times greater than those used in plain film skeletal surveys.
Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.
Despite improved sensitivity, CT also remains inherently limited to primarily imaging the secondary effects of myeloma on cortical bone rather than bone marrow itself. Consequently, plain film and skeletal surveys should not be used for restaging at disease relapse, as cortical bone defects can represent old inactive treated sites of disease. The addition of quantitative information on tumor metabolism in the form of 18F fluorodeoxyglucose (FDG) PET/CT provides a highly attractive combination of anatomic and functional information albeit at radiation doses 4 to 5 times higher than those used in low-dose CT alone. The IMWG accepts FDG PET/CT as a possible choice of staging tool, particularly for patients with smoldering myeloma. However, MR imaging has greater sensitivity and specificity than FDG PET/CT, its greatest advantage being in assessment of diffuse marrow infiltration, small disease foci (sensitivity and specificity of 68% and 83% for MR imaging compared with 59% and 75% for FDG PET/CT),
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).
International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma.
demonstrated overall significantly increased detection of focal and diffuse infiltration on DW-MR imaging compared with FDG PET/CT (P<.02), with scores higher at all anatomic locations except the pelvis and long bones, where both techniques were equivalent.
The reported false-negative rate of 15% for FDG PET/CT was confirmed by a subsequent larger prospective study, which reported that 10% of the patients would be misclassified using FDG PET/CT as the only functional imaging modality.
also found that gene expression for hexokinase-2, which is involved in the glycolysis pathway, was significantly lower in false-negative FDG PET/CT cases.
Fig. 1Plain film of the bony pelvis in a patient with suspected myeloma (A) shows no focal lytic lesions. However, low-dose CT (B) clearly demonstrates a lytic lesion in the left iliac bone (arrow).
Fig. 2A b900 DW MR imaging inverse gray-scale maximum-intensity projection (MIP) (A), axial b900 DW MR imaging (B), and ADC map (C) of a patient with a new diagnosis of myeloma show multifocal bone lesions (arrows, A), including a restricted lesion in the posterior left acetabulum (arrows, B, C). The posterior acetabular lesion is not evident on corresponding CT (D) or FDG PET/CT (E) performed on the same day. Following induction chemotherapy, the b900 DW MR imaging inverse gray scale MIP shows reduced burden of disease (F). Although the posterior acetabular lesion is only marginally smaller on b900 DW MR imaging (arrow, G), the increased ADC (arrow, H) indicates a good response.
Fig. 3FDG PET/CT (A) in a patient with a suspected new diagnosis of myeloma was reported as not showing evidence of marrow disease. Conversely, sagittal T1-weighted MR imaging of the spine (B) shows diffuse low signal in vertebral marrow relative to the discs; b900 maximum-intensity projection (C), b900 axial DW MR imaging (D), and corresponding ADC map (E) confirm diffuse abnormal marrow signal. Trephine confirmed 80% plasma cell infiltration of bone marrow.
Whole-body MR imaging is recognized as the gold standard for the diagnosis of bone involvement in myeloma and is particularly recommended for the workup of patients with smoldering or asymptomatic myeloma or those with solitary plasmacytoma.
The National Institute for Health and Care Excellence (NICE). Myeloma: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng35. Accessed March 19, 2018.
In some countries, such as the United Kingdom, whole-body MR imaging is now recommended as first-line imaging in all patients with a suspected diagnosis of myeloma.
The National Institute for Health and Care Excellence (NICE). Myeloma: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng35. Accessed March 19, 2018.
Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease.
demonstrated a potential benefit of early therapy for patients with high-risk smoldering multiple myeloma, whereas evidence suggests that MR imaging can be used as a prognostic biomarker in this population.
whereas abnormal signal on MR imaging has been shown to be associated with a very high risk of smoldering myeloma progression with the development of lytic bone lesions.
Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease.
These studies have been highly influential in guiding the IMWG’s decision to suggest treatment based on MR imaging focal lesions without confirmation of bone destruction.
International Myeloma Working Group Definitions of Myeloma Bone Involvement
Care should be taken to avoid overinterpretation of equivocal or tiny lucencies seen only on CT or PET/CT. For equivocal lesions, a repeat study in 3 to 6 months should be done before a diagnosis of multiple myeloma is established. Such patients might be followed up closely at 1- to 3-month intervals before systemic therapy is started.
aCare should be taken to avoid overinterpretation of equivocal or tiny lucencies seen only on CT or PET/CT. For equivocal lesions, a repeat study in 3 to 6 months should be done before a diagnosis of multiple myeloma is established. Such patients might be followed up closely at 1- to 3-month intervals before systemic therapy is started.
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18F FDG PET/CT: one or more osteolytic lesions (≥5 mm); increased FDG uptake alone is not sufficient; evidence of osteolytic bone destruction is needed on the CT component of the study
Care should be taken to avoid overinterpretation of equivocal or tiny lucencies seen only on CT or PET/CT. For equivocal lesions, a repeat study in 3 to 6 months should be done before a diagnosis of multiple myeloma is established. Such patients might be followed up closely at 1- to 3-month intervals before systemic therapy is started.
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MR imaging: more than one focal lesion of a diameter greater than 5 mm
In cases of equivocal small lesions, a second MR imaging should be performed after 3 to 6 months; if the MR imaging shows progression, patients should be treated as having symptomatic myeloma.
; diffuse marrow abnormality does not qualify
bIn cases of equivocal small lesions, a second MR imaging should be performed after 3 to 6 months; if the MR imaging shows progression, patients should be treated as having symptomatic myeloma.
Different patterns of myeloma marrow infiltration are encountered on MR imaging. The presence of focal lesions and more than one focal lesion have been shown to be the strongest adverse prognostic factors for progression followed by diffuse infiltration.
Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.
A micronodular or salt-and-pepper pattern of marrow infiltration is also recognized. Between 3% and 8% of the patients are also thought to have extramedullary sites of disease, although these figures are likely to increase with the growing trend toward the use of cross-sectional imaging.
Frequency, distribution and clinical management of incidental findings and extramedullary plasmacytomas in whole body diffusion weighted magnetic resonance imaging in patients with multiple myeloma.
Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma.
Prospective evaluation of magnetic resonance imaging and [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM Study.
The speed, coverage, and high sensitivity of whole-body DW-MR imaging, with its ability to quantify both the burden of disease and response to treatment, has made it a critical component of whole-body MR imaging for patients with myeloma.
The inverse correlation between cell density in soft tissues and apparent diffusion coefficient (ADC) has been extensively described
However, cellularity is not the sole factor influencing ADC, and the relationship between cellularity and ADC has not been so impressive in all cell types.
Other factors may influence ADC, for example, cytoplasmic viscosity, capillary bulk flow, active transport, and cell architecture, size and size variability within tissue have been variously implicated in small studies. Therefore, it is likely that ADC is a complex function of tissue microarchitecture that is, influenced by several components.
In response to treatment, the increased extracellular spaces within a tumor manifest as increases in distances of water motion and an increase in ADC.
However, the presence of fat in marrow necessitates an adapted approach. In normal adult marrow, there is a predominance of fat and a paucity of free water. The motion of the small amount of water that is present is restricted by fat; hence, normal adult marrow has very little signal on DW-MR imaging. As cellularity in marrow increases secondary either to disease or increased hematopoietic tissue, the amount of free water increases and so does the ADC.
Hence, in adults, the different microarchitecture of plasma cell–infiltrated marrow results in markedly different signal on DW-MR imaging and contrasts against normal marrow, which returns little signal.
The excellent image contrast between normal and diseased marrow on DW-MR imaging results in superior lesion conspicuity compared with conventional short tau inversion recovery (STIR) and contrast-enhanced MR imaging sequences.
Bone metastases from prostate, breast and multiple myeloma: differences in lesion conspicuity at short-tau inversion recovery and diffusion-weighted MRI.
The diagnostic value of SE MRI and DWI of the spine in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma.
Furthermore, unlike extraskeletal tumor types, the ADC value of myeloma-infiltrated marrow is significantly different from that of normal adult marrow, with very little overlap.
Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.
This difference means that qualitative differences in image contrast translate into quantitative differences and the ADC value can be used to separate myelomatous from normal marrow with a sensitivity of 90% and specificity of 93%. The ADC of the marrow of patients in remission and with monoclonal gammopathy of undetermined significance is not significantly different from that of healthy age-matched volunteers, making whole-body DW-MR imaging a promising tool for monitoring of these patients.
It should be noted that the IMWG’s new guidelines stipulate only focal lesions as an indication to treat patients with asymptomatic myeloma. This stipulation is perhaps because the diagnosis of diffuse infiltration on conventional MR imaging is challenging and is most often a subjective diagnosis based on a comparison of marrow signal with intervertebral discs. There is potential for ADC measurements to reduce this subjectivity, and this should be a priority for future studies. However, whole-body MR imaging can currently be used to make a judgment on whether posterior iliac crest trephine is likely to be representative, which facilitates the diagnosis of diffuse infiltration (Fig. 4).
Fig. 4A b900 DW MR imaging inverse gray-scale maximum-intensity projection (A) shows subtle alteration in background marrow signal suspicious but not confirmatory for diffuse infiltration. There are no focal lesions. Axial b50 (B), b900 (C), and ADC map (D) of the pelvis confirm suspicion for diffuse abnormal signal. The right-sided trephine tract is clearly seen at b50, b900, and on the ADC map (arrows) and suggests that marrow sampled appears similar to marrow elsewhere and should, therefore, be representative. Trephine confirmed 20% plasma cell infiltration.
Although whole-body DW-MR imaging is emerging as one of the most sensitive tools for imaging bone marrow with increased lesion conspicuity compared with conventional MR imaging sequences
Bone metastases from prostate, breast and multiple myeloma: differences in lesion conspicuity at short-tau inversion recovery and diffusion-weighted MRI.
Can whole-body magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer?.
Can whole-body magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer?.
presented data to suggest high specificity for detection of metastatic bone disease (98%–100%), a recent meta-analysis showed a pooled specificity of 86.1%.
The paucity of specific prospective studies on myeloma and marked heterogeneity in reference standards make current judgments on specificity challenging, and biopsy of all lesions is not feasible. The approach offered by the IMWG of a 3- to 6-month follow-up of equivocal solitary small lesions is a pragmatic solution.
Fig. 5Sagittal T1-weighted (T1W) MR imaging of the spine in a patient with a suspected new diagnosis of myeloma shows a subtle focal lesion in anterior T11 (arrow, A). Axial b900 images confirm the focal lesion in T11 (C) but also demonstrate small focal lesions in T7 (B, arrow), T12 (D, arrow), and L4 (E, arrow), which were not evident on T1W imaging.
The skull and ribs have historically been difficult sites for interrogation with MR imaging; however, DW imaging has shown increased sensitivity for lesion detection in the ribs compared with skeletal surveys in 2 studies.
Assessing myeloma bone disease with whole-body diffusion-weighted imaging: comparison with x-ray skeletal survey by region and relationship with laboratory estimates of disease burden.
Additionally, a lesion detection in the skull was reduced compared with skeletal surveys in both studies. This finding is possibly because the small volume of marrow in the skull is challenging to interrogate against adjacent high-diffusion signal in the brain. Still, false positives on plain film of the skull secondary to venous lakes and granulations are also possible and difficult to confirm.
Whole-body MR imaging protocols
The core whole-body MR imaging protocol, when used alone, is targeted primarily toward imaging bone marrow but can also detect extramedullary disease and should be completed within 45 minutes of table time (Fig. 6, Table 1). Sagittal imaging of the spine contributes to disease detection but also provides an essential assessment of mechanical complications, such as vertebral fractures or expansile disease threatening the spinal canal or nerve roots. Particularly for patients with symptoms, it is prudent to perform sagittal spine imaging first, so that essential information is obtained in case of an aborted scan. Axial anatomic detail is provided by Dixon images, but this also facilitates disease detection and quantification in the form of fat-fraction maps. Axial DW-MR imaging is the most sensitive sequence for detecting disease and also provide quantitative capabilities for assessing response. Anatomic correlation is supported by b50 and Dixon imaging. The core protocol can be supplemented with axial T2-weighted (T2W) sequences, but these are not considered mandatory. Regional assessments can be used as clinically indicated, that is, small field-of-view T2W axial imaging through levels of suspected cord compression. Although 45-minute protocols are generally well tolerated, longer examination times are challenging for some patients.
Fig. 6Core whole-body MR imaging protocol comprises sagittal T1 (A) and T2-weighted (B) sequences of the spine; axial b50 (C), b900 DW MR imaging (D), ADC map (E), and b900 DW MR imaging inverse gray-scale maximum-intensity projection (F); axial water-only (G) and fat-only (H) Dixon imaging. Two focal lesions within T8 are clearly seen on DW MR imaging (D, arrow) but are less well seen on sagittal imaging of the spine (arrow, B). The b50 DW MR imaging through the pelvis (I) shows the left-sided trephine tract (arrow), which suggests that background marrow but not focal lesions are sampled.
A 3D FSE T1W sequence offering multiplanar capability maybe performed as an alternative to replace sequences 1 and 3
Axial (5 mm)
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Whole-body (vertex to knees): axial, DW, STIR fat suppression, 5- to 7-mm contiguous slicing, multiple stations
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ADC calculations with mono-exponential data fitting
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3D-MIP reconstructions of highest b-value images
2 b-values (b50–100 and b800–1000 s/mm2)
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Whole-body (vertex to knees): axial, T2W, TSE without fat suppression, 5-mm contiguous slicing, multiple stations, preferably matching the DW images
Optional
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Regional assessments, for example, symptomatic/known sites outside the standard field of view, axial T2W through sites of suspected cord compression, para-coronal T1 sacrum for suspected sacral nerve root involvement
The evaluation of source b800 to 1000 value images of DW-MR imaging sequences is based on comparing high b-value image intensity to adjacent muscle signal intensity, but ADC maps are quantitative. Inverse gray-scale maximum-intensity projection (MIP) reconstructions are a means of displaying disease distribution and can be useful for identifying sites of disease in the ribs or vertebral spinous processes but should never be interpreted in isolation from source images.
The definitions for hypointense and hyperintense signal on b800 to 1000 value images remains subjective but can be gauged by using adjacent muscle as the reference background tissue.
METastasis reporting and data system for prostate cancer: practical guidelines for acquisition, interpretation, and reporting of whole-body magnetic resonance imaging-based evaluations of multiorgan involvement in advanced prostate cancer.
The combination of morphologic and functional data also allows for detection and characterization of vertebral fractures. Although morphologic features of diffuse T1 low signal, convex vertebral contour, involvement of pedicles, and a lumbar level are more frequently observed in malignant fractures,
Differentiation of acute osteoporotic and malignant compression fractures of the spine: use of additive qualitative and quantitative axial diffusion-weighted MR imaging to conventional MR imaging at 3.0 T.
Theoretically, benign fractures have more edema and free water and, therefore, a higher ADC than malignant fractures, where packed tumor cells lower the ADC. However, there has been conflict in the literature as to whether ADC can reliably be used as a sole discriminator.
Differentiation of acute osteoporotic and malignant compression fractures of the spine: use of additive qualitative and quantitative axial diffusion-weighted MR imaging to conventional MR imaging at 3.0 T.
Quantitative evaluation of benign and malignant vertebral fractures with diffusion-weighted MRI: what is the optimum combination of b values for ADC-based lesion differentiation with the single-shot turbo spin-echo sequence?.
Comparison of qualitative and quantitative evaluation of diffusion-weighted MRI and chemical-shift imaging in the differentiation of benign and malignant vertebral body fractures.
It seems likely that fracture age and mixed edema and tumor are likely to contribute to overlapping in ADC values of benign versus malignant fracture. Greater understanding of appropriate diffusion protocols and combination with morphologic imaging is likely to move this forward as a useful tool.
The diffusion sequences are also exquisitely sensitive to trephine tracts and, if already performed, whole-body DW-MR imaging can give some indication of the representation of the trephine sample. Alternatively, whole-body DW-MR imaging can be used to select the side for trephine sampling.
Pearls, pitfalls, and variants
T2 Shine Through
T2 shine through refers to a high signal on DW imaging that is not due to restricted diffusion but to high T2 signal shining through. Shine through may be seen on high b-value images and MIPs (Fig. 7). To avoid misinterpreting this signal, ADC maps should always be interrogated alongside the source b-value images and MIPs.
Fig. 7Sagittal T1-weighted MR imaging (A) and b900 DW MR imaging inverse gray-scale MIP (B) in a patient with treated myeloma suggest the presence of multifocal lesions. However, the ADC map (example left humeral lesion arrow, B, C) showed uniformly very high ADC (similar to cerebral spinal fluid) suggesting that these were acellular treated sites of disease. The appearance of multifocal disease on the b900 DW MR imaging inverse gray-scale MIP is an example of T2 shine through.
; therefore, detection of marrow disease in younger patients can be challenging. However, this is rarely problematic in myeloma, as its incidence is strongly related to age and nearly half of newly diagnosed patients are 75 years old and older (Cancer Research UK statistics). Granulocyte colony-stimulating factor (G-CSF) given either as part of the preparation for autologous stem-cell transplantation (ASCT) or supportive measures leads to a hypercellular marrow, which can mimic diffuse infiltration (Fig. 8). This is also problematic for other imaging techniques, such as conventional MR imaging sequences and FDG PET/CT. Therefore, both DW-MR imaging and FDG PET/CT should be avoided in the days following G-CSF administration; but if this is not possible, diffuse abnormalities should be interpreted with caution.
Fig. 8A b900 DW MR imaging inverse gray-scale MIP of a patient with diffuse myeloma marrow infiltration confirmed on trephine, which showed 80% infiltration (A). Follow-up b900 DW MR imaging inverse gray-scale MIP (B) following induction chemotherapy shows stable imaging appearances of diffuse abnormal signal; but trephine showed no evidence of myeloma, only reactive, regenerative marrow. The diffuse abnormal signal following therapy was secondary to G-CSF administration.
Vertebral hemangiomas are extremely common, with an incidence of up to 26%. The ADC of hemangiomas is significantly higher than that of focal active myeloma deposits: 1085 × 10−6 mm2s−1 compared with 682 × 10−6 mm2s−1.
Therefore, the ADC map combined with appearances on sagittal T1 and T2W imaging of the spine should avoid misdiagnosis as active myeloma deposits (Fig. 9).
Fig. 9Sagittal T1-weighted (A) and T2W (B) MR imaging of the spine in a patient with a suspected new diagnosis of myeloma demonstrates characteristic appearances of a vertebral T10 hemangioma (arrows), which is T1 and T2 bright. The corresponding axial b900 image also shows a corresponding focal lesion (arrow, C); the ADC map (arrow, D) confirms a high ADC, which is more in keeping with a hemangioma than active disease.
Although visualization of posterior iliac trephine tracts can allow some estimation of the possibility of sampling errors (see Fig. 6), on occasion a trephine will cause a hematoma. Blood products can cause restriction of diffusion mimicking disease; therefore, a solitary lesion in the posterior iliac crest, in particular, should be carefully interrogated for the presence of a trephine tract (Fig. 10).
Fig. 10b900 DW MR imaging and ADC map of a patient with a suspected diagnosis of myeloma demonstrates a focal lesion in the left posterior iliac crest (arrows, A, B). The intermediate/high ADC is unusual for a new site of focal active disease, which would usually appear restricted. Close interrogation of the corresponding fat-only and water-only images reveals a trephine tract (arrows, C, D) through the lesion. The lesion was a hematoma that resolved on follow-up.
Incidental findings on whole-body MR imaging are very common (up to 38%); however, the proposed core protocol allows for characterization of most incidental findings, and reportedly only 3% of the scans will lead to an equivocal finding that requires further investigation.
Frequency, distribution and clinical management of incidental findings and extramedullary plasmacytomas in whole body diffusion weighted magnetic resonance imaging in patients with multiple myeloma.
It is important for reporting radiologists to be clear about their level of concern and make recommendations for investigation/management of incidental findings.
Imaging response
The capability of whole-body MR imaging including DW-MR imaging to demonstrate both focal and diffuse marrow infiltration throughout the whole skeleton makes this technique extremely promising as a subjective tool for monitoring disease status and assessment of response. For focal lesions, changes in size and number can be easily assessed; for diffuse infiltration, signal changes are evident. However, ADC measurements offer the capability to quantify disease throughout the skeleton. This capability is particularly relevant, as changes in ADC are known to predate changes in the size of focal marrow deposits
(see Fig. 2); dimension-based assessments are not applicable to diffuse infiltration. Advances in data informatics have made semiautomated skeletal segmentation a reality, enabling histogram quantification of a patient’s whole marrow. This capability has been demonstrated by Giles and colleagues,
who used these techniques to segment patients’ bone marrow on DW-MR imaging to quantify the response to treatment. Reassuringly, the reproducibility was excellent, with a coefficient of variation of 2.8%. The mean ADC increased in 95% of the responding patients and decreased in all nonresponders (P<.002). A 3.3% increase in ADC helped identify the response with 90% sensitivity and 100% specificity. Visual assessment was also able to identify the response to treatment with high sensitivity (sensitivity 86%, specificity 95%), with good agreement in posttreatment change between 2 observers. There was a significant negative correlation between change in ADC and change in laboratory markers of response. Conversely, Hillengas and colleagues
Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.
demonstrated a decrease in ADC following therapy; it is likely that the direction of ADC change was influenced by the timing of the measurement. Messiou and colleagues
have confirmed that early following treatment, ADC increases presumably due to plasma cell death and resultant increased extracellular spaces. Later follow-up measurements show an ADC decrease when normal marrow architecture including marrow fat is restored (see Fig. 2; Fig. 11).
Fig. 11A b900 DW MR imaging inverse gray-scale MIP (A), axial b900 DW MR imaging (B), and ADC map (C) of the pelvis in a patient with a new diagnosis of diffuse myeloma infiltration confirmed on trephine. Corresponding sagittal T1-weighted MR imaging of the spine shows diffuse low signal in vertebral marrow (D). Following induction chemotherapy, b900 DW MR imaging inverse gray-scale MIP (E), b900 DW MR imaging (F), and ADC map (G) show normalization of marrow signal. Increased T1 marrow signal (H) confirms the return of normal marrow fat.
Fat-fraction measurements from Dixon imaging also give insight into the treatment response, as normal marrow fat is restored when the disease is responding
Fig. 12Axial b900 DW MR imaging, ADC map, axial water-only, and fat-only images of the pelvis before (A–D) and after treatment (E–H) in a patient with a new diagnosis of diffuse myeloma infiltration confirmed on trephine. Following induction chemotherapy, the ADC map shows subtle patchy islands of increasing ADC (E), suggesting some response (arrows,F). Corresponding water-only images show diffuse reduced water signal (reduced signal G compared with C), and returning fat signal is seen on fat-only images (increased signal on H compared with D) in keeping with response.
Prospective evaluation of magnetic resonance imaging and [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM Study.
have shown FDG PET/CT to be prognostic in the postinduction and posttransplant phases. Accurate prognostic information in these settings, where treatment can be both costly and associated with toxicity, is highly desirable for patient selection but also as a tool to stratify treatment intensity, consolidation, or maintenance therapy. Hillengass and colleagues
performed conventional whole-body MR imaging in patients before and after single or double ASCT treatment and found that the number of detected focal lesions on MR imaging significantly correlated with and predicted the overall survival in the patients. Although FDG PET/CT has been shown to be a powerful tool in detecting residual disease, the increased sensitivity of DW-MR imaging and its capability to detect both tiny deposits and diffuse disease gives it a potential advantage, which merits prospective evaluation.
recommends whole-body MR imaging in the workup of solitary bone plasmacytoma and patients with smoldering multiple myeloma. In some countries, whole-body MR imaging is recommended as first-line imaging in all patients with a suspected diagnosis of myeloma.
The National Institute for Health and Care Excellence (NICE). Myeloma: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng35. Accessed March 19, 2018.
Experienced centers have extended the service to monitoring patients with nonsecretory myeloma. On a case-by-case basis, whole-body MR imaging is also used to guide therapeutic decisions and monitor remission status in patients with symptomatic clinically or genetically defined high-risk disease. For patients with previously treated myeloma with borderline remission status or possible recurrence, whole-body DW-MR imaging is also extremely useful in differentiating treated from active sites of disease to guide management.
In many countries, limited MR imaging capacity presents a tangible barrier to providing a whole-body MR imaging service. Clear local referral pathways and guidelines ensure appropriate use of scanner time. Referring physicians should be aware that although 45 minutes of scanning time is well tolerated by most patients,
this is not universal. For example, when a patient presents with clinical symptoms and signs of spinal cord compression, the examination may be limited to MR imaging of the spine alone in order to address the acute clinical question. It is imperative that factors such as pain and claustrophobia, which might influence a patient’s tolerance for whole-body MR imaging, are communicated to the MR imaging team because, in some circumstances, forward planning, such as arranging analgesia or light sedation, can circumvent an unsuccessful scan attempt.
There is a strong case that the approach of using cross-sectional imaging at the time of diagnosis is a cost-effective strategy for diagnosis in patients with a suspected diagnosis of myeloma. In a recent analysis by the UK National Institute for Health and Care Excellence, the main influence presented was the avoidance of further cross-sectional imaging to guide treatment decisions, following a positive result on a skeletal survey.
The National Institute for Health and Care Excellence (NICE). Myeloma: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng35. Accessed March 19, 2018.
The cross-sectional approach could be cost saving and health improving. Whole-body MR imaging showed the largest increase in incremental quality-of-life-adjusted life-years, which was heavily influenced by it being assigned as the most sensitive imaging technique. In terms of incremental net monetary benefit, whole-body CT and MR imaging were almost equivalent, followed by MR imaging of the spine. Strikingly, FDG PET/CT was the only imaging modality with a negative incremental net monetary benefit.
Future directions and summary
The advent of whole-body DW-MR imaging has been one of the most significant advances for imaging in oncology patients over the last decade. The high sensitivity, speed, and quantitative capabilities have addressed an unmet need in imaging primary and secondary marrow malignancies.
Combined with anatomic imaging, whole-body DW-MR imaging now forms an imaging tool that has been tailored to detect both focal and diffuse disease and quantify burden and response, while also assessing mechanical complications. This blend of anatomic and functional imaging is well suited to serve the imaging needs of patients with myeloma. The necessity for whole-body imaging of patients with smoldering multiple myeloma and solitary plasmacytoma is now recognized. However, future studies will need to direct positioning of whole-body DW-MR imaging alongside emerging molecular and genetic signals as predictive and prognostic biomarkers. If future studies corroborate the usefulness of whole marrow segmentation techniques, academic and industrial collaborations will be essential to translate this from research to clinical settings. It is also likely that whole-body DW-MR imaging will have an increasing role in stratifying risk; as the number of treatment options continues to grow, it is likely to find its place in guiding therapeutic strategies.
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).
Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.
International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma.
The National Institute for Health and Care Excellence (NICE). Myeloma: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng35. Accessed March 19, 2018.
Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease.
Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.
Frequency, distribution and clinical management of incidental findings and extramedullary plasmacytomas in whole body diffusion weighted magnetic resonance imaging in patients with multiple myeloma.
Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma.
Prospective evaluation of magnetic resonance imaging and [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM Study.
Bone metastases from prostate, breast and multiple myeloma: differences in lesion conspicuity at short-tau inversion recovery and diffusion-weighted MRI.
The diagnostic value of SE MRI and DWI of the spine in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma.
Can whole-body magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer?.
Assessing myeloma bone disease with whole-body diffusion-weighted imaging: comparison with x-ray skeletal survey by region and relationship with laboratory estimates of disease burden.
METastasis reporting and data system for prostate cancer: practical guidelines for acquisition, interpretation, and reporting of whole-body magnetic resonance imaging-based evaluations of multiorgan involvement in advanced prostate cancer.
Differentiation of acute osteoporotic and malignant compression fractures of the spine: use of additive qualitative and quantitative axial diffusion-weighted MR imaging to conventional MR imaging at 3.0 T.
Quantitative evaluation of benign and malignant vertebral fractures with diffusion-weighted MRI: what is the optimum combination of b values for ADC-based lesion differentiation with the single-shot turbo spin-echo sequence?.
Comparison of qualitative and quantitative evaluation of diffusion-weighted MRI and chemical-shift imaging in the differentiation of benign and malignant vertebral body fractures.
Disclosure: The authors acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Center, Clinical Research Facility in Imaging, and the Cancer Research Network. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health.
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