Multiple Myeloma
Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group
Michele Cavo et al.
The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of 18Fluorodeoxyglucose (18F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. 18F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of 18F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of 18F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. 18F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.
Assessment of bone damage in multiple myeloma
Consensus statement
We recommend incorporating these novel imaging techniques into the diagnostic work-up of multiple myeloma because of their higher sensitivity and ability to detect bone damage at an earlier phase than WBXR (evidence level 1, grade A). Several guidelines2,43 have established whole-body low-dose CT as the preferred method for the detection of lytic bone lesions in multiple myeloma. 18F-FDG PET/CT should be considered as a valuable option, because of its ability to identify lytic lesions and extramedullary masses, while also being able to provide reliable prognostic information (evidence level 2, grade B). We recommend 18F-FDG PET/CT to distinguish active from smouldering multiple myeloma, if WBXR is negative and whole-body MRI is unavailable (evidence level 1, grade A). In the current era of highly active novel agents, availability of 18F-FDG PET/CT scans at baseline allows the comparison of pre-treatment images with post-treatment images, and to identify patients who are now considered as having imaging minimal residual disease (MRD) negativity (evidence level 2, grade B).
Prediction of prognosis in multiple myeloma
In newly diagnosed patients eligible or ineligible for autologous stem-cell transplantation
Consensus statement
18F-FDG PET/CT done at the onset of multiple myeloma is a reliable tool as a predictor of prognosis (evidence level 1, grade A). More robust data from studies in newly diagnosed patients treated with ASCT are available compared with those done in patients who were not eligible for ASCT or who have relapsed or who have refractory multiple myeloma. We encourage studies in such patients to further explore the role of 18F-FDG PET/CT as a prognostic indicator. Consistencies between independent studies confirm the negative prognostic value of EMD and the presence of more than three focal lesions, particularly after upfront ASCT, while the prognostic role of SUVmax is more conflicting (evidence level 3, grade C). A high number of focal lesions or the presence of EMD more frequently correlates with adverse prognostic factors associated with the burden or the biology of multiple myeloma (evidence level 3).
Assessment of response to therapy in multiple myeloma
Consensus statement
We recommend that 18F-FDG PET/CT should be considered the preferred imaging technique to evaluate and monitor metabolic response to therapy in multiple myeloma (evidence level 1, grade A). Changes in 18F-FDG avidity provide an earlier evaluation of response compared with MRI; data for diffusion-weighted imaging whole-body MRI are still limited. 18F-FDG PET/CT negativity before ASCT is an early predictor of favourable post-ASCT outcomes (evidence level 3, grade B). For patients with conventionally defined complete response after treatment, in particular after ASCT, persistent 18F-FDG PET/CT-positive scans after 3–6 months predict worse outcomes (evidence level 3, grade B). In view of the ability of 18F-FDG PET/CT to detect the presence of EMD, this technique should be coupled with sensitive bone marrow-based assays as part of MRD assessment to confirm MRD negativity both inside and outside the bone marrow. The combination of negative multiparametric flow cytometry or next-generation sequencing, negative 18F-FDG PET/CT scans and a normal heavy/light chain ratio might ultimately reflect the complete eradication of myeloma cells from all compartments.
18F-FDG PET/CT use in smouldering multiple myeloma
Consensus statement
Patients who meet the criteria for smouldering multiple myeloma but have one or more lytic lesions on 18F-FDG PET/CT should be defined as having multiple myeloma that requires therapy (evidence level 1, grade A). 18F-FDG PET/CT is required to distinguish active from smouldering multiple myeloma, if WBXR is negative and whole-body MRI is unavailable (evidence level 1, grade A). Early data suggest that focal lesions without underlying bone changes on 18F-FDG PET/CT predict for a higher risk of early progression from smouldering multiple myeloma to active multiple myeloma, but further confirmation is warranted (evidence level 3, grade B). We encourage the incorporation of 18F-FDG PET/CT into prospective studies of patients with newly diagnosed smouldering multiple myeloma.
18F-FDG PET/CT use in solitary plasmacytoma
Consensus statement
We think integration of the novel functional imaging techniques into the diagnostic procedures in patients with suspected solitary plasmacytoma is warranted to more carefully assess the extent of the tumour and to confirm the diagnosis by ruling out the presence of additional occult sites of proliferating clonal plasma cells (evidence level 1, grade A). On the basis of the limited availability of whole-body MRI, we recommend 18F-FDG PET/CT as part of the initial investigations in patients with a suspicion of either extramedullary plasmacytoma or solitary bone plasmacytoma.
Recommendations for the use of 18F-FDG PET/CT in patients with multiple myeloma and other plasma cell disorders
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Active multiple myeloma
18F-FDG PET/CT should be considered as part of the initial investigations in patients with newly
diagnosed multiple myeloma because it provides information useful for prognostication and allows
to more carefully assess the bulk of the disease, particularly in patients with extramedullary sites of the
disease; assessing the bulk of the disease with 18F-FDG PET/CT also applies to patients with relapsed or
refractory multiple myeloma
B
In patients with newly diagnosed multiple myeloma, with or without EMD, and more than three
focal lesions, 18F-FDG PET/CT identifies subgroups of patients with unfavourable outcomes;
controversies exist about the prognostic role of SUVmax
B
18F-FDG PET/CT is now the preferred technique for evaluating and monitoring response to therapy;
metabolic changes assessed by 18F-FDG PET/CT provide an earlier evaluation of response compared
with MRI
A
18F-FDG PET/CT should be coupled with sensitive bone marrow-based assays as part of minimal
residual disease detection inside and outside the bone marrow
B
Smouldering multiple myeloma
Patients who meet the diagnostic criteria for smouldering multiple myeloma and have one or
more lytic lesions on 18F-FDG PET/CT should be defined as having multiple myeloma that requires
immediate therapy
A
18F-FDG PET/CT is recommended to distinguish smouldering multiple myeloma from active
multiple myeloma if whole-body X-ray is negative and whole-body MRI is unavailable
A
Solitary plasmacytoma
Patients with focal lesions on PET but without underlying lytic lesions on the CT part of 18F-FDG PET/
CT are at high risk of progression to active multiple myeloma
B
Patients with suspected solitary plasmacytoma, either extramedullary plasmacytoma or solitary bone
plasmacytoma without symptoms or signs suggestive of cord compression, should receive 18F-FDG
PET/CT to unequivocally confirm the diagnosis, provided whole-body MRI is unavailable
A
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18F-FDG= 18F-fluorodeoxyglucose. EMD=extramedullary disease. ASCT=autologous stem-cell transplantation.
SUV=standardised uptake value.
Panel: Use of 18F-FDG PET/CT at diagnosis and after treatment in multiple myeloma
At diagnosis
Advantages
• Provides a whole body evaluation at one session while detecting with relatively high sensitivity and specificity myeloma bone disease
• Optimal to detect extramedullary sites of the disease
• Detects lytic bone lesions (diameter of >5 mm)
• Optimal to assess the burden and metabolism of the tumour
• Valuable tool for predicting prognosis (particularly, absence or presence of focal lesions, and of extramedullary disease)
• Mandatory to confirm the diagnosis of solitary plasmacytoma
Disadvantages
• Suboptimal for detecting diffuse bone marrow plasma-cell infiltration and lytic lesions in the skull
• Higher costs compared with MRI and whole-body MRI
• Radiation dose is greater than that given for whole-body X-ray, whole-body low-dose CT
• Poor availability
• False positivity due to bone metallic implants, accumulation of the tracer in physiological districts, inflammation, infections, post-surgical areas, concomitant tumours, or recent chemotherapy or radiotherapy or use of growth factors inducing a false diffuse bone marrow pattern
• False negativity due to hyperglycaemia, recent use of high-dose steroids inducing a transient metabolic suppression, presence of sub-centimetre lytic lesions in the skull, or close to the brain
After treatment
Advantages
• Powerful tool for evaluating metabolic response to therapy
• Provides earlier assessment of response compared with MRI
• Identifies those patients who are imaging MRD-negative
• Correlates well with biochemical markers of response
Disadvantages
• Lack of standardisation
• Only applicable in 75% of patients
• Poor availability
• High costs
18F-FDG=18F-fluorodeoxyglucose.