PET/CT in Multiple Myeloma and Plasma-Cell Disorders

1. The clinical problem

Plasma-cell disorders run from monoclonal gammopathy of undetermined significance (MGUS), through smouldering myeloma, to active multiple myeloma, with solitary plasmacytoma, POEMS syndrome and light-chain (AL) amyloidosis as related entities. Imaging answers four questions: is there a myeloma-defining event that means treatment should start; is an apparently solitary plasmacytoma really solitary; how much disease is there and where (including outside the bone); and has treatment eradicated it?

The IMWG 2014 definitions

Multiple myeloma needs clonal bone marrow plasma cells of 10% or more, or a biopsy-proven bony or extramedullary plasmacytoma, plus at least one myeloma-defining event (Rajkumar 2014). The events are the CRAB features of end-organ damage and three biomarkers of malignancy (SLiM): Sixty per cent or more clonal marrow plasma cells, an involved-to-uninvolved serum free Light-chain ratio of 100 or more (involved light chain at least 100 mg/L), and more than one focal lesion on MRI.

Selected IMWG 2014 definitions (Rajkumar 2014).

The imaging rules inside the criteria

• CRAB bone lesion: one or more osteolytic lesions on skeletal radiography, CT or PET/CT. Clear osteolysis of 5 mm or more on CT, including WB-LDCT or the CT of a PET/CT, qualifies even if radiographs are normal.
• Uptake alone is not enough: IMWG states that increased uptake on PET/CT without underlying osteolytic destruction on the CT is not adequate for the diagnosis.
• Fewer than 10% clonal marrow cells: more than one bone lesion is needed, to separate myeloma from a solitary plasmacytoma with minimal marrow involvement.
• MRI biomarker: more than one focal lesion, each 5 mm or more. In 149 patients with smouldering myeloma, 70% of those with more than one MRI focal lesion progressed within 2 years. Small or equivocal lesions need CT or PET/CT, or a repeat scan in 3–6 months, before myeloma is diagnosed.
• Not bone disease: osteoporosis or vertebral compression fractures without lytic lesions, and diffuse MRI marrow infiltration alone, do not meet the criteria.

Where nuclear medicine changes management

• Finding lytic lesions that radiographs missed, which starts treatment in a patient labelled smouldering.
• Upstaging an apparent solitary plasmacytoma to myeloma, which changes treatment from radiotherapy alone to systemic therapy.
• Detecting paramedullary and extramedullary disease, which carry a poor prognosis and which marrow sampling cannot see.
• Defining imaging MRD negativity after treatment, alongside marrow MRD.

Staging systems for prognosis (the International Staging System and its revisions, R-ISS and R2-ISS) use laboratory and cytogenetic markers; they do not include imaging. PET findings add prognostic information on top of them.

2. Tracers and imaging modalities

Why FDG works, and why it sometimes fails

Malignant plasma cells in focal lesions and extramedullary sites are usually glycolytic, so ¹⁸F-FDG shows active disease and separates it from inactive, burnt-out lytic holes. Uptake is heterogeneous, from barely above marrow to very intense. In 227 newly diagnosed patients imaged with both FDG PET and diffusion-weighted MRI, 11% had disease on MRI but a false-negative PET; these cases expressed markedly less hexokinase-2, the enzyme that phosphorylates and traps FDG (Rasche 2017). The EANM guideline puts the FDG-negative fraction at 10–20%. Such patients cannot be followed with FDG.

Why the bone scan fails

Myeloma activates osteoclasts and suppresses osteoblasts, so lesions are purely lytic with little new bone formation for a bone-seeking tracer to bind. The IMWG imaging statement concluded that bone scintigraphy has no place in the routine staging of myeloma (Dimopoulos 2009). A 'normal bone scan' should never be used to exclude myeloma bone disease. POEMS syndrome, with sclerotic or mixed lesions, is the exception in the plasma-cell family (section 6).

The three whole-body tests

Whole-body imaging options (EANM 2024 summary of IMWG and other guidelines).

Head-to-head data: in the prospective IMAJEM study, MRI of spine and pelvis was positive at diagnosis in 95% and PET/CT in 91% (not significantly different), but after therapy only PET normalisation predicted outcome (Moreau 2017). A retrospective series summarised by EANM found higher per-patient sensitivity for whole-body MRI than PET/CT (91.3% vs 69.6%) with similar treatment decisions, and DWI detects more focal lesions than PET, especially in smouldering myeloma. PET/CT, in turn, sees lesions outside a spine-and-pelvis MRI field (about 10% of disease lies outside it).

Other PET tracers

¹¹C-methionine detected focal lesions in 76% of 78 patients against 60% for FDG in the largest retrospective comparison, and a systematic review found a patient-level sensitivity advantage of more than 10% in five studies (194 patients). ¹¹C-acetate showed marrow involvement in 94% of 64 patients against 66% for FDG. Short half-life and cyclotron access limit both to specialist centres; the EANM guideline suggests methionine in selected FDG-negative cases. CXCR4 and CD38 tracers are covered in section 8.

3. Indications by clinical scenario

IMWG and EANM statements are consensus recommendations without formal grades. Guidelines disagree on the first test at diagnosis: IMWG, ESMO and the European Myeloma Network start with WB-LDCT (PET/CT acceptable), NICE starts with whole-body MRI.

4. Evidence at a glance

5. Patient preparation and acquisition

Fasting, glucose checks and uptake conditions follow the EANM tumour-imaging procedure. The myeloma-specific points come from the 2024 EANM plasma-cell guideline (Nanni 2024).

• Field of view: vertex to toes, or at least to the knees, because myeloma involves the skull and appendicular skeleton. Acquire the PET from the feet upwards so the bladder is scanned soon after voiding.
• Arms down: arms alongside the body (humeri are common disease sites), on foam supports to limit beam-hardening across the spine; avoid CT truncation, using an extended field of view if available.
• CT component: WB-LDCT without contrast is the standard; the IMWG Bone Working Group WB-LDCT parameters apply to the CT of the PET/CT so that the lysis criterion can be read from it. If contrast is needed, check renal function and hydrate: dehydration promotes light-chain precipitation and acute kidney injury.
• History to record: myeloma type, known extramedullary sites, date and type of last treatment, corticosteroids and growth factors (erythropoietin, G-CSF), fractures, vertebroplasty and orthopaedic hardware, infection, and earlier imaging for comparison.
• Positioning and pain: bone pain is common; give analgesia and position carefully, as fractures and cord compression are real risks.
• Reconstruction: IMPeTUs and the Deauville response criteria were developed on OSEM reconstructions; EANM advises not applying them to time-of-flight or other noise-optimised algorithms. Keep the reconstruction constant between baseline and follow-up.
• Reference regions: liver region of at least 3 cm radius in the central right lobe away from the edges; mediastinal blood pool inside the aortic arch lumen, avoiding the wall and calcification.
• Check before the patient leaves: urgent findings such as impending fracture or spinal cord compression need same-day communication.

6. Interpretation

What counts as disease

The Deauville scale as used in myeloma

The EANM guideline defines the five points for myeloma as: 1 no uptake; 2 at or below the mediastinal blood pool; 3 above blood pool but at or below liver; 4 above liver (at least 10% more); 5 markedly above liver (at least twice). Note that score 5 is anchored at twice the liver, which differs slightly from lymphoma practice.

IMPeTUs

The Italian Myeloma criteria for PET Use (IMPeTUs) were agreed within the EMN02 trial as a purely visual, descriptive system (Nanni 2016) and proved reproducible in 86 patients and 211 scans read by five blinded reviewers (Nanni 2018). Lesion-to-background SUV ratios may support, but do not replace, the visual score.

IMPeTUs items (Nanni 2016; EANM 2024 Table 1).

Baseline findings that carry prognosis

• Number of focal lesions: more than 3 FDG-avid lesions (Bartel 2009) or 3 or more (Zamagni 2011) predicted shorter survival.
• Intensity: a focal-lesion SUVmax above 4.2 predicted shorter PFS and OS, and its persistence after induction predicted early progression (Zamagni 2011). A pooled analysis cited by EANM found bone SUVmax to be the only independent PET factor, with an OS threshold of 7.1; thresholds are cohort-dependent.
• Extramedullary disease: present in 5–11% at diagnosis and more than 20% at relapse; independently predicted PFS and OS in IMAJEM.
• Paramedullary disease: reported in 18% of the CASSIOPET baseline population and associated with shorter PFS (EANM summary of CASSIOPET).
• A normal baseline PET: better prognosis than a positive one, but it also means FDG cannot be used for response.
• Volumetric measures: total metabolic tumour volume and total lesion glycolysis are prognostic in some series, but cut-offs differ widely and segmentation is not standardised; not for routine reports.

Smouldering myeloma and MGUS

A positive PET in smouldering myeloma predicts progression: 2-year rates of 75% vs 30% (Siontis 2015) and 58% vs 33% (Zamagni 2016). Focal uptake with underlying lysis of 5 mm or more is a myeloma-defining event. Focal uptake without lysis is not, however high the risk: report it clearly, recommend whole-body MRI (where more than one focal lesion of 5 mm or more would define myeloma) and close follow-up, and let the haematologist decide.

Solitary plasmacytoma and radiotherapy planning

Before radiotherapy, whole-body imaging must exclude other lesions: whole-body MRI for a bony lesion and FDG PET/CT for an extramedullary one, with PET/CT required whenever whole-body MRI cannot be done (Cavo 2017). PET/CT finds lesions outside a spine-and-pelvis MRI field. Two or more focal lesions on PET/CT at diagnosis predicted a shorter time to myeloma. For planning, the International Lymphoma Radiation Oncology Group recommends 35–40 Gy for solitary bone plasmacytomas under 5 cm and 40–50 Gy for extramedullary plasmacytomas (Tsang 2018); PET/CT and MRI help define the gross tumour volume, particularly soft-tissue extension. Follow-up is yearly for 5 years with the same technique used at diagnosis.

POEMS syndrome and AL amyloidosis

• POEMS: polyneuropathy and a monoclonal plasma-cell disorder (almost always lambda) plus a major criterion, one of which is sclerotic bone lesions (IMWG 2014). In 90 patients, FDG PET/CT showed 140 avid bone lesions, mostly mixed lytic-sclerotic and often in the pelvis, with hepatosplenomegaly in 65 and serous effusions in 46; lesion metabolism fell 3 months after therapy (Pan 2015). Read sclerotic lesions on the CT carefully: they are part of the diagnosis, not an incidental finding.
• AL amyloidosis: cardiac uptake of bone-seeking tracers (⁹⁹ᵐTc-DPD, -PYP, -HMDP) is over 99% sensitive for transthyretin (ATTR) amyloid, but false positives come almost entirely from AL amyloid. Grade 2–3 uptake allows a non-biopsy diagnosis of ATTR only when serum and urine show no monoclonal protein (Gillmore 2016). In a patient with a plasma-cell disorder, a positive scan needs tissue typing. See the article on nuclear medicine in cardiac amyloidosis.

Pitfalls and mimics

Sources: EANM 2024; Nanni 2020 (anaemia, erythropoietin, vertebroplasty, metalwork); Reinert 2024 (osteonecrosis of the jaw).

Wording the conclusion

• Give the IMPeTUs string, then translate it: 'more than 10 FDG-avid focal lesions, the hottest Deauville 5 (SUVmax 9.8) at L3; paramedullary extension at T11; no extramedullary disease'.
• State whether there is lysis of 5 mm or more on CT, because that, not the uptake, answers the diagnostic question.
• Name the baseline risk features that matter (more than 3 focal lesions, SUVmax above 4.2, paramedullary or extramedullary disease) and flag urgent findings (fracture risk, cord or root compression).
• If the scan is FDG-negative, say so explicitly and recommend another test for future response assessment.

7. Response assessment and follow-up

Two definitions of PET negativity

• IMWG 2016 (imaging MRD): MRD negativity in the marrow plus disappearance of every area of increased uptake found at baseline or a preceding PET/CT, or a decrease to less than the mediastinal blood pool SUV, or to less than surrounding normal tissue (Kumar 2016).
• Deauville-based complete metabolic response (Zamagni 2021; EANM 2024): uptake at or below liver (Deauville 1–3) in the marrow and in all previously involved focal lesions, paramedullary and extramedullary sites. This threshold was chosen a posteriori from outcome data in 228 patients and validated in FORTE and CASSIOPET; EANM recommends it, while noting it still needs further external validation before formal inclusion in the IMWG criteria.

The two are not the same: a lesion between blood pool and liver (Deauville 3) is residual uptake under the IMWG 2016 wording but a complete metabolic response under the Deauville criteria. Say which definition you applied.

PET and marrow MRD are complementary

Marrow MRD samples one site; myeloma is patchy and can persist in focal lesions or outside the bone. In FORTE, patients with both a complete metabolic response and flow-cytometry MRD negativity before maintenance had the longest PFS (HR 0.41). In CASSIOPET, double negativity again gave the best PFS in the daratumumab era. MRD-negative but PET-positive patients are few (about 5–7%) but relapse earlier, and in the PETHEMA/GEM2012 trial six patients progressed with extramedullary plasmacytomas on PET despite undetectable marrow MRD and no M-protein (EANM 2024).

Timing and consequences

• There is no consensus on scan timing; the strongest data are for a scan after induction and transplant, before maintenance.
• Scan against a baseline FDG PET/CT with the same reconstruction; response cannot be judged if the baseline was FDG-negative (IMWG then advises a WB-LDCT at the end of treatment as the new reference).
• IMWG: unless there is progression, treatment should not be changed on post-treatment imaging alone.
• Progression on CT (IMWG 2016): new osteolytic lesions; a 50% or greater increase from nadir in the sum of the products of diameters of more than one lesion; or a 50% or greater increase in the longest diameter of a previous lesion over 1 cm in short axis.

Relapse and surveillance

At suspected relapse, WB-LDCT is the standard, with MRI if it is negative; FDG PET/CT is optional but separates active from healed lesions and shows extramedullary disease, which is more common at relapse. For follow-up, IMWG advises yearly PET/CT when the post-treatment scan was positive, and EHA–ESMO advises yearly PET/CT in marrow-MRD-negative patients to confirm extramedullary negativity. Smouldering myeloma is followed with yearly spine-and-pelvis or whole-body MRI for at least 5 years, with PET/CT if MRI is not feasible.

8. Theranostics and emerging tracers

No radiopharmaceutical is approved for imaging or treating myeloma in 2026. CXCR4-directed therapy is marrow-ablative by design, so it belongs in transplant-centre protocols.

9. Structured report example

10. Take-home points

1. Lysis of 5 mm or more on CT meets the IMWG bone criterion; FDG uptake without lysis does not, however suspicious.
2. WB-LDCT is the first bone survey, whole-body MRI is best for smouldering myeloma and bony plasmacytoma, and FDG PET/CT is the test for response and extramedullary disease. Do not use a bone scan.
3. Report with IMPeTUs and the myeloma Deauville scale; name the hottest site, the paramedullary and extramedullary disease, and fractures.
4. More than 3 focal lesions, SUVmax above 4.2 and paramedullary or extramedullary disease are adverse at baseline.
5. Complete metabolic response means marrow and all previous sites at or below liver; combine it with marrow MRD.
6. Check baseline avidity: 10–20% of myelomas are FDG-negative and need another test for follow-up.
7. In a patient with a monoclonal protein, cardiac uptake on a bone scan does not diagnose ATTR amyloid.

Test yourself

5 quick questions. Pick an answer to see the explanation.

References

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