Multiple Myeloma (Suspected)

Multiple myeloma is a haematological malignancy arising from the clonal proliferation of bone marrow plasma cells in which there is an abnormal serum and/or urine immunoglobulin or free immunoglobulin light chain. 1, 2 It is often associated with complications of bone loss (diffuse osteopenia or focal lytic lesions), hypercalcaemia, renal failure, anaemia, and immune suppression 3

There are usually three stages of disease: 1-6

An asymptomatic pre-malignant precursor condition - monoclonal gammopathy of undetermined significance

An intermediate asymptomatic but more advanced pre-malignant stage - smouldering multiple myeloma

Symptomatic or active multiple myeloma

A solitary plasmacytoma is a biopsy proven solitary lesion of bone or soft tissue with < 10% clonal bone marrow plasma cells. There are no other lesions elsewhere and there is no end-organ damage 7

Bone disease is the most frequent clinical feature of multiple myeloma with up to 80% of newly diagnosed patients presenting with osteolytic lesions: 8-11

Vertebrae 66%

Ribs 45%

Skull 40%

Shoulder 40%

Pelvis 30%

Long bones 25%

Expansion of malignant myeloma cells in the bone marrow causes excess osteoclast activity and suppression of osteoblast activity. Various cytokines are produced from stromal cells which further promotes multiple myeloma clone proliferation 1

Patients can present with refractory pain, fractures, vertebral collapse or spinal cord compression 12

Initial diagnostic workup includes a thorough history, examination, blood and urine investigations. Once a plasma cell disorder has been identified, a bone marrow aspirate and biopsy and imaging investigations may be necessary to determine the diagnosis: active (symptomatic) multiple myeloma, smouldering multiple myeloma, monoclonal gammopathy of undetermined significance, or a solitary plasmacytoma 13, 14

Imaging is crucial in the diagnosis, staging, and management. Because disease can occur anywhere in the skeleton, wide skeletal coverage is mandatory 1, 8, 11, 15

The choice of imaging modality varies between institutions and depends on availability, cost and individual patient features. Conventional skeletal survey was previously the gold standard initial imaging performed. However, owing to their higher sensitivity in the detection of bone lesions, cross-sectional imaging techniques (CT, MRI and PET/CT) are now more widely used and have been incorporated into a number of guidelines 10, 11, 16-18

Myeloma is defined as clonal bone marrow plasma cells ≥ 10% or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: 7

≥ Sixty percent (≥ 60%) clonal bone marrow plasma cells

Serum free light chain ratio involved:uninvolved ≥ 100

> 1 focal lesion (≥ 5mm each) detected by MRI

Calcium elevation (serum calcium > 0.25mmol/L higher than the upper limit of normal or > 2.75mmol/L)

Renal insufficiency (creatinine clearance < 40ml/min or serum creatinine > 177μmol/L)

Anaemia (Hb < 100g/L or > 20g/L below lower limit of normal)

Bone disease (≥ 1 lytic lesion on skeletal survey, CT, or PET/CT)

• WBLDCT is recommended as the first-line imaging modality to assess for bone disease in multiple myeloma by the International Myeloma Working Group (IMWG), European Myeloma Network and European Society for Medical Oncology 10, 11, 14, 18, 19
• Studies have demonstrated that WBLDCT is superior to conventional skeletal survey (CSS) for the detection of osteolytic lesions. Small lytic lesions (<5mm) often missed by plain radiographs are detectable by CT. 10 One large study found that 61% of patients with a normal CSS had more than one osteolytic lesion on CT 11, 17, 18, 20, 21
• Because bone has high tissue contrast (mineralised bone vs. fat-containing bone marrow), radiation doses needed for optimal skeletal imaging are lower than those required for evaluating soft tissue pathology 22
• Radiation dose from dedicated WBLDCT is much lower than standard CT, currently 1.5 to 4 times higher than CSS. 22, 23 As technology improves, however, ultra-low-dose protocols are being designed 1, 24
• Benefits of WBLDCT include: 10, 25, 26
• Sensitivity is much greater than CSS
• Fast entire body exploration (5 minutes or less)
• Patients can lie on their back without the need to change positions
• Can assess spinal fracture instability, and depict spinal cord and cauda equina compression
• Can visualise soft-tissue involvement
• Cost is less than MRI or PET/CT
• Can guide needle biopsies, surgical interventions and radiotherapy
• Limitations include: 1, 10, 18, 25
• Radiation dose remains higher than CSS
• Suboptimal for intra-medullary lesions. CT is inherently limited to primarily imaging the secondary effects of myeloma on cortical bone rather than the bone marrow itself. It is less sensitive than MRI for detection of medullary infiltration
• Limited ability to assess diffuse bone marrow involvement
• Inaccurate for monitoring treatment response because osseous lesions often persist even when disease is in remission
• Increased length of time for radiologists to report findings
• Lack of availability at some centres
• Lacks specificity for differentiating between malignant and osteoporotic fractures

Traditionally CSS was the first-line imaging performed in the workup for suspected multiple myeloma. However, owing to its higher sensitivity, WBLDCT has now replaced CSS in many centres 27

CSS consists of a series of plain radiographs of the axial skeleton and proximal limbs: 9-11, 26, 28

Posteroanterior view of the chest

Anteroposterior and lateral views of the cervical, thoracic, lumbar spine, humeri and femora

Anteroposterior and lateral views of the skull

Posteroanterior view of the pelvis

Imaging of any symptomatic areas

For a lytic lesion to become apparent it requires loss of more than 30% of trabecular bone 8

CSS therefore has a lower sensitivity than cross-sectional imaging techniques for detecting osteolytic lesions. It is thought to underestimate the presence of active disease in 25-40% of cases 6, 8, 9, 22

Benefits of CSS include: 10, 11, 17, 25

Widely available

Large field of view

Relatively inexpensive

Relatively low radiation dose

Simple to use and interpret

Effective at detecting lesions in the skull and ribs

Limitations include: 18, 25

Low sensitivity (particularly in early disease)

Difficult to assess some areas (e.g. pelvis and spine) due to superimposition of overlying tissue

Relatively long imaging time. Often 20 separate films need to be obtained and this may not be tolerable for patients in severe pain

Limited ability to monitor response to treatment because of delayed evidence of bone healing

Wide inter-observer agreement and low reproducibility between centres - a higher number of osteolytic lesions are detected in academic centres compared with non-academic centres

A precursor to smouldering multiple myeloma and symptomatic multiple myeloma

MGUS is present in approximately 3-4% of the population over 50 years of age 7

It is defined as: 4

Serum monoclonal protein < 30g/L

Clonal bone marrow plasma cells < 10%; and

Absence of end-organ damage (CRAB features: Calcium – hypercalcaemia Renal insufficiency, Anaemia, Bone lesions)  that can be attributed to the plasma cell proliferative disorder

Imaging is not necessary as part of the routine work-up of patients with MGUS unless there is clinical or biochemical abnormalities which increase suspicion for active disease 8

In patients with “low risk MGUS” – IgG type, monoclonal protein < 15g/L, normal free light-chain ratio, and no concerning clinical features – bone marrow biopsy and imaging can usually be deferred 29

In all other patients with MGUS, bone marrow examination and whole body low-dose CT is recommended 29

Recommended follow-up of patients with MGUS varies between guidelines but is usually 3-6 months initially and less frequently thereafter if they are stable 29

An intermediate clinical stage between MGUS and symptomatic multiple myeloma 7

Risk of progression to symptomatic disease is about 10% per year in the first 5 years after diagnosis 7

Similar to MGUS but the thresholds for monoclonal protein level and bone-marrow plasma cell percentage are different: 4, 7

Serum monoclonal protein ≥ 30g/L, or urinary monoclonal protein ≥ 500mg per 24 hours and/or clonal bone marrow plasma cells 10-60% and

Absence of end-organ damage (CRAB features) that can be attributed to the plasma cell proliferative disorder

Patients with SMM should undergo further imaging with MRI (or PET/CT if MRI is not available) to look for occult bone disease 7

If one or more sites of osteolytic bone destruction (≥ 5mm in size) are found, this is regarded as meeting the CRAB criteria for multiple myeloma and these patients should be treated 7

In patients with more than one focal lesion on MRI which are small (< 5mm) or equivocal, additional imaging with CT (if not already performed) or PET/CT should be considered before making the diagnosis of multiple myeloma 7

A plasma cell dyscrasia containing abnormal plasma cell clones within soft tissue (extramedullary plasmacytoma) or bone 8

Defined as: 4

Biopsy proven lesion of bone or soft tissue with evidence of clonal plasma cells

Otherwise normal bone marrow with no evidence of clonal plasma cells

No other bony lesions on imaging (apart from the primary solitary lesion)

Absence of end-organ damage (CRAB features) that can be attributed to a lymphoplasma cell proliferative disorder

Patients with a solitary plasmacytoma on CSS or WBLDCT should undergo further imaging with MRI (or PET/CT if MRI is not available) to rule out the presence of other occult lesions because patients with more than one focal lesion (≥ 5mm) on MRI should be treated as symptomatic multiple myeloma 8

Multiple myeloma is defined by the International Myeloma Working Group (IMWG) as clonal bone marrow plasma cells ≥ 10% or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events :

• “CRAB” features: 2, 7
• Calcium – hypercalcaemia
• Renal insufficiency
• Anaemia
• Bone lesions – one or more osteolytic lesions on skeletal radiography, CT or PET/CT
• Or clonal bone marrow plasma cells ≥ 60% (sixty percent), involved:uninvolved serum free light chain ratio ≥ 100, or more than one 5mm or above focal lesion(s) on MRI (“SLiM” components of “SLiMCRAB” features)

Multiple myeloma was traditionally treated when symptomatic 30

However, it is now recommended that treatment should be considered in asymptomatic patients with an elevated risk of progression, when there is more than one focal lesion on MRI, or one or more lytic lesions detected on whole body low-dose CT or PET/CT 31, 32

MRI is the most sensitive imaging modality for detecting osseous, bone marrow, or extraosseous disease 33

Either whole-body MRI or MRI of the spine and pelvis can be used in the diagnostic workup and for monitoring treatment response

MRI directly visualises bone marrow infiltration by myeloma cells rather than secondary osseous destruction effects on cortical bone and can therefore detect disease earlier than CSS or WBLDCT 10, 11, 18, 34, 35

Sensitivity of MRI for detecting bone disease is higher than both CSS and WBLDCT. 17, 18 A systematic review by Regelink et al. found that MRI detected 12-82% more lesions compared with CSS 17

In comparison to PET/CT, MRI has been found to be superior for detecting diffuse marrow disease, however the two modalities have a similar sensitivity for detecting focal lesions 36

However, issues regarding availability, cost, and standardisation of technique remain, and MRI is not used for all patients with suspected multiple myeloma. MRI should be used for patients with suspected spinal cord compression, or in patients with smouldering myeloma or a solitary plasmacytoma after CSS or WBLDCT: 9, 10, 37

The National Institute for Health and Care Excellence (NICE, UK) guidelines recommend whole-body MRI as first-line imaging for suspected myeloma. If this is unsuitable or the person declines, WBLDCT is recommended and if this is not available a CSS 38

The Australian Multiple Myeloma Clinical Practice Guidelines recommend full axial and pelvis MRI in patients: 3

With severe back pain, severe bony disease, suspected vertebral compression or suspected solitary plasmacytoma

Without myeloma defining events (CRAB) but in whom positive biomarker of malignancy with MRI lesions is suspected

Similarly, IMWG guidelines recommend that all patients with smouldering myeloma should undergo whole-body MRI and if a patient is found to have more than one focal lesion ≥ 5mm in diameter, then they should be considered to have symptomatic myeloma that requires therapy 30, 34, 39

Another important consideration is the value of whole-body MRI (which is not available everywhere) over MRI of the spine and pelvis. A study of 100 patients with multiple myeloma or MGUS who underwent whole-body MRI, demonstrated that 10% of patients were found to have focal lesions merely in the extra-axial skeleton which would have been missed if only MRI of the spine and pelvis had been performed. The IMWG therefore recommends MRI of the spine and pelvis only when whole-body MRI is not available 34

Benefits: 25

Superior imaging modality for detection of diffuse bone marrow involvement

Sensitivity > plain radiographs and CT

Cost < PET/CT

No radiation

Optimal for brain and spinal cord imaging

Optimal for pathological fracture characterisation

Limitations: 25

Imaging time > plain radiographs and CT

Relatively expensive

Limited field of view for coverage of the entire skeleton

Limited availability

18F-fluorodeoxyglucose PET/CT is useful as part of the diagnostic work-up and monitoring of multiple myeloma 31

IMWG guidelines recommend PET/CT to distinguish active from smouldering multiple myeloma (SMM) if MRI is unavailable or contraindicated. PET/CT should also be considered in patients with active disease for monitoring treatment response 31

It combines functional imaging assessed by PET with morphological evaluation provided by CT

It is more accurate than CSS or CT in the early detection of bone lesions 17, 31, 40

It shows similar sensitivity to MRI for detecting discrete bone lesions but is less sensitive in the detection of diffuse bone marrow infiltration 31

PET/CT can also detect additional medullary lesions or extra-medullary disease in regions not examined by MRI 41, 42

The most significant advantage of PET/CT, however, is its ability to distinguish between metabolically active and inactive disease. PET/CT is therefore the preferred modality to evaluate and monitor the effect of therapy and for follow-up 31, 43-45

In addition to 18F-FDG, newer tracers which target metabolic pathways or receptors expressed by multiple myeloma cells have been preliminarily investigated. There is currently, however, no data which consistently supports the superiority of these tracers over 18F-FDG 31

99mTc-MIBI scintigraphy is another nuclear imaging modality often used to evaluate the extent of disease and has a high sensitivity and specificity in detecting sites of active disease 46

Myeloma lesions show good uptake of MIBI and this is usually visible before radiological changes are seen. Similar to PET/CT, MIBI scintigraphy can help differentiate active from old burnt-out lesions 47

Both 18F-FDG PET/CT and 99mTc-MIBI scintigraphy have also been found to help predict disease progression and are more accurate in predicting disease outcomes than MRI 46

Benefits of PET/CT: 25

Optimal for extra-medullary disease assessment

Best imaging modality to monitor disease activity

Limitations: 25, 31

Cost > CSS, CT, MRI. There are also differences in reimbursement between countries

Radiation > CSS, CT, MRI. Radiation dose is 4-5 times higher than low-dose CT 1

Sub-optimal for diffuse bone marrow involvement and skull lesions

False positives can occur at a bone marrow biopsy site or from other causes (e.g. infectious or inflammatory processes) 28

Lack of standardised imaging criteria and inter-observer reproducibility

Limited availability