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Box 1. When to consider screening for multiple myeloma

• Acute kidney injury in an over 50 year old with no alternative explanation

• Complaints of bone pain with pathological fractures where common causes have been excluded

• Elevated serum protein / globulin

• Anaemia – after exclusion of common causes such as iron deficiency, gastrointestinal losses and chronic kidney disease

IN RARE CASES, PATIENTS MAY PRESENT WITH SYMPTOMS OF AMYLOIDOSIS, HYPERVISCOSITY OR SPINAL CORD COMPRESSION DUE TO OSTEOLYTIC VERTEBRAL COLLAPSE.

All suspected myeloma cases

• FBC, differential and blood film

• EUC, CMP, urate, LFT, albumin, LDH, CRP, beta-2-microglobulin

• Serum protein electrophoresis( SPEP) and immunofixation electrophoresis( IFEP)

• 24-hour urine for protein, creatinine clearance and Bence Jones proteins

• Serum free light chains( SFLC)

• Bone marrow aspirate and trephine: morphology, immunohistochemistry( IHC),( CD138 kappa and lambda expression, p53), cytogenetics( if > 15 % plasma cells in aspirate), fluorescence in-situ hybridisation( FISH) for translocations, flow cytometry

• Low-dose CT, X-ray skeletal survey, MRI or PET-CT

Adapted from MMSTG by MSAG 2017 16

WHILE formal diagnosis requires specialty procedures including bone marrow biopsy, multiple myeloma will most commonly be suspected by the astute GP. The most common presenting symptoms are anaemia and / or bone pain / pathological fractures( see table 1), symptoms that can be attributed to many and varied alternative diagnoses. 2 Consider myeloma when patients present with anaemia or bone pain not explained by more common causes( see box 1).

Other, less common presenting symptoms include renal impairment( 25 %), hypercalcaemia( 30 %) and recurrent infection. 2 In rare cases, patients may present with symptoms of amyloidosis, hyperviscosity or spinal cord compression due to osteolytic vertebral collapse.

Hypercalcaemia is a presenting symptom in up to 30 % of cases of multiple myeloma and can be a cause of renal failure.

In amyloid multiple myeloma, the amyloid light chains secreted form insoluble fibrils that deposit in the body’ s tissues. The most important sites of deposition are in the kidney and heart, however, amyloid can also cause significant neuropathy.

Symptomatic light chain amyloidosis occurs in up to 15 % cases, but asymptomatic amyloidosis is reported to be present in up to 38 % of newly diagnosed cases( see box 2 for when to consider testing). 10 A fat pad biopsy is more sensitive than bone marrow biopsy alone for diagnosis of amyloidosis. However, as asymptomatic amyloidosis does not appear to affect clinical outcome, routine screening is not indicated.

Hyperviscosity due to immunoglobulin burden is rare in myeloma, especially at presentation. This is because most multiple myeloma is IgG( monomer) or IgA( dimer), rather than the significantly larger IgM pentamer, which is seen in Waldenstrom’ s macroglobulinaemia. Symptoms

Table 2. Myeloma diagnostic work up

Monoclonal gammopathy of uncertain significance and smouldering myeloma

• 3-12 monthly monitoring depending on progression risk

• Clinical assessment

• Serum and urine protein electrophoresis +/- IFE

• FBC, EUC, calcium

• Targeting imaging as indicated

• Bone marrow aspirate as indicated

Confirmed multiple myeloma

• HBV, HCV, HIV, CMV, VZV

• HLA typing for siblings / family if aged < 65 years and an allogeneic transplant is a potential future therapeutic option

• Sestamibi, PET or MRI for occult disease sites( none are PBS funded)

• Echocardiogram / cardiac MRI if amyloid suspected

Box 2. When to consider testing for amyloidosis in multiple myeloma

• Nephrotic range proteinuria

• Heart failure without clear cause( no coronary artery disease, no history of hypertension)

• Neuropathy: carpal tunnel syndrome, predominant sensory loss, autonomic neuropathy

• Macroglossia, early satiety

• Interstitial lung disease 9

of hyperviscosity may include headache, dizziness, acute renal failure or other end organ ischaemia.

Peripheral neuropathy due to myelin-associated glycoprotein( MAG) antibodies is another rare complication of myeloma. Neuropathy occurring as treatment toxicity is also well recognised. 7

MONOCLONAL gammopathy of undetermined significance refers to the finding of a paraprotein in the serum of less than 30g / L or abnormal free light chain ratio, in the context of less than 10 % clonal plasma cells in the bone marrow and no myeloma defining events. These patients should be monitored every 3-12 months for progression, and have a progression rate of 1 % per year.

Like monoclonal gammopathy of undetermined significance, smouldering multiple myeloma is often found on serum electrophoresis. The diagnosis requires the absence of myeloma-defining events in the context of a serum IgG or IgA paraprotein of equal to or greater than 30g / L, 24 hours urinary protein greater than or equal 500mg, or clonal bone marrow plasma cells of 10-60 %. Progression occurs at a significantly faster rate of 50 % in five years. 11 Table 2 outlines a diagnostic approach for myeloma.

Criteria for the diagnosis of multiple myeloma are defined by the International Myeloma Working Group and were recently revised in 2014( see table 3). Diagnosis requires a myeloma defining event plus the presence of clonal plasma cells( greater than or equal to 10 %) on bone marrow biopsy( see figure 6) or a biopsy confirmed plasmacytoma( see figure 7). Myeloma defining events

Condition

Smouldering multiple myeloma

Multiple myeloma

Table 3. Revised International Myeloma Working Group Diagnostic Criteria

Diagnostic criteria

Serum IgG / IgA paraprotein ≥ 30g / L or 24hr urinary monoclonal protein ≥500mg or clonal bone marrow plasma cells 10-60 %

AND

Absence of myeloma defining events or amyloidosis Must fulfil either criterion A or B

A Clonal bone marrow plasma cells ≥ 10 % or Biopsy confirmed plasmacytoma

AND

include hyercalcaemia, renal failure, anaemia and bone lesions( the CRAB symptoms), more than one focal lesion on MRI or a serum free light chain ratio more than 100. 12 Alternatively, the presence of more than 60 % clonal plasma cells in the bone marrow( see figure 8) is adequate for diagnosis in

≥1 myeloma defining event

• serum calcium > 0.25mmol / L above ULN or > 2.75mmol / L

• creatinine clearance < 40ml / min or serum creatinine > 177umol / L

• haemoglobin ≥20g / L below LLN, or < 100g / L

• ≥1 oseteolytic lesion on skeletal X-ray, CT or PET-CT

• serum free light chain ratio > 100( with involved light chain ≥100mg / L)

• > 1 focal lesion on MRI(> 5mm in size)

B ≥60 % clonal bone marrow plasma cells Adapted from Rajkumar S, et al. Lancet Oncology 2014 10

the absence of any myeloma defining events.

Table 4. Multiple Myeloma risk stratification based on cytogenetics

Degree of risk Chromosomal abnormalities

Standard risk

No high risk chromosomal abnormalities

High risk del( 17p) t( 4; 14) t( 4; 16)

Adapted from Palumbo et al, Journal of Clinical Oncology, 2015 12

Figure 6. Micrograph of myeloma neoplasm from bone marrow biopsy.

Risk stratification Cytogenetic investigations contribute useful information in the risk stratification of patients with plasma cell disorders( see table 4). They provide prognostic information for patients with both smouldering multiple myeloma( about the risk of developing active multiple myeloma) and multiple myeloma( about overall survival expectations as well as responses to some therapies).

Conventional cytogenetic testing

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