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Table 1. Classes of antibodies Isotype

Adult reference range

Half life

Secreted form

IgD

Less than 0.08g / L

Function

Mucosal immunity

IgE

Less than 115kU / L

Source: Abbas A et al 2021 2

Figure 3. A crystal of Bence- Jones protein created for X-ray crystallography, which can reveal detailed, threedimensional protein structures.

Table 2. Percentage of the paraprotein subsets in myeloma

Type IgG 52 % IgA 21 % IgM 12 % Light chain only 11 % IgD 2 % No M-protein 2 %

Percentage

Two M-proteins Less than 1 % Heavy chain only Less than 1 % IgE Less than 0.01 %

Source: Rajkumar SV et al 2005 3

Albumin

Routine protein electrophoresis

α 1

α 2

Serum protein electrophoresis

Normal Multiple myeloma have a detectable paraprotein and are only identifiable with the addition of a serum free light chain assay. The short half-life of the free light chains( 2-6 hours compared with 21 days for IgG) also makes them a useful marker in disease monitoring after treatment.

The combination of these three tests has a diagnostic sensitivity of 98 % for MM. 3 Two per cent of patients have non-secretory disease( undetectable paraprotein or light chain in both serum and urine) that cannot be detected by these methods. The diagnosis is usually made late, in the presence of bony lesions that prompt further investigation with a bone marrow biopsy. When patients have detectable paraprotein and / or light chains but they are not able to be quantitated to accurate amounts( because of low detectable levels compared with the background immunoglobulins), they are termed oligosecretory. Clinically their paraprotein levels are not a reliable source of disease monitoring and the monitoring of disease in oligosecretory and non-secretory myeloma is difficult.

MULTIPLE MYELOMA

THIS is a malignant proliferation of a single clone of plasma cells in the bone marrow. MM is the second most common blood cancer after non-Hodgkin’ s lymphoma, and in 2019 the Australian incidence was β 1

β 2

M band →

Application → well for serum

7.1 cases per 100,000 people. 5 The cells usually invade adjacent bone leading to lesions that frequently cause pain and may lead to pathological fractures. Lesions can be detected radiologically( see figure 6). Marrow replacement with myeloma cells can produce anaemia, and the osteoclastic activity produced by these cells can lead to bony resorption and hypercalcaemia. The monoclonal paraprotein secreted into the blood may lead to renal damage via a variety of mechanisms including cast nephropathy( paraprotein forming casts and blocking renal tubules), light chain deposition in the glomerulus,

Albumin α 1 α 2 β γ

Figure 4. On the left is a patient’ s serum separated by charge on a gel matrix. An abnormal band can be seen in the γ region caused by the paraprotein. On the right is an electropherogram which shows a visual representation of the serum proteins achieved through a densitometer. This allows for quantification of the abnormal protein.

hypercalcaemia, hyperuricaemia and an acquired Fanconi syndrome.

At high levels the paraprotein may lead to a hyperviscosity syndrome( HVS) that classically presents with a triad of neurological deficits, visual changes and mucosal bleeding. The HVS occurs most commonly with an IgM paraprotein as it is a pentamer; however, the syndrome is also well recognised in patients with high levels of IgG and IgA. 6 HVS is a medical emergency and requires rapid recognition to start inpatient plasma exchange. Occasionally the paraprotein may affect nerves( via direct damage to the myelin sheath or by deposition of amyloid fibrils) causing a peripheral neuropathy.

Myeloma is often preceded by two phases: initially by MGUS that is then followed by SMM, also known as asymptomatic myeloma. All three conditions are typically characterised by the presence of a paraprotein( see table 3). Symptomatic MM requiring treatment is differentiated from MGUS and SMM by the presence of a myeloma-defining event( see box 2).

Diagnosis and investigation

After a paraprotein or light chain imbalance in the blood is detected, refer patients to a haematologist for assessment and consideration of a bone marrow biopsy. A diagnosis of MM requires first, the demonstration of a clonal population of plasma cells, 10 % or greater of total cells in the bone marrow, or one or more biopsy-proven bony or extramedullary plasmacytoma; and second, at least one myeloma-defining event. Clonality is demonstrated by showing kappa / lambda light chain restriction on flow cytometry, immunohistochemistry or immunofluorescence on the suspected plasma cells

A CT skeletal survey( see figure 7) has replaced the traditional plain X-ray skeletal survey as the preferred method of identifying myeloma bony lesions,