Guidelines on the Diagnosis and Management of Multiple Myeloma

3. Diagnosis, Investigation and Indications for Treatment

Diagnosis and Investigation

• Patients typically present with bone pain, renal impairment, anaemia, or a combination of these
• Myeloma should also be considered in patients with:
  • unexplained backache
  • loss of height or radiological evidence of osteoporosis
  • recurrent bacterial infection
• Asymptomatic patients may be diagnosed on routine testing

Investigation of a patient with suspected myeloma should include the following (NB it is a government recommendation that clinical pathology investigations are undertaken in CPA accredited laboratories):

• full blood count
• serum urea, electrolytes and creatinine
• serum calcium
• serum albumin
• serum uric acid
• electrophoresis of serum and concentrated urine followed by immunofixation to confirm and type any paraprotein present. Immunofixation is also indicated in patients where there is a strong suspicion of myeloma but in whom routine electrophoresis is negative
• quantification of serum paraprotein
• quantification of urinary light chain excretion; either calculated on a random urine sample in relation to the urine creatinine or measured directly on a 24 hour urine collection
• quantification of non-isotypic serum immunoglobulins
• creatinine clearance, measured or calculated
• plasma viscosity
• standard X-rays of the skeleton including lateral and AP cervical, thoracic and lumbar spine, skull, chest, pelvis, humeri and femora (radionucleide bone scanning is not usually helpful)
• MRI is an essential investigation for patients with suspected spinal cord compression
• CT scanning is not routinely indicated in assessment but is helpful for imaging extramedullary disease
• bone marrow aspirate
• trephine biopsy and clonality studies (e.g. light chain restriction) are helpful in selected patients
• b₂-microglobulin (in the presence of normal renal function), LDH and C-reactive protein are prognostic markers
• a marrow sample should be sent for cytogenetic studies wherever possible

Although routine cytogenetic studies rarely provide helpful diagnostic or prognostic information, interphase cytogenetics using FISH analysis will identify abnormalities in most patients, the most frequent being translocations involving 14q and deletions of chromosome 13. Complete or partial deletion of chromosome 13 is a powerful adverse prognostic factor (Desikan et al, 2000; Konigsberg et al, 2000; Zojer et al, 2000; Facon et al, 2001). Cytogenetic information may therefore be useful in guiding decisions about treatment.

The diagnosis is usually confirmed by demonstration of a paraprotein in serum or urine and/or lytic lesions on x-ray together with over 10% plasma cells in bone marrow (Greipp, 1992).

Other conditions in which a paraprotein may be present include:

• monoclonal gammopathy of undetermined significance (MGUS)
• primary amyloidosis
• B-cell non-Hodgkin's lymphoma including Waldenstrom's Macroglobulinaemia
• chronic lymphocytic leukaemia
• connective tissue disorders

Currently accepted criteria for distinguishing myeloma from MGUS are shown in Table II below. Clear distinction may require careful observation over time (3-6 months). In patients where the investigations fulfil the diagnostic criteria of myeloma rather than MGUS but in whom the disease is asymptomatic and stable over the period of observation, the disease has variously been termed equivocal, indolent or smouldering myeloma (Greipp, 1992; Malpas 1998). Distinguishing between each of these terms is of no practical value as the main issue is whether or not treatment is required.

A new staging system and clinical classification of MGUS and myeloma is currently in preparation by an international working group. It is anticipated that the recommendations will be incorporated in the next revision of these guidelines.

Table II

	MYELOMA	MGUS
Bone marrow plasma cells	>10% on aspirate	<10% on aspirate
Serum paraprotein	Variable concentration in serum; no specific diagnostic levels	IgG usually <20 g/l IgA usually <10 g/l
Bence-Jones proteinuria	>50% cases	rare
Immune paresis	>95% cases	rare
Lytic bone lesions	often present	absent
Symptoms	frequent	absent
Anaemia	frequent	absent
Hypercalcaemia	may be present	absent
Abnormal renal function	may be present	absent

Indications for Starting Therapy

Chemotherapy is indicated for management of symptomatic myeloma. Chemotherapy is not indicated for patients with MGUS or those with equivocal/indolent/smouldering myeloma. Patients with no symptoms, normal Hb, calcium and renal function and no bone lesions may remain stable for a long period without treatment. Early intervention has shown no benefit in 2 randomised controlled trials (Hjorth et al, 1993; Riccardi et al, 2000)

An observational study of factors influencing disease progression showed that patients who are asymptomatic but have radiological evidence of bone disease (at least one lytic lesion) are at high-risk of progression with a median time to progression of 8 months (Dimopoulos et al, 1993). Two studies have shown that patients with no evidence of bone disease but with abnormal marrow appearences on MRI examination are also at higher risk of disease progression (Weber et al, 1997; Mariette et al, 1999). The prognostic effect of an abnormal MRI is much less marked than that of lytic bone disease. In the study reported by Mariette et al, (1999) median time to progression had not been reached by 25 months even in patients with an abnormal MRI, while in the study of Weber et al, (1997) MRI was only discriminatory in patients with other adverse features (high levels of paraprotein or BJP excretion or IgA isotype).

Recommendations: