Focusing on Diagnosis

A diagnosis of Multiple Myeloma (MM) is based on a number of clinical features and biomarkers.[1] This page will explore the investigative work in more detail.

Diagnostic pathway

Symptoms in MM are often vague and include musculoskeletal pain and tiredness.[2] The presentation of symptoms, the course of the disease and the clinical behaviour vary greatly from patient to patient.[3] Due to this heterogeneous nature it may be challenging for general health practitioners (GPs) to decide on when to refer patients with MM to a haematologist or hospital.[2] As a result, MM patients are more likely than other cancer patients to have three or more GP visits before their referral.[2] The other route of diagnosis is through emergency diagnosis which is usually associated with poorer outcomes.[2]

The MM diagnostic pathway[2][3]


Diagnosis of MM should be based on the following tests:

  • Complete blood cell count, differential serum creatinine, creatinine clearance and calcium level
  • Bone marrow aspirate or biopsy: number and characteristics of plasma cells, cytogenetic/FISH analysis
  • Immunofixation: heavy- and light-chain characterisation
  • Nephelometry:
    • Immunoglobulin quantification (IgG, IgA and IgM)
    • Serum FLC assay
  • Serum and/or urine protein electrophoresis: M-protein quantification
  • MRI (whole body or spine and pelvis): evaluation of focal bone lesions
  • Whole-body low-dose CT: evaluation of lytic bone lesions
  • PET-CT: evaluation of bone lesions

CT, computed tomography; FISH, fluorescence in situ hybridisation; FLC, free light chain; Ig, immunoglobulin; M, monoclonal; MRI, magnetic resonance imaging; PET-CT, positron-emission tomography with computed tomography

Signs and symptoms

Disease presentation and progression can vary significantly from patient to patient.[1][3] These symptoms are referred to as CRAB (Calcium (elevated), Renal impairment, Anaemia and Bone disease).

Patients most commonly present with:[4]


Calcium levels elevated (hypercalcaemia)


Renal impairment




Bone disease

Less common symptoms

Less common symptoms (occurring in 5% of patients) include extramedullary soft-tissue plasmacytomas or spinal cord compression following vertebral fractures.[4] Patients may also present with recurring bacterial infections, with about one-third of patients diagnosed following investigation of elevated erythrocyte sedimentation rate, total protein or immunoglobulins.[4] Patients with increased monoclonal (M) protein can experience headaches, nose bleeds, confusion and blurred vision.[4]

Some patients may consult their GP because of non-specific symptoms such as fatigue or back pain, while others may present at the emergency room with acute symptoms such as a long bone fracture or spinal compression.[4]

Diagnosing Multiple Myeloma

Smouldering MM

The diagnosis of smouldering MM requires the following criteria to be met:[1]

  1. Serum M-protein of ≥30 g/L or urinary M-protein of ≥500 mg per 24 hours
  2. 10–60% clonal bone marrow plasma cells
  3. Absence of any myeloma-defining events or amyloidosis

The role of M-protein

Not all patients with MM have M-protein in their serum or urine.[5] For this reason, the presence of M-protein is not required for a diagnosis of MM; rather, it is used to differentiate between secretory and non-secretory types.[1]

Symptomatic MM

Although each patient may present very differently, the diagnosis of symptomatic MM requires a number of specific criteria.

Patients should have at least 10% clonal bone marrow plasma cells or biopsy-proven bony or extramedullary plasmacytoma, and any one or more myeloma-defining events (CRAB and/or biomarker of malignancy).[1]

CRAB criteria providing evidence of end-organ damage related to the underlying plasma cell disorder:[3]

  • Calcium levels elevated
  • Renal insufficiency
  • Anaemia
  • Bone lesions

Any one or more biomarkers of malignancy:[3]

  • At least 60% clonal bone marrow plasma cells
  • Involved: uninvolved serum free light chain (FLC) ratio ≥100
  • At least one focal lesion on magnetic resonance imaging (MRI)
    (each at least 5 mm in size)

Find out more

About Multiple Myeloma

Even with significant advances in treatment, MM remains a challenging disease. Find out more about the evolution of MM.

Response measurements

The right treatment plan can improve a patient treatment response. Find out how treatment response is measured and what strides are being taken to optimise it.

EM-64626 - November 2021