Multiple myeloma

Dr Owen Kang and Dr Ki Yap et al.

Multiple myeloma is the most common primary malignant bone neoplasm in adults arising from red marrow due to monoclonal proliferation of the plasma cells, and results in a wide range of radiographic abnormalities. Treatment remains difficult.


Four main patterns are recognised:

  1. disseminated form: multiple well-defined "punched out"lytic lesions: predominantly affecting the axial skeleton
  2. disseminated form: diffuse skeletal osteopaenia
  3. solitary plasmacytoma: single large/expansile lesion most commonly in a vertebral body or in the pelvis
  4. osteosclerosing myeloma

The remainder of this article relates to the disseminated forms. Please refer to the article plasmactyoma for discussion of the latter.

Smoldering multiple myeloma refers to a form that exists between monoclonal gammopathy of unknown significance (MGUS) and active multiple myeloma. These asymptomatic patients had biochemistry which was worse than MGUS but did not have end-organ damage of active multiple myeloma 9.


Multiple myeloma is a common malignancy of older patients above 40 years old (70% of cases are diagnosed between 50 and 70 years of age), which has a male predilection (M:F 2:1) 7. It accounts for 1% of all malignancies and 10% of all haematological disease. Together with osteosarcoma, multiple myeloma account for approximately 50% of all primary bone malignancies 7.

Clinical presentation

Clinical presentation of patients with multiple myeloma is varied, and includes 1-2,7:

  • bone pain
    • initially intermittent, but becomes constant
    • worse with activity/weight bearing, and thus is worse during the day
  • anaemia
    • typically normochromic/normocytic
  • renal failure/proteinuria

Presentation may also be with a complication, including:

  • pathological fracture
    • vertebral compression fracture
    • long bone fracture (e.g. proximal femur)
  • amyloidosis
  • recurrent infection: e.g. pneumonia due to leukopaenia
  • plasmacytomas typically progress to multiple myeloma

Occasionally presentation is with polyneuropathy, when multiple myeloma is part of  POEMS syndrome (mostly sclerotic form).

Laboratory findings include:

  • reverse albumin/globulin ratio (low albumin, high globulin)
  • monoclonal gammopathy (IgA and/or IgG peak)
  • proteinuria: Bence Jones proteins in urine (Ig light chains)
  • hypercalcaemia
  • decreased or normal ALP unless there is a pathologic fracture due to impaired osteoblastic function.

The International Staging System, the most popular staging system, uses the combination of beta 2 microglobulin and serum albumin 6

Approximately 1% of cases will have negative serum electrophoresis and negative urine Bence Jones proteins.  


Multiple myeloma results from monoclonal proliferation of malignant plasma cells which produce immunoglobulins (commonly IgG) and infiltrate haemopoietic locations (i.e. red marrow).  

Renal involvement is common and renal failure is multifactorial:

  • obstructive casts form in the renal tubules composed of Bence Jones proteins, immunoglobulins, albumin and Tamm-Horsfall proteins
    • most common cause of renal failure in MM
  • direct nephrotoxicity of Bence Jones proteins on the epithelial cells of the renal tubules
  • hypercalcaemia and dehydration
  • hyperuricaemia and urate nephropathy due to high cell turnover
  • amyloidosis (AL type)
  • increased risk of renal infection

Distribution of multiple myeloma mirrors that of red marrow in the older individual, and thus this is mostly encountered in the axial skeleton and proximal appendicular skeleton:

  • vertebrae (most common)
  • ribs
  • skull
  • shoulder girdle
  • pelvis
  • long bones
  • extra skeletal structures (extraosseous myeloma): rare 

Radiographic features

Radiology has a number of roles in the diagnosis and management or multiple myeloma:

  1. suggest the diagnosis/exclude other causes
  2. assess possible mechanical complications (e.g. pathological fracture)
  3. assess disease progression

Disseminated multiple myeloma has two common radiological appearances, although it should be noted that initially radiographs may be normal, despite the presence of symptoms. The two main diffuse patterns are:

  1. numerous, well-circumscribed, lytic bone lesions (more common)
  2. generalised osteopaenia (less common)
Plain film

A skeletal survey is essential in not only the diagnosis of multiple myeloma, but also in assessing response, and pre-empting potential complications (e.g. pathological fracture). A typical skeletal survey consists of the following films:

  1. lateral skull
  2. frontal chest film
  3. cervico-thoraco-lumbar spine
  4. shoulders
  5. pelvis
  6. femurs

The vast majority of lesions are purely lytic, sharply defined/punched out with endosteal scalloping when abutting cortex. In only 3% of patients are the lesions sclerotic 7


CT does not have a great role in the diagnosis of disseminated multiple myeloma, however it may be useful to determine the extent of extra-osseous soft tissue component in patients with a large disease burden. 

It may also better assess the risk of fracture in severely affected bones.


MRI is generally more sensitive in detecting multiple lesions compared to the standard plain film skeletal survey. Infiltration and replacement of bone marrow is exquisitely visualised, and newer scanners are able to perform whole body scans for this purpose which has been shown to be superior to both CT and skeletal surveys 8.

Nuclear medicine

Bone scintigraphy appearance of patients with disseminated multiple myeloma is variable due to the potential lack of osteoblastic activity. Larger lesions may be hot or cold. Bone scans may also be normal. Therefore bone scans usually do not contribute significant information in the work-up of patients with suspected or established disseminated multiple myeloma, as the sensitivity of detecting lesions is less than that of a plain film skeletal survey 7.

PET-CT has a growing role to play in the management of this disease, as it is effective in identifying the distribution of disease. Uptake of the F18-FDG molecule by the myeloma lesions corresponds to areas of bone lysis seen on CT.

Treatment and prognosis

Currently multiple myeloma remains incurable although the introduction of thalidomide, lenalidomide and bortezomib (proteasome inhibitor) have provided significant treatment gains 6. These are typically used in combination with older agents such as cyclophosphamide, melphalan, prednisolone and doxyrubicin 6

Treatment response is usually assessed by measuring serum markers and bone marrow sampling. 

Stem-cell harvest and autologous stem cell transplant post chemotherapeutic/radiotherapy bone marrow ablation is also used, although relapse is inevitable. 

Differential diagnosis

The main differential is that of widespread bony metastases. Findings that favour the diagnosis of bony metastases over that of multiple myeloma include:

  • more commonly affect the vertebral pedicles rather than vertebral bodies
  • rarely involve mandible, distal axial skeleton
  • although both entities have variable bone scan appearances (both hot and cold) unlike myeloma, extensive bony metastases rarely have a normal appearance

Other rare entities include:

Bone tumours

The differential diagnosis for bone tumours is dependent on the age of the patient, with a very different set of differentials for the paediatric patient.

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