Multiple myeloma

Dr Henry Knipe and Dr Ki Yap et al.

Multiple myeloma is a monoclonal gammopathy and is the most common primary malignant bone neoplasm in adults. It arises from red marrow due to monoclonal proliferation of plasma cells and manifests in a wide range of radiographic abnormalities. Multiple myeloma remains incurable.

Four main patterns are recognized:

  1. disseminated form: multiple well-defined "punched out" lytic lesions: predominantly affecting the axial skeleton
  2. disseminated form: diffuse skeletal osteopenia
  3. solitary plasmacytoma: a 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 plasmacytoma for discussion of the latter.

Smouldering multiple myeloma refers to a form that falls on the spectrum between monoclonal gammopathy of unknown significance (MGUS) and active multiple myeloma. Patients are asymptomatic, with worse biochemistry than MGUS but without the end-organ damage of active multiple myeloma 9.

Multiple myeloma is a common malignancy in patients above 40 (70% of cases are diagnosed between ages 50 and 70 with a median age of diagnosis being 69 years) with a male predilection (M:F 2:1) 7,12. It accounts for 1% of all malignancies and 10% of all hematological disease 12. Multiple myeloma and osteosarcoma combined account for approximately 50% of all primary bone malignancies 7.

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
  • anemia
    • typically normochromic/normocytic
  • renal failure
  • proteinuria
  • hypercalcemia

The typical features can be recalled with the mnemonic CRAB 12

Presentation may also be with a complication, including:

The initial presentation occasionally is a polyneuropathy when it is part of a POEMS syndrome (mostly the sclerotic form).

Laboratory findings include:

  • reverse albumin/globulin ratio (i.e. low albumin, high globulin)
  • monoclonal gammopathy (IgA and/or IgG peak)
  • Bence Jones protein (Ig light chain) proteinuria
  • hypercalcemia
  • decreased or normal ALP unless there is a pathological fracture due to impaired osteoblastic function

The most popular staging system, the International Staging System, uses the combination of β2-microglobulin test and serum albumin 6

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

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 multiple myeloma
  • direct nephrotoxicity of Bence Jones proteins on the epithelial cells of the renal tubules
  • hypercalcemia and dehydration
  • hyperuricemia 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
  • extraskeletal structures (extraosseous myeloma): rare 

Radiology has a number of roles in the diagnosis and management for 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 12:

  1. numerous, well-circumscribed, lytic bone lesions (more common)
  2. generalized osteopenia (less common)

A skeletal survey is essential not only for the diagnosis of multiple myeloma but also in pre-empting potential complications (e.g. pathological fracture) and assessing response to therapy. ~40% bone destruction is required for lesion detection, thus giving the skeletal survey a high false-negative rate of ~50% (range 30-70%) 12

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

Whole-body low dose (WBLD) CT is more accurate than a skeletal survey with a sensitivity of ~70% and specificity of ~90% with a dose 1-2x that of a skeletal survey 12. WBLD CT is also better to assess the risk of pathological fracture in severely affected bones as well as the presence of extramedullary lesions 12. 

MRI is more sensitive in detecting multiple lesions compared to the standard plain film skeletal survey and CT 8,12. Five patterns have been described 12:

  • normal bone marrow signal
  • diffuse involvement
  • focal involvement
  • combined diffuse and focal involvement
  • variegated ("salt and pepper")

Most frequently used MR sequences for the evaluation of bone marrow are conventional T1 spin-echo and T2 spin-echo sequences 11.

  • T1
    • typically low signal 
    • high-grade, diffuse involvement may become isointense to adjacent normal marrow
  • T2 with fat-suppression
    • high signal
    • infiltration of the ribs is probably best appreciated on T2 images with fat suppression, appearing bright: ‘white ribs sign
  • T1 C+ (Gd)
    • ​​hyperintense
    • several enhancement curves may be seen.
      • type 4 curve: 
        • represents a steep wash-in of contrast medium, due to the high vascularization and perfusion with leakage through the highly permeable capillaries, followed by an early wash-out back into the intravascular space because of the small interstitial space with closely packed plasma cells 10-11
      • ​type 3 and type 5 curves may also be seen.
  • DWI/ADC: lesions can appear as areas of increased diffusivity compared to the very low diffusion of normal background marrow 11

Bone scintigraphy appearance of patients with disseminated multiple myeloma is variable due to the potential lack of osteoblastic activity. Larger lesions may be either hyperactive (hot) or photopenic (cold). Bone scans may also be normal. Therefore, bone scans usually do not contribute significant information to the workup 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 had a growing role in the management of this disease, as it is effective in identifying the distribution of disease. 18F-FDG uptake by the myeloma lesions corresponds to areas of bone lysis seen on CT.

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

The main differential is that of widespread bony metastases. Findings that favor the diagnosis of bone 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 tumors is dependent on the age of the patient, with a very different set of differentials for the pediatric patient.

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Article information

rID: 9555
Synonyms or Alternate Spellings:
  • Disseminated multiple myeloma
  • Smoldering multiple myeloma

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Cases and figures

  • Figure 1: illustration - distribution of multiple myeloma
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  • Case 1: with raindrop skull
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  • Case 2
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  • Case 3: MRI T1
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  • Case 4: endosteal scalloping
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  • Case 5
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  • Case 6
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  • Case 7
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  • Case 8: T1 C+
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  • Case 9: involving orbit
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  • Case 10
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  • Case 11
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  • Case 12
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  • Case 13: with vertebra plana
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  • Case 14
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  • Case 15
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  • Case 16
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  • Case 17
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  • Case 18
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  • Case 19
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  • Case 20
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  • Case 21: involving skull base
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  • Case 22: with generalized osteopaenia
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  • A lytic lesion is...
    Case 23
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  • Case 24
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  • Case 25
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  • Case 26
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  • Case 27
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  • Case 28
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  • Case 29: raindrop skull
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  • Case 30
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  • Case 31: raindrop skull
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