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:
- disseminated form: multiple well-defined "punched out" lytic lesions: predominantly affecting the axial skeleton
- disseminated form: diffuse skeletal osteopaenia
- solitary plasmacytoma: single large/expansile lesion most commonly in a vertebral body or in the pelvis
- 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 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
- 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)
- 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)
- 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)
- shoulder girdle
- long bones
- extra skeletal structures (extraosseous myeloma): rare
Radiology has a number of roles in the diagnosis and management or multiple myeloma:
- suggest the diagnosis/exclude other causes
- assess possible mechanical complications (e.g. pathological fracture)
- 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:
- numerous, well-circumscribed, lytic bone lesions (more common)
- punched out lucencies
- endosteal scalloping
- generalised osteopaenia (less common)
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:
- lateral skull
- frontal chest film
- cervico-thoraco-lumbar spine
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.
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.
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:
- 1. Dähnert W. Radiology review manual. Lippincott Williams & Wilkins. (2003) ISBN:0781738954. Read it at Google Books - Find it at Amazon
- 2. Weissleder R. Primer of diagnostic imaging. Mosby Inc. (2007) ISBN:0323040683. Read it at Google Books - Find it at Amazon
- 3. Hanrahan CJ, Christensen CR, Crim JR. Current concepts in the evaluation of multiple myeloma with MR imaging and FDG PET/CT. Radiographics. 30 (1): 127-42. doi:10.1148/rg.301095066 - Pubmed citation
- 4. Delorme S, Baur-melnyk A. Imaging in multiple myeloma. Eur J Radiol. 2009;70 (3): 401-8. doi:10.1016/j.ejrad.2009.02.005 - Pubmed citation
- 5. Roodman GD. Skeletal imaging and management of bone disease. Hematology Am Soc Hematol Educ Program. 2008;: 313-9. doi:10.1182/asheducation-2008.1.313 - Pubmed citation
- 6. Saba HI, Mufti G. Advances in Malignant Hematology. Wiley-Blackwell. (2011) ISBN:1444393995. Read it at Google Books - Find it at Amazon
- 7. Yochum TR, Rowe LJ. Essentials of Skeletal Radiology. Philadelphia, Pa. : Lippincott Williams & Wilkins, c2005. (2004) ISBN:0781739462. Read it at Google Books - Find it at Amazon
- 8. Reimer P, Parizel PM, Meaney JF et-al. Clinical MR Imaging, A Practical Approach. Springer Verlag. (2010) ISBN:3540745017. Read it at Google Books - Find it at Amazon
- 9. Dispenzieri A, Stewart AK, Chanan-Khan A et-al. Smoldering multiple myeloma requiring treatment: time for a new definition?. Blood. 2013;122 (26): 4172-81. doi:10.1182/blood-2013-08-520890 - Free text at pubmed - Pubmed citation
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.
- bone-forming tumours
- cartilage-forming tumours
- chondromyxoid fibroma
- fibrous bone lesions
- bone marrow tumours
- other bone tumours or tumour-like lesions
- aneurysmal bone cyst
- benign fibrous histiocytoma
- giant cell tumour of bone
- Gorham massive osteolysis
- haemophilic pseudotumour
- intradiploic epidermoid cyst
- intraosseous lipoma
- musculoskeletal angiosarcoma
- musculoskeletal haemangiopericytoma
- primary intraosseous haemangioma
- simple bone cyst
- impending fracture risk