Multiple myeloma
Updates to Article Attributes
Multiple myeloma is the most common primary malignant bone neoplasm in adults, and results in a wide range of radiographic abnormalities.
Four main patterns are recognised:
- disseminated form
-: multiple defined lesions: predominantly affecting the axial skeleton - disseminated form
-: diffuse skeletal osteopaenia - solitary plasmacytoma
-: single large/ expansile/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.
Epidemiology
Multiple myeloma is a common malignancy of older patients (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/weight bearing, and thus is worse during the day
- anaemia:
- typically normochromic
/ normocytic/normocytic
- typically normochromic
- renal failure
/ proteinuria/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.
Laboratory findings include:
- reverse albumin
/ globulin/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.
Pathology
Multiple myeloma results from monoclonal proliferation of malignant plasma cells which produce immunoglobulins (commonly IgG) and infiltrate haemopoietic locations (i.e. red marrow).
Distribution
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:
- 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-circumscribed lytic bone lesions (more common):- punched out lucencies e.g. pepperpot skull or raindrop skull 7
- endosteal scalloping
- generalized osteopaenia (less common):
- often associated with vertebral compression fractures / vertebra plana
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:
- lateral skull
- frontal chest film
- cervico-thoraco-lumbar spine
- shoulders
- pelvis
- femurs
The vast majority of lesions are purely lytic, sharply defined / punched/punched out with endosteal scalloping when abutting cortex. In only 3% of patients are the lesions sclerotic 7.
CT
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 assesassess the risk of fracture in severely affected bones.
MRI
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
-<li>disseminated form - multiple defined lesions: predominantly affecting the axial skeleton</li>-<li>disseminated form - diffuse skeletal osteopaenia </li>-<li>solitary <a href="/articles/plasmacytoma">plasmacytoma</a> - single large / expansile lesion most commonly in a vertebral body or in the pelvis</li>- +<li>disseminated form: multiple defined lesions: predominantly affecting the axial skeleton</li>
- +<li>disseminated form: diffuse skeletal osteopaenia </li>
- +<li>solitary <a href="/articles/plasmacytoma">plasmacytoma</a>: single large/expansile lesion most commonly in a vertebral body or in the pelvis</li>
-</ol><p>The remainder of this article relates to the disseminated forms. Please refer to the article <a href="/articles/plasmacytoma">plasmactyoma</a> for discussion of the latter.</p><p><strong>Smoldering multiple myeloma</strong> refers to a form that exists between <a href="/articles/mgus">monoclonal gammopathy of unknown significance</a> (MGUS) and active <strong>multiple myeloma</strong>. These asymptomatic patients had biochemistry which was worse than MGUS but did not have end-organ damage of active multiple myeloma <sup>9</sup>.</p><h4>Epidemiology</h4><p>Multiple myeloma is a common malignancy of older patients (70% of cases are diagnosed between 50 and 70 years of age), which has a male predilection (M:F 2:1) <sup>7</sup>. It accounts for 1% of all malignancies and 10% of all haematological disease. Together with osteosarcoma, multiple myeloma account for approximately 50% of all <a href="/articles/primary-bone-malignancy">primary bone malignancies</a> <sup>7</sup>. </p><h4>Clinical presentation</h4><p>Clinical presentation of patients with multiple myeloma is varied, and includes <sup>1-2,7</sup>:</p><ul>-<li>bone pain<ul>- +</ol><p>The remainder of this article relates to the disseminated forms. Please refer to the article <a href="/articles/plasmacytoma">plasmactyoma</a> for discussion of the latter.</p><p><strong>Smoldering multiple myeloma</strong> refers to a form that exists between <a href="/articles/mgus">monoclonal gammopathy of unknown significance</a> (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 <sup>9</sup>.</p><h4>Epidemiology</h4><p>Multiple myeloma is a common malignancy of older patients (70% of cases are diagnosed between 50 and 70 years of age), which has a male predilection (M:F 2:1) <sup>7</sup>. It accounts for 1% of all malignancies and 10% of all haematological disease. Together with osteosarcoma, multiple myeloma account for approximately 50% of all <a href="/articles/primary-bone-malignancy">primary bone malignancies</a> <sup>7</sup>. </p><h4>Clinical presentation</h4><p>Clinical presentation of patients with multiple myeloma is varied, and includes <sup>1-2,7</sup>:</p><ul>
- +<li>bone pain:<ul>
-<li>worse with activity / weight bearing, and thus is worse during the day</li>- +<li>worse with activity/weight bearing, and thus is worse during the day</li>
-<li>anaemia<ul><li>typically normochromic / normocytic</li></ul>- +<li>anaemia:<ul><li>typically normochromic/normocytic</li></ul>
-<li>renal failure / proteinuria</li>- +<li>renal failure/proteinuria</li>
-<li>pathological fracture<ul>- +<li>pathological fracture:<ul>
-<li>reverse albumin / globulin ratio (low albumin, high globulin)</li>- +<li>reverse albumin/globulin ratio (low albumin, high globulin)</li>
-<li>proteinuria = Bence Jones proteins in urine (Ig light chains)</li>- +<li>proteinuria: Bence Jones proteins in urine (Ig light chains)</li>
-</ul><p>The International Staging System, the most popular staging system, uses the combination of beta 2 microglobulin and serum albumin <sup>6</sup>. </p><p>Approximately 1 % of cases will have negative serum electrophoresis and negative urine Bence Jones proteins. </p><h4>Pathology</h4><p>Multiple myeloma results from monoclonal proliferation of malignant plasma cells which produce immunoglobulins (commonly IgG) and infiltrate haemopoietic locations (i.e. red marrow). </p><h5>Distribution</h5><p>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:</p><ul>- +</ul><p>The International Staging System, the most popular staging system, uses the combination of beta 2 microglobulin and serum albumin <sup>6</sup>. </p><p>Approximately 1% of cases will have negative serum electrophoresis and negative urine Bence Jones proteins. </p><h4>Pathology</h4><p>Multiple myeloma results from monoclonal proliferation of malignant plasma cells which produce immunoglobulins (commonly IgG) and infiltrate haemopoietic locations (i.e. red marrow). </p><h5>Distribution</h5><p>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:</p><ul>
-<li>extra skeletal structures (<a href="/articles/extraosseous-myeloma">extraosseous myeloma</a>) - rare </li>- +<li>extra skeletal structures (<a href="/articles/extraosseous-myeloma">extraosseous myeloma</a>): rare </li>
-<li>numerous, well circumscribed lytic bone lesions (more common)<ul>- +<li>numerous, well-circumscribed lytic bone lesions (more common):<ul>
-<li>generalized osteopaenia (less common)<ul><li>often associated with <a href="/articles/vertebral-compression-fracture">vertebral compression fractures</a> / <a href="/articles/vertebra-plana">vertebra plana</a>- +<li>generalized osteopaenia (less common):<ul><li>often associated with <a href="/articles/vertebral-compression-fracture">vertebral compression fractures</a> / <a href="/articles/vertebra-plana">vertebra plana</a>
-</ol><p>The vast majority of lesions are purely lytic, sharply defined / punched out with <a href="/articles/endosteal-scalloping">endosteal scalloping</a> when abutting cortex. In only 3% of patients are the lesions sclerotic <sup>7</sup>. </p><h5>CT</h5><p>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. </p><p>It may also better asses the risk of fracture in severely affected bones.</p><h5>MRI</h5><p>MRI is generally more sensitive in detecting multiple lesions compared to the standard plain film skeletal survey. Infiltration and replacement of <a href="/articles/bone-marrow"> bone marrow</a> 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 <sup>8</sup>.</p><h5>Nuclear medicine</h5><p>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 <sup>7</sup>.</p><p>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 F<sup>18</sup>-FDG molecule by the myeloma lesions corresponds to areas of bone lysis seen on CT.</p><h4>Treatment and prognosis</h4><p>Currently multiple myeloma remains incurable although the introduction of thalidomide, lenalidomide and bortezomib (proteasome inhibitor) have provided significant treatment gains <sup>6</sup>. These are typically used in combination with older agents such as cyclophosphamide, melphalan, prednisolone and doxyrubicin <sup>6</sup>. </p><p>Treatment response is usually assessed by measuring serum markers and bone marrow sampling. </p><p>Stem-cell harvest and autologous stem cell transplant post chemotherapeutic / radiotherapy bone marrow ablation is also used, although relapse is inevitable. </p><h4>Differential diagnosis</h4><p>The main differential is that of widespread <a href="/articles/bony-metastases">bony metastases</a>. Findings that favour the diagnosis of bony metastases over that of multiple myeloma include:</p><ul>- +</ol><p>The vast majority of lesions are purely lytic, sharply defined/punched out with <a href="/articles/endosteal-scalloping">endosteal scalloping</a> when abutting cortex. In only 3% of patients are the lesions sclerotic <sup>7</sup>. </p><h5>CT</h5><p>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. </p><p>It may also better assess the risk of fracture in severely affected bones.</p><h5>MRI</h5><p>MRI is generally more sensitive in detecting multiple lesions compared to the standard plain film skeletal survey. Infiltration and replacement of <a href="/articles/bone-marrow"> bone marrow</a> 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 <sup>8</sup>.</p><h5>Nuclear medicine</h5><p>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 <sup>7</sup>.</p><p>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 F<sup>18</sup>-FDG molecule by the myeloma lesions corresponds to areas of bone lysis seen on CT.</p><h4>Treatment and prognosis</h4><p>Currently multiple myeloma remains incurable although the introduction of thalidomide, lenalidomide and bortezomib (proteasome inhibitor) have provided significant treatment gains <sup>6</sup>. These are typically used in combination with older agents such as cyclophosphamide, melphalan, prednisolone and doxyrubicin <sup>6</sup>. </p><p>Treatment response is usually assessed by measuring serum markers and bone marrow sampling. </p><p>Stem-cell harvest and autologous stem cell transplant post chemotherapeutic / radiotherapy bone marrow ablation is also used, although relapse is inevitable. </p><h4>Differential diagnosis</h4><p>The main differential is that of widespread <a href="/articles/bony-metastases">bony metastases</a>. Findings that favour the diagnosis of bony metastases over that of multiple myeloma include:</p><ul>
-<li>although both entities have variable bone scan appearances (both hot and cold) unlike myeloma, extensive bony metastases rarely have a normal appearance.</li>- +<li>although both entities have variable bone scan appearances (both hot and cold) unlike myeloma, extensive bony metastases rarely have a normal appearance</li>
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