You are in: eMedicine Specialties > Radiology > MUSCULOSKELETAL Multiple MyelomaArticle Last Updated: Oct 2, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Steven M Sorenson, MD, Consulting Staff, Department of Radiology, Coast Radiology Imaging and Intervention Steven M Sorenson is a member of the following medical societies: Radiological Society of North America Coauthor(s): Amilcare Gentili, MD, Clinical Professor of Radiology, University of California at San Diego; Consulting Staff, Department of Radiology, Thornton Hospital; Sulabha Masih, MD, Associate Professor of Diagnostic Radiology, University of California at Los Angeles; Consulting Staff, Department of Radiology, Section of Musculoskeletal Radiology, West Los Angeles Veterans Affairs Medical Center; Carol L Andrews, MD, Consulting Musculoskeletal Radiologist, Mink Radiologic Imaging; Consulting Staff, Department of Radiology, Antelope Valley Medical Center Editors: Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Wilfred CG Peh, MD, MBBS, FRCP(Glasg), FRCP(Edin), FRCR, MHSM, Clinical Professor, Faculty of Medicine, National University of Singapore; Senior Consultant Radiologist, Programme Office, Singapore Health Services; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Felix S Chew, MD, MBA, EdM, Professor, Department of Radiology, Vice Chairman for Radiology Informatics, Section Head of Musculoskeletal Radiology, University of Washington Author and Editor Disclosure Synonyms and related keywords: plasma cell myeloma, myeloma, Bence-Jones protein, light chains, heavy chains, monoclonal gammopathy of unknown significance, MGUS, plasmacytoma, hypergammaglobulinemia, POEMS syndrome INTRODUCTIONSection 2 of 12
  BackgroundMultiple myeloma is the most common primary neoplasm of the skeletal system. The disease is a malignancy of plasma cells. Radiologically, multiple destructive lesions of the skeleton as well as severe demineralization characterize multiple myeloma. The etiology of the disease is the monoclonal proliferation of B cells, with a resultant increase of a single immunoglobulin and its fragments in the serum and urine. Electrophoretic analysis shows increased levels of immunoglobulins in the blood as well as light chains (Bence-Jones protein) in the urine (see Pathophysiology). (See also the eMedicine articles Multiple Myeloma [Hematology] and Myeloma [Radiology].) The marrow infiltration process may involve any bone, but the predominant sites include the vertebral column, ribs, skull, pelvis, and femora (axial skeleton). Although the osseous structures may appear radiographically normal or simply osteopenic, the classic appearance is of multiple, discrete, small, lytic lesions. Occasionally, a single lytic lesion is discovered and is termed a plasmacytoma (solitary myeloma). Patients with a single focus of disease often progress to multiple sites of myelomatous involvement. For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Myeloma. PathophysiologyPlasma cells are a subset of B cells, which are the producers of humoral immunity factors termed antibodies. Antibody molecules are composed of 2 polypeptide chains: a light chain and a heavy chain. Cleavage results in the production of Fab and Fc fragments; the Fab fragment is termed the Bence-Jones protein and is found in the urine of patients with myeloma. An individual plasma cell can produce antibody molecules of only a single immunoglobulin to combine with a single antigen. As such, a plasma cell is termed monoclonal. Most infections produce a polyclonal response because multiple antigens are present on a single bacillus or virus and activate multiple plasma cells. Electrophoresis during infections demonstrates an increase in multiple types of proteins as a result of the multiple humoral and cellular products that are produced to combat the invading organism. However, if malignant transformation occurs in a single plasma cell, its clones produce only a single type of immunoglobulin, and electrophoresis demonstrates a monoclonal peak that corresponds to this particular immunoglobulin. Infection, as well as collagen vascular disorders, rheumatoid arthritis, and ulcerative colitis, can also produce diffuse hypergammaglobulinemia. Waldenström macroglobulinemia, leukemia, lymphoma, and myeloma produce monoclonal peaks. (See also the eMedicine article Waldenstrom Hypergammaglobulinemia.) If a monoclonal protein elevation is discovered in a patient and additional tests do not reveal an underlying etiology (as they often do not), the condition is termed monoclonal gammopathy of undetermined significance. Most of these patients do not progress to multiple myeloma, but they must be followed up regularly to evaluate for an increase in monoclonal protein levels or the development of lytic bone lesions. The cause of multiple myeloma is unknown. One theory is chronic antigenic stimulation of a plasma cell, which results in transformation and the development of myeloma. However, once a plasma cell is transformed, it is known to produce innumerable clones, which spread hematogenously to other myelogenous areas. Once there, these neoplastic cells form sheets that replace the normal bone marrow. In addition, the myeloma cells produce osteoclast-stimulating factor, a cytokine that results in bone destruction. The plasma cell activating factor interleukin-6 (IL-6) is found within bone marrow, resulting in plasma cell proliferation. The osteoblastic response in myeloma tends to be suppressed, resulting in the severe demineralization and bone destruction that are characteristic of the disease. Secondary hypercalcemia is present. FrequencyUnited StatesThe annual incidence of multiple myeloma is approximately 4.4 cases per 100,000 persons.1, 2 Multiple myeloma is responsible for 10-20% of hematologic malignancies.1, 2 InternationalNo exact figures are available internationally. The incidence of multiple myeloma is believed to be the same as in the United States, but this disease is diagnosed less frequently elsewhere. Mortality/MorbidityIn 1975, Durie and Salmon proposed the initial clinical staging system for multiple myeloma.3 Measured myeloma cell mass was correlated with 5 clinical features as follows:
Using these 5 features, a 3-stage system was proposed that divided patients into those with low, intermediate, and high myeloma cell burden.3
In constructing this staging system, researchers found that stage I patients had a median survival of 191 months, stage II patients survived 11-54 months, and stage III patients survived 5-34 months. In the United States, approximately 10,000 persons per year die of multiple myeloma. Without treatment, most patients die in less than 1 year; with treatment, life expectancy may be extended 2-3 years. RaceMultiple myeloma accounts for 10% of all hematologic malignancies in whites and 20% in blacks.1 The reason for the apparent racial predilection for blacks is unknown. SexMen appear to be at an increased risk of multiple myeloma. The male-to-female ratio is estimated to be 1.4:1.1, 2 AgeMultiple myeloma is a disease of older people. The majority of patients are older than 65 years.4 Only 1% of patients with multiple myeloma are younger than 40 years.4 The disease is rare in children. AnatomyMultiple myeloma is a diffuse disease of the bone marrow. Almost 90% of patients with myeloma have osseous involvement. Although any bone can be affected, 4 distinct radiographic patterns of involvement are seen, including (1) normal bone mineralization without a discrete lytic lesion, (2) diffuse demineralization and no lytic lesion, (3) a single lesion (plasmacytoma), and (4) widespread lytic lesions. The predominant sites of involvement are within the axial skeleton and include the vertebral column, ribs, skull, pelvis, and femora. Most patients have either a number of lytic foci or diffuse demineralization at diagnosis. Fewer than 10% of patients with multiple myeloma are diagnosed with only a plasmacytoma found on radiography. Interestingly, extraosseous myeloma deposits are occasionally found, most commonly in the lungs, nasopharynx, or paranasal sinuses. Clinical DetailsThe underlying pathology of multiple myeloma is expansion of a single line of plasma cells that replace normal bone marrow and produce monoclonal immunoglobulins. As a result, in more than 80% of patients, the disease manifests with bone destruction and pain. Because bone loss occurs mostly in the axial skeleton, patients with myeloma are at risk for compression fractures of the spine and pathologic fractures of the major weight-bearing bones of the body. The classic presentation is low back pain in an older man, with resultant discovery of demineralization or a myelomatous deposit. The classic presentation has dropped to a frequency of 37% from a high of almost 70% in the 1960s, which may be related to increased surveillance for other diseases and the incidental discovery of myeloma or may be a result of increased awareness of the nonclassic manifestations of the disease. Patients with myeloma develop disorders relating to replacement of myelogenous marrow by plasma cells. In particular, anemia is a primary manifestation of the disease (>90% of patients). Patients may also develop frequent unexplained infections that result from an inability to mount an immune response by normal plasma cells (decreased in number by the favored production of malignant myeloma cells). Generalized weakness as a result of anemia is a frequent finding, as are the neurologic symptoms believed to be related to disruption in calcium homeostasis. More than 40% of patients with myeloma develop weight loss that is related to their disease. Finally, as many as 13% of myeloma patients have bleeding disorders, mostly related to low platelet production. The diagnostic laboratory finding in myeloma is monoclonal hypergammaglobulinemia. IgG myeloma is the most common, followed by IgA myeloma. As a result of bone destruction, hypercalcemia is a common manifestation and can be difficult to manage. Other laboratory abnormalities include hyperuricemia (as a result of elevated cell turnover), elevated erythrocyte sedimentation rate (ESR), and increased levels of alkaline phosphatase. Renal disorders are a common manifestation of multiple myeloma. Myeloma cells produce large numbers of proteins. Fragmentation of some of these immunoglobulins produces a special protein (ie, Bence-Jones protein) that was elucidated in the original description of the disease. This protein, as well as others produced by the malignant plasma cells, may be deposited in the kidney tubules. The proteinemia in myeloma often exceeds the resorptive ability of the kidney, resulting in proteinuria—in particular, spillage of Bence-Jones protein. In addition, amyloidosis is a frequent finding (8-15%) in patients with myeloma and further contributes to parenchymal dysfunction. Calculi are often found because of elevated uric acid and calcium levels. All of these factors can eventually result in renal failure and death. The unequivocal diagnosis of myeloma is made when the following 3 criteria are satisfied:
Note that as many as 37% of cases are discovered in asymptomatic patients. Most commonly, examination of the blood for an unrelated reason reveals an elevated protein level and leads to the eventual diagnosis of myeloma. These patients may not always meet all 3 diagnostic criteria. Other laboratory studies have been proposed to provide an unequivocal diagnosis of myeloma, including the use of special stains and the detection of nuclear abnormalities. Beta-2 microglobulin has been shown to be the peripheral marker most associated with the activity and progression of this disease. Preferred ExaminationThe preferred initial radiographic examination for the staging and diagnosis of myeloma remains the skeletal survey. Patients suspected of having multiple myeloma based on bone marrow aspirate results or hypergammaglobulinemia should undergo a radiographic skeletal survey. Conventionally, this skeletal survey has consisted of a lateral radiograph of the skull, anteroposterior (AP) and lateral views of the spine, and AP views of the pelvis, ribs, femora, and humeri. Inclusion of these bones is important for both staging and diagnosis. The finding of more than one lytic lesion in a patient with myeloma indicates stage III disease. Focused examinations of newly painful bones are of value in assessing for impending pathologic fracture. Limitations of TechniquesThe skeletal survey has limitations. Most importantly, a large number of patients diagnosed with asymptomatic myeloma may have radiographically occult myeloma deposits. At least 30% cortical bone loss is required to visualize a destructive process, such as myeloma, with radiographs. In addition, myeloma is a disease of older patients; the disease can present with diffuse demineralization, which may be indistinguishable from the pattern found in patients with osteoporosis. Magnetic resonance imaging (MRI) has been suggested as an additional imaging examination in patients with myeloma. MRI has the advantage of rapidity and sensitivity for the presence of disease; however, specificity is limited. Some reports have suggested that an MRI examination of the spine may be of value in staging patients with myeloma because radiographically occult lesions may be found that can change therapeutic intervention. DIFFERENTIALSSection 3 of 12
Acute Lymphoblastic Leukemia Chronic Lymphocytic Leukemia Non-Hodgkin Lymphoma Osteoporosis, Involutional Waldenstrom Hypergammaglobulinemia Other Problems to Be ConsideredMetastases RADIOGRAPHSection 4 of 12
FindingsThe classic radiographic appearance of multiple myeloma is that of multiple, well-circumscribed, lytic, punched-out, round lesions within the skull, spine, and pelvis (see Images 1 and 3). The lesions tend to vary slightly in size. In addition, the bones of myeloma patients are, with few exceptions, diffusely demineralized. Because myeloma is a disease of the medullary compartment of the bone, more subtle lesions can be detected by the appearance of endosteal scalloping that is seen as slight undulation to the inner cortical margin of bone. This finding is suggestive of myelomatous involvement. Although patients with advanced and extensive myeloma tend to have a number of circumscribed lytic lesions, some may simply have diffuse osteopenia on radiography. Fewer than 10% of patients present with a single myelomatous lesion, a plasmacytoma, found on radiographs (see Image 1). These lesions are bubbly expansions of a single bone, often the ribs or posterior elements of the spine, and are occasionally associated with a soft-tissue mass. A rare form of myeloma known as POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) may demonstrate sclerotic lesions on radiographs, but this condition is responsible for fewer than 1% of myeloma cases. Radiographs of treated myeloma lesions may also show areas of abnormal bone architecture with sclerosis. Usually, little periosteal reaction is seen. Degree of ConfidenceAs many as 79% of patients with myeloma demonstrate skeletal involvement. The finding of multiple lytic lesions on a skeletal survey involves 2 primary differential considerations, including myeloma and metastases. However, when these lesions are found together with bone marrow plasmacytosis and elevated blood gamma-globulins, the diagnosis of myeloma is certain. If tests for these 2 parameters have not been performed (ie, bone marrow plasmacytosis, blood gamma-globulins), the finding of multiple lytic lesions statistically represents widespread metastatic disease in 60-70% of patients, with the remainder representing myeloma. In diffuse osteopenia found on radiography, consider the diagnosis of myeloma and perform additional tests; however, most of these patients only have age-related osteoporosis. False Positives/NegativesDiffuse osteopenia that is found on radiographs is often a source of false-negative examinations because a substantial amount of cortex must be destroyed before it becomes visible radiographically. False-positive examinations are encountered when multiple lytic lesions are found. In these patients, perform additional studies because the most likely source of this pattern is metastatic disease, not myeloma. CT SCANSection 5 of 12
FindingsComputed tomography (CT) scanning depicts osseous involvement in myeloma. However the usefulness of this modality has not been well studied, and CT scanning is not required in most patients because the standard skeletal surveys usually depict most of the lesions that CT scans can detect. The single clinical situation in which CT scan studies may be of value is in cases in which the patient has bone pain and a negative radiograph.5 In this scenario, demonstration of a myeloma lesion may alter therapy significantly. CT scanning can also guide percutaneous biopsies, especially of osseous or extraosseous lesions that are suspected of being plasmacytomas (see Image 13). MRISection 6 of 12
FindingsMRI is potentially useful for imaging multiple myeloma because of this modality's superior soft-tissue resolution. The typical MRI appearance of a myeloma deposit is a round, low signal intensity (relative to muscle) focus on T1-weighted images, which becomes high in signal intensity on T2-weighted sequences. Images 5-7 demonstrate the appearance of a typical myeloma lesion in the proximal humerus. Myeloma lesions tend to enhance somewhat with gadolinium administration. In addition, diffuse areas of replacement of the normal fatty marrow may be seen, resulting in large regions of low T1-weighted signal. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape. Degree of ConfidenceUnfortunately, almost any musculoskeletal tumor has the same signal-intensity profile and enhancement pattern as myeloma. MRI, although sensitive to the presence of disease, is not disease specific. Additional tests must be employed to diagnose myeloma, such as measurement of gamma-globulin levels and direct aspiration of bone marrow to assess for plasmacytosis. Because of this, MRI may understage or overstage patients with myeloma. In patients with extraosseous lesions, MRI may be useful to define the degree of involvement and to evaluate for cord compression. ULTRASOUNDSection 7 of 12
FindingsUltrasound is not used for the diagnosis of myeloma. NUCLEAR MEDICINESection 8 of 12
FindingsMyeloma is a disease that results in overactivity of osteoclasts and the resultant liberation of bone. Nuclear medicine bone scans rely on osteoblastic activity (bone formation) for diagnosis. As such, historically, bone scans have underestimated the extent and severity of disease and have not been used routinely.8 Degree of ConfidenceThe false-negative rate of bone scintigraphy in diagnosing multiple myeloma is high. Scans may be positive with normal radiographs, requiring another test for confirmation. ANGIOGRAPHYSection 9 of 12
FindingsAngiographic findings are nonspecific. Tumors may have a peripheral zone of increased vascularity. Generally, this technique is not used for the diagnosis of myeloma. INTERVENTIONSection 10 of 12
Myeloma is treated with chemotherapy and, possibly, radiation. CT scanning may be used for percutaneous biopsy. Vertebroplasty has been suggested as a treatment for pathologic fractures within the spine. Images 8-12 show a myeloma lesion in the left glenoid that expanded over the course of 1 year. Because the coracoid process was involved, it was selected for biopsy (see Image 13). Medical/Legal Pitfalls
MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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