eMedicine Specialties > Radiology > Musculoskeletal

Multiple Myeloma

Author: Steven M Sorenson, MD, Consulting Staff, Department of Radiology, Coast Radiology Imaging and Intervention
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
Contributor Information and Disclosures

Updated: Oct 2, 2007

Introduction

Background

Multiple 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.

Pathophysiology

Plasma 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.

Frequency

United States

The 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

International

No 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/Morbidity

In 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:

• Hemoglobin level
• Serum calcium level
• Number of bone lesions on a radiographic skeletal survey
• Immunoglobulin level
• Serum creatinine level

Using these 5 features, a 3-stage system was proposed that divided patients into those with low, intermediate, and high myeloma cell burden.³

• Stage I consists of all the following:
  • Hemoglobin >10 g/dL
  • Serum calcium <12 mg/dL
  • Plasmacytoma to no lytic lesions on a skeletal survey
  • Low immunoglobulin production (immunoglobulin G [IgG] <5 g/dL or IgA <3 g/dL)
• Stage II patients are defined as fitting into neither stage I nor stage III.
• Stage III patients demonstrate one or more of the following:
  • Hemoglobin <8.5 g/dL
  • Serum calcium >12 mg/dL
  • More than one lytic bone lesion on a bone survey
  • High immunoglobulin production (IgG >7 g/dL or IgA >5 g/dL)

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.

Race

Multiple 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.

Sex

Men appear to be at an increased risk of multiple myeloma. The male-to-female ratio is estimated to be 1.4:1.^1,2

Age

Multiple 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.

Anatomy

Multiple 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.

Presentation

The 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:

• A minimum 10-15% of a bone marrow aspirate demonstrates plasma cells
• Radiographic survey demonstrates lytic lesions
• Monoclonal immunoglobulins present in the urine or blood

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 Examination

The 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 Techniques

The 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.

Differential Diagnoses

Acute Lymphoblastic Leukemia
Chronic Lymphocytic Leukemia
Non-Hodgkin Lymphoma
Osteoporosis, Involutional
Waldenstrom Hypergammaglobulinemia

Other Problems to Be Considered

Metastases
Nodular histiocytic lymphoma

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