Multiple myeloma is a malignancy of plasma cells that, in turn, are derived from B-type lymphocytes. The neoplastic plasma cells involve bone marrow and frequently produce multisystem disease. Patients are usually age 40 or older, with a peak incidence occurring in age group 60-65 years. About two thirds of the patients are male (literature range, 54%-72%). Clinically, the most common symptom is bone pain, reported in about 70%. Pathologic fractures are common. Infections are more common in myeloma (10%-52% of cases) than in the general population. The classic infecting organisms are encapsulated bacteria such as pneumoccoci and, much less frequently, Haemophilus influenzae; some reports indicate that gram-negative infections are becoming more frequent. Recurrent infections are relatively frequent. Weight loss, weakness, and various GI symptoms are found in 35%-65% of cases. Neurologic symptoms are present in 30%-50% of cases. Some are due to nerve root or spinal cord compression by myelomatous infiltrates; some to amyloid deposition, and some to peripheral neuropathy. Hepatomegaly is present in about 20% of cases (literature range, 10%-38%) and splenomegaly in about 10% (range, 5%-15%). Acute or chronic renal failure occurs in over 50% of patients. When patients over age 40 are seen because of bone pain, recurrent infection or unexplained nonpulmonary infection or fracture, myeloma should be considered.

Laboratory abnormalities

Standard laboratory test findings. Anemia is found in 60%-80% of patients. It is generally moderate in degree (although sometimes severe) and is usually of the normocytic-normochromic type. RBC rouleaux formation (RBCs adhering together like a stack of coins due to the presence of abnormal protein) in peripheral blood smears is a clue to possible myeloma and can be found in 60%-85% of cases. Frequency of rouleaux detection depends to some extent on the degree of abnormality and also on the experience and interest of the examiner. Total white blood cell (WBC) count is usually normal except during episodes of infection, with leukopenia reported in 15%-20% of cases. Although myeloma plasma cells infiltrate the bone marrow at some time during the course of the disease, ordinarily this does not result in peripheral blood plasmacytosis. In 1%-2% of patients there are more than 5% plasma cells in the peripheral blood, and some of these patients have been considered to have plasma cell leukemia. Some require as many as 20% of the peripheral blood WBCs to be plasma cells in order to make that diagnosis. Occasionally patients display some degree of myeloid cell immaturity. Thrombocytopenia is found in approximately 10% of patients.

Among other laboratory test results that may be abnormal, the ESR is usually moderately to markedly elevated (90% of patients in a large Mayo Clinic series). Hypercalcemia occurs in about 30% (literature range, 20%-50%). Azotemia is reported in 40%-55% of patients, and proteinuria is detected in 60%-90%. Hyperglobulinemia is present in approximately 60% of patients (literature range, 50%-80%) and hypogammaglobulinemia in about 10%. Serum albumin is decreased in about 50% of patients. The alkaline phosphatase level is most often normal unless a fracture is present, but reports of alkaline phosphatase abnormality in the literature range from 0%-48%. The total lactic dehydrogenase value (LDH) is elevated (according to several reports) in 24%-60% of cases; LDH isoenzyme fractionation most often shows elevated LDH-3 values. Amyloid is found in 5%-10% of cases and cryoglobulins in approximately 5%. Uric acid levels are increased in about 40% of patients.

X-ray findings. X-ray examination displays abnormality in 80%-85% of patients. The most typical finding is the “punched-out” osteolytic lesion, most commonly in the skull, vertebral spine, and pelvis. Between 6% and 25% of patients demonstrate diffuse osteoporosis as the only abnormality; the rest have various combinations of focal osteolytic lesions, osteoporosis, and pathologic fractures. Results of radionuclide bone scan are not as frequently abnormal in myeloma as in metastatic tumor involving bone.

Bone marrow diagnosis. Diagnosis of myeloma is made through bone marrow aspiration. The bone marrow of myeloma patients usually contains more than 20% plasma cells (however, criteria listed in the literature range from 5%-30%, sometimes based on presence or absence of other abnormalities such as bone lesions). If the plasma cell percentage is less than 20%, a considerable number of the plasma cells must be immature to make the diagnosis, because other diseases may be associated with an increase in mature marrow plasma cells. Ordinarily, a benign plasmacytic marrow reaction produces a plasma cell percentage less than 10%, but in some cases this figure may reach 20% and, rarely, even higher (e.g., in a few patients with human immunodeficiency virus [HIV] infection). Bone marrow aspiration is usually diagnostic by the time symptoms appear. However, about 15% of patients have less than 20% plasma cells in the marrow aspirate, and about 8% have less than 20% plus no evidence of plasma cell immaturity. Since marrow infiltration may have an irregular distribution in some patients, a repeat aspiration may be necessary. In some cases a cytologic diagnosis cannot be made until a later date. In occasional patients a bone marrow biopsy specimen may show changes suggestive of myeloma when the marrow smear is not diagnostic.

Abnormal proteins (monoclonal immunoglobulins). About 75%-80% of myeloma patients have plasma cell secretion of abnormal monoclonal serum protein with a molecular weight (160,000 daltons or 7S) typical of a normal complete immunoglobulin molecule. This has a highly concentrated appearance or spikelike densitometer pattern on electrophoresis; usually located in the gamma-globulin area, occasionally in the beta-globulin area, and rarely in the alpha-2 globulin area. Of all patients with monoclonal protein, about two thirds have myeloma. Of those myeloma patients with normal weight serum monoclonal protein, roughly 70% have monoclonal protein categorized as IgG, about 25% have IgA, and fewer than 2% have IgD or IgE.

In addition to normal weight serum monoclonal protein, many patients excrete an abnormal, incomplete, low weight protein known as Bence Jones protein. Bence Jones protein is composed only of immunoglobulin light chains and therefore has a low molecular weight (40,000 daltons, or 3.5S). Unlike normal weight monoclonal proteins, it is able to pass the glomerular filter into the urine. In most cases it is cleared rapidly from plasma; therefore, even when Bence Jones proteinuria is marked, this substance usually is not demonstrable in serum by ordinary electrophoretic techniques and frequently not even by immunoelectrophoresis. About 70%-80% of myeloma patients show Bence Jones protein on urine electrophoresis, whereas urine Bence Jones protein can be detected only in about 50% of patients using the old heat test. About 50%-60% have a normal weight serum monoclonal protein in addition to Bence Jones protein in the urine, and about 20% (literature range, 10%-26%) have Bence Jones protein in the urine as the only protein abnormality (“light chain” myeloma). Light chain myeloma is frequently associated with hypogammaglobulinemia on standard serum protein electrophoresis. Clinically, there tends to be a somewhat greater incidence of azotemia, hypercalcemia, and lytic bone lesions than in ordinary myeloma.

The classic method of detecting Bence Jones protein is by a carefully done heat coagulability test, in which the protein appears on heating to 60° C and disappears on boiling, only to reappear if the urine is cooled. As mentioned in Chapter 12, with a few exceptions the sulfosalicylic acid test result for urine protein is positive with Bence Jones protein, but dipsticks frequently give negative results. Since various technical and human factors make the heat method unreliable, urine electrophoresis is the best method for demonstrating Bence Jones protein. In a large Mayo Clinic series, 49% of myeloma patients revealed urine Bence Jones protein by heat test, whereas 75% had a Bence Jones peak in nonconcentrated urine on electrophoresis. On urine electrophoresis, Bence Jones protein appears as a single homogeneous spike similar to that of monoclonal protein in serum. The normal weight monoclonal serum proteins of myeloma usually do not appear in the urine. In many cases it is necessary to concentrate the urine (5-100 times) to detect small quantities of Bence Jones protein. Urine immunoelectrophoresis is about 5% more sensitive than standard urine protein electrophoresis.

Bence Jones protein is excreted in urine by approximately 70% (literature range, 54%-80%) of myeloma patients, about 30% (0%-78%) of patients with Waldenstrцm’s macroglobulinemia, about 20% (15%-62%) of patients with monoclonal gammapathy associated with lymphoproliferative malignancy, and about 10% (0%-24%) of patients with so-called benign (secondary and idiopathic) monoclonal gammopathy. In general, patients with benign monoclonal gammopathy and Bence Jones protein excrete only small amounts of Bence Jones protein (Ј60 mg/L). Only 2%-3% (0%-6%) of these patients excrete greater quantities. Patients with malignant gammopathies and Bence Jones proteinuria tend to excrete quantities greater than 60 mg/L. However, about 10% of myeloma patients with Bence Jones proteinuria excrete less than 60 mg/L.

About 2% (range, 1%-5%) of myeloma patients do not show detectable serum or urine monoclonal proteins or free light chains (“nonsecretory” myeloma).

Immunoglobulin D myeloma

IgD myeloma has some unusual features that are worth mentioning. This entity is rare, seen in about 1% of myeloma patients. In IgD myeloma, the light chain of the abnormal IgD molecule is lambda type in about 90% of cases, whereas in other types of myeloma about 66% are kappa and about 33% are lambda. Also, Bence Jones proteinuria occurs in more than 90% of IgD cases, compared with an incidence of about 75% in IgG and IgA myeloma (literature range, 60%-80%). It is claimed that IgD myeloma is more likely to be associated with extraosseus myeloma spread, although about 50%-75% of myeloma patients display microscopic extramedullary (nonbone) foci (predominantly in liver, spleen, and lymph nodes), which usually are not evident clinically.


A word should be said about amyloidosis. There are several categories of amyloidosis, including primary, secondary, familial, localized, and senile. The amyloid of primary amyloidosis is derived from the variable region of immunoglobulin light chains (most often lambda), and myeloma is associated with 20%-30% of these patients. Standard electrophoresis is said to detect a monoclonal peak in serum and urine in about 50% of cases, whereas immunoelectrophoresis of serum and urine is abnormal in 90% of cases. Diagnosis is made through tissue biopsy and special stains with or without polarized light. Biopsy can be obtained from clinically affected tissue (e.g., the carpal ligament in those patients with carpal tunnel syndrome) or from certain other tissues such as subcutaneous fat aspirates (in two reports, positive in 75% or more cases). However, the yield from subcutaneous fat aspiration is only about 17% if the patient has amyloid-induced carpal tunnel syndrome without any other clinical evidence of amyloidosis, and is only 0%-40% if the patient has amyloidosis but is on renal dialysis.

Solitary plasmacytoma

About 3% (literature range, 2%-5%) of patients with plasma cell dyscrasias have a single plasma cell localized tumor. There is considerable confusion in the literature as to the nomenclature of these lesions. In general, those within bone tend to be regarded as solitary myeloma, whereas those in soft tissue are usually called “extramedullary plasmacytomas.” The most common location for extramedullary plasmacytoma is the upper respiratory tract, whereas solitary bone lesions are found most often in the spine. About 60% of patients with solitary (bone) myeloma lesions when first seen have disseminated myeloma by 10 years after diagnosis. Extramedullary plasmacytomas are usually regarded as having a better prognosis than myeloma, with some being cured by therapy, some recurring, and some metastasizing or developing into myeloma in spite of treatment. In one review of the literature, only about 20% of patients with localized plasma cell tumors in bone were found to have monoclonal proteins in serum on standard electrophoresis and about 25% on immunoelectrophoresis.

Heavy chain disease

Whereas light chain myeloma involves selective production of the light chain fragment of immunoglobulin molecules, there is a rare condition known as “Franklin’s disease” (heavy chain disease) that is characterized by selective production of the heavy chain fragment. The clinical picture most often resembles that of malignant lymphoma. Bone marrow aspiration findings are variable, and lymph node biopsy may suggest lymphoma or contain a mixed cell infiltrate.

Waldenstrцm’s (primary) macroglobulinemia

Waldenstrцm’s macroglobulinemia is a lymphoproliferative disorder characterized by monoclonal IgM (molecular weight 1,000,000 daltons or 19S) production, with classic clinical features of lymphadenopathy, hepatosplenomegaly, anemia, hyperglobulinemia with rouleaux formation, and the hyperviscosity syndrome. From 10%-30% of patients with Waldenstrцm’s macroglobulinemia (literature range, 0%-60%) excrete Bence Jones protein in the urine. Although typical biopsy findings are a mixture of mature lymphocytes and plasmacytoid lymphocytes, in some cases the histologic picture is suggestive of a diffuse type of lymphocytic lymphoma. Bone marrow aspiration may yield either normal findings, nonspecific lymphoid infiltration, or lymphoma-like infiltrate. On skeletal x-ray film, punched-out osteolytic lesions of the type seen in myeloma are usually absent. The hyperviscosity syndrome consists of shortness of breath, various neurologic abnormalities, and visual difficulty with sausage-shaped segmentation of retinal veins. Serum viscosity (as measured by the Ostwald viscosimeter or other method) is increased. In some patients the disease could be interpreted as malignant lymphoma or lymphocytic leukemia with IgM production. In a few instances, plasma cells predominate, and osteolytic bone lesions compatible with an IgM myeloma are present. Since plasma cells are derived from lymphocytes, many are inclined to view these disorders as a spectrum. However, since clinicians usually insist on a specific diagnosis, the “intermediate” forms create a problem.

Idiopathic monoclonal gammopathy

Idiopathic monoclonal gammopathy is defined as a monoclonal protein detected in a person without any monoclonal protein-associated disease. There is confusion with the term “monoclonal gammopathy of uncertain significance” (MGUS), that usually includes both idiopathic monoclonal gammopathy and noneoplastic secondary gammopathies (page 252). The incidence of nonneoplastic monoclonal gammopathy apparently is increased with advanced age. Some investigators found an incidence of 0.3%-3.0% in populations tested, with the higher rates in the elderly. Using high-sensitivity detection methods, monoclonal peaks (usually small) have been reported by a few investigators in 10% or even up to 20% of persons age 75-90. In a Mayo Clinic series of 241 patients with monoclonal gammopathy of uncertain significance, 19% developed myeloma, Waldenstrцm’s, amyloidosis, or lymphoma in 10 years of follow-up, and about 25% after 20-35 years.

IgM monoclonal proteins. In one series of 430 patients who had monoclonal IgM detected, 56% had idiopathic IgM at the time of diagnosis, 17% had Waldenstrцm’s macroglobulinemia, 7% had malignant lymphoma, 5% had chronic lymphocytic leukemia, 14% had other malignant leukemias or lymphomas, and 17% had amyloidosis. About 20% of those who had idiopathic IgM eventually developed lymphocytic leukemia or lymphoma.