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April 2001 Volume 4, Issue 4:
ASK THE EXPERTS
By Robert A. Kyle, MD
Diagnosis and Differential Diagnosis Of Multiple Myeloma
04.01.01

Multiple myeloma is a malignant disease characterized by the proliferation of a single clone of plasma cells. This clone of plasma cells proliferates in the bone marrow and frequently damages the bone resulting in pain and fractures. The plasma cells produce an excessive amount of a monoclonal (M-) protein that can lead to increased thickness of the blood (hyperviscosity) or kidney failure from light chains (Bence Jones protein). The diagnosis of multiple myeloma (MM) depends upon re-cognition of abnormal plasma cells in the bone marrow, M-protein in the serum, M-protein in the urine (Bence Jones protein), damage to the bones (lytic lesions or fractures) and a clinical picture consistent with the diagnosis.

CLINICAL FINDINGS

Bone pain is present in two-thirds of patients at the time of diagnosis and is often the first clue. It most often involves the back or ribs and may be severe and incapacitating. Pain is usually aggravated by movement and relieved by lying down. Compression fractures of the spine may occur and result in loss of height. Weakness and fatigue often occur. Occasionally an infection is the first sign of the disease. Patients with MM may present with acute or chronic kidney failure. The first manifestation may be an elevated blood calcium value which often produces weakness, fatigue, excessive urination, nausea, vomiting, constipation or confusion. 
MM involves the older patient. The average age is 65 to 70 years. Only one-fifth of patients are younger than 50 years. The most frequent physical finding is pallor which is due to anemia. Localized tenderness or tumors involving the bone may be found. Enlargement of the liver, spleen or lymph nodes are uncommon.

 LABORATORY FINDINGS
Anemia is present initially in two-thirds of patients. The white count and platelet values are usually normal or slightly decreased. Elevation of blood calcium is present in one-sixth of patients at diagnosis while decreased kidney function is present in one-fourth.


The serum protein electrophoretic pattern shows a spike or localized band in 80% of patients. This spike represents the M-protein and is most often IgG or IgA. About one-sixth of patients have no spike on the electro-phoretic pattern and many of these patients produce only light chains (Bence Jones proteins) which are promptly excreted in the urine. The urine contains a monoclonal light chain in 75% of patients. Kappa light chains are twice as common as lambda. An M-protein is found in the serum or urine in 98% of patients with MM at diagnosis. IgG and IgA myeloma have similar clinical and laboratory features at diagnosis. Patients with light-chain (Bence Jones) myeloma and IgD myeloma have a higher incidence of kidney failure, lower M-protein components, more light-chain excretion and a higher frequency of associated amyloidosis than those with IgG and IgA myeloma. It is important to remember that the size of the M-spike in the serum and the M-protein in a 24-hour urine specimen is a direct reflection of the tumor (MM) mass in the patient. Measurements of the M-proteins in the serum or urine are good indications of response of the MM to treatment or progression of disease. The protein abnormality in the blood can also be measured by determination of the IgG, IgA and IgM immunoglobulin values. The IgG, IgA and IgM values are frequently higher than those obtained by measurement of the M-spike on electrophoresis. Consequently, one should use the same technique when comparing the protein abnormality at follow-up visits. In many instances it is helpful to determine the protein abnormality by both techniques. 


Conventional x-rays show abnormalities consisting of punched-out lytic lesions, osteoporosis (thinning of bone) or fractures in 75% of patients at diagnosis. The vertebrae, skull, ribs, pelvis and proximal humeri and femora are the sites most frequently involved. Bone scans are inferior to x-rays for detection of lesions and should not be used. Magnetic resonance imaging (MRI) patterns are abnormal in 80%-90% of patients with myeloma but are expensive and we do not use them routinely. MRIs are extremely valuable when evaluating the possibility of spinal cord compression from a plasmacytoma (plasma cell tumor).
The bone marrow in MM usually contains more than 10% plasma cells but the number may range from less than 5% to almost 100%. The bone marrow involvement may be more focal than diffuse and some patients will require repeat bone marrow examinations in order to make a diagnosis. The average number of monoclonal plasma cells in the bone marrow is about 40%. This means that all of the plasma cells are producing one type of heavy chain (IgG, IgA or IgD) and one type of light chain (kappa or lambda). The plasma cells may have a lymphoid appearance and at first glance resembles lymphoma. Plasma cells may exhibit plasmablastic properties and this indicates a poorer diagnosis.

DIAGNOSIS
The following laboratory tests should be obtained when the diagnosis of MM is considered: complete history and physical examination, measurement of the serum M-protein by serum protein electro-phoresis and quantitation of IgG, IgA and IgM immunoglobulins; measurement of urine M-protein by collection of a 24-hour urine specimen and performing electrophoresis; identification of the heavy and light chain type of M-protein by immuno-fixation; measurement of hemoglobin, white count, differential and platelet levels; measurement of calcium, creatinine, and alkaline phosphatase; measurement of serum viscosity if the serum M-protein is high; bone marrow aspirate and biopsy with cytogenetic studies and plasma cell labeling if available; and x-rays of the skull, spine, ribs, pelvis, shoulders and long bones and measurement of ß2-microglobulin, C-reactive protein and lactate dehydrogenase levels as prognostic factors. 

The diagnosis of MM is often not difficult because most patients present with typical symptoms and laboratory abnormalities. Minimal criteria for the diagnosis include a bone marrow with more than 10% plasma cells or a tissue biopsy demonstrating monoclonal plasmacytosis plus one of the following: M-protein in serum (usually > 3 g/dL), M-protein in urine or lytic bone lesions. The patient must have the usual clinical features of multiple myeloma. Connective tissue disorders such as rheumatoid arthritis or its variants, metastatic cancer, lymphoma, leukemia and chronic infections must be excluded. 

DIFFERENTIAL DIAGNOSIS
The main conditions to consider in the differential diagnosis are monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), primary amyloidosis (AL), and metastatic cancer. In MGUS, the M-component is less than 3 g/dL, the bone marrow contains fewer than 10% plasma cells, skeletal x-rays show no osteolytic lesions or fractures and there is no anemia, elevation of serum calcium or kidney failure. Patients with SMM have an M-protein value greater than 3 g/dL or a bone marrow containing more than 10% plasma cells. The patient is asymptomatic and has no anemia, hypercalcemia, kidney failure or bone lesions.

The size of the serum M-protein, the amount of M-protein in the urine and the number of plasma cells in the bone marrow are helpful in differentiating MGUS and SMM from MM. If the serum M-spike is 5 or 6 g/dL, or if the urine contains 4 or 5 grams of Bence Jones protein or the bone marrow plasma cell content is 60% or 70%, the likelihood of MM is very high. However, many patients have a serum M-protein of 3-4 g/dL, urine protein of more than 100 mg/24 h or a bone marrow containing 15%-20% plasma cells. These patients present a challenge from the diagnostic standpoint.

The presence of a serum M-protein of greater than 3 g/dL usually indicates MM but some patients may have SMM and remain stable for long period. The level of uninvolved or background immunoglobulins may help in differentiating benign from malignant disease. In most patients with MM, levels of normal or uninvolved immunoglobulin are reduced but a similar reduction also occurs in about 40% of patients with MGUS. The presence of monoclonal light chains in the urine of a patient with a monoclonal gammopathy suggests a malignant process. However, it is not uncommon to find patients with MGUS who have a small monoclonal light chain in the urine and remain stable for many years. Usually the presence of >10% plasma cells in the bone marrow indicates MM but some patients with a greater degree of plasmacytosis may remain stable for long intervals. Generally the morphologic appearance of the plasma cells is of little help in differentiating malignant from benign disease. The presence of lytic bone lesions is strong evidence of MMbut metastatic cancer may produce lytic lesions and be associated with an unrelated MGUS. Although ß2-microglobulin level is an important prognostic factor, it is not useful in differentiating MM from SMM or MGUS. 

The plasma cell labeling index is a measurement of the growth rate of the plasma cells and is helpful in differentiating MGUS or SMM from MM. When the plasma cell labeling index is elevated, the patient either has MM or will develop it within a short period of time. However, 40% of patients with symptomatic MM requiring therapy have a normal plasma cell labeling index so it has major shortcomings in the differential diagnosis. The plasma cell labeling index of peripheral blood plasma cells correlates well with the bone marrow labeling index and is useful. Monoclonal plasma cells can be detected in the peripheral blood of almost 80% of patients with active multiple myeloma. Patients with MGUS or SMM have few or no circulating plasma cells.

In summary, no single technique reliably differentiates a patient with MGUS or SMM from one with MM. Not all patients who fulfill the minimal criteria for the diagnosis of MM should be treated. Therapy should not be started until the patient is symptomatic or has significant abnormalities such as anemia, kidney failure, hypercalcemia or bone lesions. If there are doubts about whether to begin chemotherapy immediately, one should withhold treatment and reevaluate the patient in 2 or 3 months. Some patients may remain stable for long periods.


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