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Diagnosis and differential diagnosis of multiple myelomas

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  • Revised on: 2020-08-06

The possible presence of multiple myelomas is often suspected because of one of the following clinical presentations.

  • Bone pain in which lytic lesions are discovered
  • An increased level of total serum protein (hyperproteinemia) and/or the presence of a monoclonal protein in the urine or plasma
  • Hypercalcemia which is either symptomatic or discovered incidentally
  • Acute renal failure with a bland urinalysis or rarely the nephrotic syndrome due to concurrent primary amyloidosis
  • Systemic signs or symptoms are suggestive of malignancy such as unexplained anemia.

This article will review the differential diagnosis of multiple myelomas and the methods used to establish the diagnosis.

Diagnosis and Staging Criteria of multiple myelomas

The minimal criteria for the diagnosis of multiple myelomas include

  • A bone marrow containing more than 10 percent plasma cells or a plasmacytoma plus at least one of the following:
  • An M-protein in the serum (usually >3 g/dL)
  • An M-protein in the urine
  • Lytic bone lesions.

In addition, the patient must have the usual clinical features of multiple myeloma.

Connective tissue disorders, metastatic carcinoma, lymphoma, and leukemia may share some of the features of multiple myeloma and must be excluded in the differential diagnosis.

In addition, multiple myeloma must be differentiated from monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.

The Durie-Salmon clinical staging system is based upon factors correlating with tumor cell mass. While it is a standardized system for the staging of multiple myeloma, it has a number of shortcomings relating to prognosis and survival.

Plasma cell leukemia – Plasma cell leukemia is a rare disease variant, occurring in two to four percent of all cases of MM. The diagnosis is made when the absolute plasma cell count exceeds 2,000/µL, along with a neoplastic proliferation of monoclonal plasma cells

Approximately 60 percent of the cases present as a primary disease, with an advanced and aggressive clinical presentation (eg, extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, and renal failure), along with increased numbers of circulating plasma cells.

Chemotherapy with melphalan and prednisone is inferior to treatment with combination chemotherapy. Due to the poor prognosis, high dose chemotherapy with stem cell rescue should be offered to affected patients.

Laboratory Tests

The patients in whom multiple myelomas are suspected should have a complete history and physical examination. In addition, the following laboratory tests should be obtained:

  • A complete blood count and differential with a peripheral blood smear
  • The chemistry screen must include measurements of serum calcium and creatinine
  • Serum protein electrophoresis with immunofixation or immunoelectrophoresis and quantitation of immunoglobulins
  • Serum viscosity should be measured if the M-protein concentration is high or there are symptoms of hyperviscosity
  • Routine urinalysis and a 24-hour urine collection for electrophoresis and immunofixation
  • A metastatic bone survey including the humeri and femurs
  • Plasma cell labeling index which is useful in differentiating between benign and malignant disease and is also a powerful prognostic factor.

Care is required in interpreting the urinary findings. Patients with multiple myelomas may excrete an excess of monoclonal light chains in the urine; such patients are at risk for acute renal failure due to cast nephropathy. The dipstick primarily detects albumin; thus, the dipstick will not detect light chains, which can be detected by sulfosalicylic acid or a 24-hour urine collection including electrophoresis and immunofixation.

On the other hand, patients who have amyloidosis or light chain deposition disease typically have a glomerular leak with increased albumin excretion which is easily detected with the dipstick.

Cast nephropathy and amyloidosis rarely occur in the same patients because the biochemical characteristics of the individual monoclonal light chain are an important determinant of the type of renal disease that may be seen. 

Bone marrow examination – A bone marrow aspirate and biopsy are essential in the evaluation of a patient with possible multiple myelomas. The bone marrow of patients with multiple myeloma usually contains more than 10 percent plasma cells, but the number may range from less than 5 percent to almost 100 percent. The bone marrow involvement may be more focal than diffuse, and some patients may require bone marrow aspirate/biopsy from several sites in order to establish the diagnosis.

Immunoperoxidase staining can detect a monoclonal immunoglobulin in the cytoplasm of plasma cells, thereby confirming monoclonal plasma cell proliferation. This finding distinguishes the monoclonal gammopathies from reactive plasmacytosis due to autoimmune diseases, metastatic carcinoma, chronic liver disease, acquired immunodeficiency syndrome (AIDS), or chronic infection.

 Postdiagnosis and prognostic studies 

Further tests may be helpful once the diagnosis of multiple myeloma is established. Serum concentrations of beta-2 microglobulin, C-reactive protein, and lactate dehydrogenase should be measured since elevated values are associated with a worse prognosis.

 Cytogenetic studies 

Cytogenetic studies in multiple myeloma are difficult because of the low proliferative activity of plasma cells. Conventional cytogenetic studies show abnormal karyotypes in only 30 to 40 percent of patients; abnormalities have been characterized by complex karyotypes with frequent numerical and structural aberrations.

Cytogenetic abnormalities may be even more common (68 percent) and complex in the rarely encountered clinical variant of MM, plasma cell leukemia.

Newer techniques using interphase fluorescence in situ hybridization (FISH) have detected a higher frequency of abnormalities, even in patients with otherwise normal karyotypes.

 Chromosomal translocations

The most common chromosomal translocation in multiple myeloma involves band 14q32, the site of the IgH (heavy chain) locus.

Other translocations include t(11;14)(q13;32), t(8;14)(q24;q32), and chromosome 1q aberrations. Several new recurring translocations have been identified, including t(4;14)(p16.3;q32.3), t(6;14)(p25;q32) and t(14;16)(q32.3;q23)

The first of these translocations are associated with increased expression and mutations of fibroblast growth factor receptor 3; the mutated protein is active in the absence of ligand.

The second translocation is associated with overexpression of interferon regulatory factor which may promote B cell proliferation.

Differential Diagnoses

The main conditions to consider in the differential diagnosis of multiple myelomas are monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myelomas (SMM) primary amyloidosis (AL), and metastatic carcinoma.

MGUS and SMM – The differentiation of a patient with MGUS from one in whom multiple myeloma will eventually develop is impossible when a small M-protein is initially recognized. MGUS is characterized by the following findings: the absence of symptoms; M component <3 g/dL; fewer than 10 percent plasma cells in the bone marrow, and no lytic lesions, anemia, hypercalcemia, or renal insufficiency.

  • Higher concentrations of the serum M-protein are associated with a greater likelihood of malignancy. A serum M-protein concentration above 3 g/dL usually indicates overt myeloma, but some such patients remain stable during long-term follow-up.
  • A reduction in the serum concentration of normal polyclonal or background immunoglobulins is typical of malignant disease but can be seen in some patients with MGUS who remain stable.
  • The presence of monoclonal light chains in the urine (Bence Jones proteinuria) suggests a neoplastic process. However, we have seen many patients with MGUS who excreted a small amount of monoclonal light chain in the urine (<50 mg per day) and remained stable for many years.
  • More than 10 percent plasma cells in the bone marrow are characteristic of myeloma, but some patients with this finding remain stable. The morphologic appearance of the plasma cells is of little help unless the cells have plasmablastic morphologic features (eg, nucleoli), which favors the diagnosis of MM.
  • MRI of the thoracolumbar spine may be of value in distinguishing between MGUS and overt MM. In one series, thoracolumbar MRI was normal in patients with MGUS and abnormal in more than 80 percent of those with overt MM.

Other laboratory determinations, such as an elevated serum beta-2 microglobulin concentration, a low CD4 cell count, chromosomal abnormalities with FISH analysis, the presence of J chains in plasma cells, and elevated plasma cell acid phosphatase levels are unreliable for differentiation of MGUS and multiple myeloma.

Thus, the absence of IL-1-beta mRNA makes MM unlikely. Whether the presence or absence of IL-1-beta in patients with MGUS has prognostic value remains to be determined.

Smoldering multiple myelomas – Patients with an M-protein >3 g/dL and >10 percent bone marrow plasma cells fulfill the diagnostic criteria for SMM. In contrast