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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Hematology

      Multiple Myeloma Workup

      Updated: Sep 13, 2023
      • Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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      Workup

      Approach Considerations

      The International Myeloma Workshop developed guidelines for standard investigative workup in patients suspected to have multiple myeloma. These guidelines include the following: [1]

      • Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)
      • Serum-free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)
      • Bone marrow aspiration and/or biopsy
      • Serum beta-2 microglobulin, albumin, and lactate dehydrogenase measurement
      • Standard metaphase cytogenetics
      • Fluorescent in situ hybridization
      • Skeletal survey
      • Magnetic resonance imaging

      Consider the risk of acute kidney injury, especially in the setting of contrast medium injection for imaging studies. Take care to limit patients’ exposure and maintain hydration.

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      Blood Studies

      Perform a complete blood count (CBC) to determine if the patient has anemia, thrombocytopenia, or leukopenia. The CBC and differential may show pancytopenia. The reticulocyte count is typically low. Peripheral blood smears may show rouleau formation.

      The erythrocyte sedimentation rate (ESR) is typically increased. Coagulation studies may yield abnormal results.

      Obtain a comprehensive metabolic panel to assess levels of the following:

      • Total protein, albumin, and globulin
      • Blood urea nitrogen (BUN) and creatinine
      • Uric acid (will be elevated if the patient has high cell turnover or is dehydrated)
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      Urine Collection

      Obtain a 24-hour urine collection for quantification of the Bence Jones protein (ie, lambda light chains), protein, and creatinine clearance. Quantification of proteinuria is useful for the diagnosis of MM (>1 g of protein in 24 h is a major criterion) and for monitoring the response to therapy. Creatinine clearance can be useful for defining the severity of the patient’s renal impairment.

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      Electrophoresis and Immunofixation

      Serum protein electrophoresis (SPEP) is used to determine the type of each protein present and may indicate a characteristic curve (ie, where the spike is observed). Urine protein electrophoresis (UPEP) is used to identify the presence of the Bence Jones protein in urine. Immunofixation is used to identify the subtype of protein (ie, IgA lambda).

      National Comprehensive Cancer Network (NCCN) guidelines also recommend the use of serum free light chain assay and plasma cell fluorescence in situ hybridization (FISH) for del 13, del 17p13, t(4;14), t(11;14), 1q21 amplification as part of the initial diagnostic workup. [2]

      Chemical screening, including calcium and creatinine SPEP, immunofixation, and immunoglobulin quantitation, may show azotemia, hypercalcemia, an elevated alkaline phosphatase level, and hypoalbuminemia. A high lactate dehydrogenase (LDH) level is predictive of an aggressive lymphomalike course.

      SPEP is a useful screening test for detecting M proteins. An M component is usually detected by means of high-resolution SPEP. The kappa-to-lambda ratio has been recommended as a screening tool for detecting M-component abnormalities. An M-component serum concentration of 30 g/L is a minimal diagnostic criterion for MM. In about 25% of patients, M protein cannot be detected by using SPEP.

      Routine urinalysis may not indicate the presence of Bence Jones proteinuria. Therefore, a 24-hour urinalysis by means of UPEP or immunoelectrophoresis may be required. UPEP or immunoelectrophoresis can also be used to detect an M component and kappa or lambda light chains. The most important means of detecting MM is electrophoretic measurement of immunoglobulins in both serum and urine.

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      Quantitative Immunoglobulin Levels (IgG, IgA, IgM)

      Suppression of nonmyelomatous immunoglobulin is a minor diagnostic criterion for MM. The level of MM protein (ie, M protein level), as documented by the immunoglobulin level, can be useful as a marker to assess the response to therapy.

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      Beta-2 Microglobulin and C-Reactive Protein

      Beta-2 microglobulin is a surrogate marker for the overall body tumor burden. The level of beta-2 microglobulin is increased in patients with renal insufficiency without MM, which is one reason that it is a useful prognosticator in MM. [21] (See Prognosis.) Patients with MM and impaired renal function have a worse prognosis.

      C-reactive protein (CRP) is a surrogate marker of interleukin (IL)-6 activity. IL-6 is often referred to as the plasma cell growth factor. Like beta-2 microglobulin, CRP is useful for prognostication. [21] (See Prognosis.)

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      Serum Viscosity

      Check the serum viscosity in patients with central nervous system (CNS) symptoms, nosebleeds, or very high M protein levels. These findings may indicate hyperviscosity syndrome.

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      Radiography

      Simple radiography is indicated for the evaluation of skeleton lesions, and a skeletal survey is performed when myeloma is in the differential diagnosis. Plain radiography remains the gold standard imaging procedure for staging newly diagnosed and relapsed myeloma, according to an International Myeloma Working Group consensus statement. [25]

      Perform a complete skeletal series at diagnosis of MM, including the skull (a very common site of bone lesions in persons with MM; see the image below), the long bones (to look for impending fractures), and the spine.

      Radiograph of the skull demonstrating a typical ly Radiograph of the skull demonstrating a typical lytic lesion in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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      Conventional plain radiography can usually depict lytic lesions. Such lesions appear as multiple, rounded, punched-out areas, most often in the skull, vertebral column, ribs, and/or pelvis. Less common but not rare sites of involvement include the long bones. Plain radiographs can be supplemented by computed tomography (CT) scanning to assess cortical involvement and risk of fracture. Diffuse osteopenia may suggest myelomatous involvement before discrete lytic lesions are apparent.

      Findings from this evaluation may be used to identify impending pathologic fractures, allowing physicians the opportunity to repair debilities and prevent further morbidity.

      Also see the topic Imaging Multiple Myeloma.

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      Magnetic Resonance Imaging

      Magnetic resonance imaging (MRI) is useful in detecting thoracic and lumbar spine lesions, paraspinal involvement, and early cord compression. Findings from MRI of the vertebrae are often positive when plain radiographs are not. MRI can depict as many as 40% of spinal abnormalities in patients with asymptomatic gammopathies in whom radiographic studies are normal. For this reason, evaluate symptomatic patients with MRI to obtain a clear view of the spinal column and to assess the integrity of the spinal cord.

      Also see the topic Imaging Multiple Myeloma.

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      Positron Emission Tomography

      Comparative studies have suggested the possible utility of positron emission tomography (PET) scanning in the evaluation of MM. [26, 27] For example, a comparison study of PET scanning and whole-body MRI in patients with bone marrow biopsy-proven multiple myeloma found that although MRI had higher sensitivity and specificity than PET in the assessment of disease activity, when used in combination and with concordant findings, the 2 modalities had a specificity and positive predictive value of 100%.

      These researchers suggest that the combination of modalities may be valuable for assessing the effectiveness of treatment, when aggressive and expensive regimens are used. [27] However, PET scanning has not yet been integrated into standard practice. The International Myeloma Working Group notes the potential usefulness of PET scanning in selected patients but suggests that such studies ideally should be performed in the context of a clinical trial. [25]

      A study by Zamagni et al found that 18-F fluorodeoxyglucose (FDG) PET/CT scan findings were reliable predictors of prognosis among patients with multiple myeloma who had undergone thalidomide-dexamethasone induction therapy and double autotransplantation. [28]

      Also see the topic Imaging Multiple Myeloma.

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      Bone Scan

      Do not use bone scans to evaluate MM. Cytokines secreted by MM cells suppress osteoblast activity; therefore, typically, no increased uptake is observed. On technetium bone scanning, more than 50% of lesions can be missed.

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      Aspiration and Biopsy

      MM is characterized by an increased number of bone marrow plasma cells. Plasma cells show low proliferative activity, as measured by using the labeling index. This index is a reliable parameter for the diagnosis of MM. High values are strongly correlated with progression of the disease.

      Obtain bone marrow aspirate and biopsy samples from patients with MM to calculate the percentage of plasma cells in the aspirate (reference range, up to 3%) and to look for sheets or clusters of plasma cells in the biopsy specimen. Bone marrow biopsy enables a more accurate evaluation of malignancies than does bone marrow aspiration.

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      Histologic Findings

      Plasma cells are 2-3 times larger than typical lymphocytes; they have eccentric nuclei that are smooth (round or oval) in contour with clumped chromatin and have a perinuclear halo or pale zone (see the image below). The cytoplasm is basophilic.

      Bone marrow aspirate demonstrating plasma cells of Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
      View Media Gallery

      Many MM cells have characteristic, but not diagnostic, cytoplasmic inclusions, usually containing immunoglobulin. The variants include Mott cells, Russell bodies, grape cells, and morula cells. Bone marrow examination reveals plasma cell infiltration, often in sheets or clumps (see the image below). This infiltration is different from the lymphoplasmacytic infiltration observed in patients with Waldenstrom macroglobulinemia.

      Bone marrow biopsy demonstrating sheets of maligna Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
      View Media Gallery

      Analysis of bone biopsy specimens may reveal plasmacytic, mixed cellular, or plasmablastic histologic findings. Approximate median survival by histologic type is as follows:

      • Plasmacytic - 39.7 months
      • Mixed cellular - 16.1 months
      • Plasmablastic - 9.8 months
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      Cytogenetic Analysis

      Cytogenetic analysis of the bone marrow may contribute significant prognostic information in multiple myeloma. The most significant cytogenetic abnormality appears to be deletion of 17p13. This abnormality is associated with shorter survival, more extramedullary disease, and hypercalcemia. This locus is the site of the TP53 tumor suppressor gene. Chromosome 1 abnormalities and c-myc defects are also significant prognostic factors in multiple myeloma.

      Although not as well defined as in other hematologic malignancies, such as acute leukemia, risk-adapted therapy based on cytogenetic abnormalities is at the forefront of myeloma research.

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      Staging

      Staging is a cumulative evaluation of all of the diagnostic information garnered and is a useful tool for stratifying the severity of patients’ disease. Currently, two staging systems for multiple myeloma are in use: the Salmon-Durie system, which has been widely used since 1975; and the International Staging System, developed by the International Myeloma Working Group and introduced in 2005. [29, 30]  A revision of the International Staging System, published in 2015, added genetic information to the standard laboratory tests. [31]  See also Multiple Myeloma Staging.

      Salmon-Durie staging system

      The Salmon-Durie classification of MM is based on three stages and additional subclassifications.

      In stage I, the MM cell mass is less than 0.6 × 1012 cells/m2, and all of the following are present:

      • Hemoglobin value >10 g/dL
      • Serum calcium value < 12 mg/dL (normal)
      • Normal bone structure (scale 0) or only a solitary bone plasmacytoma on radiographs
      • Low M-component production rates (IgG value < 5 g/dL, IgA value < 3 g/dL, urine light-chain M component on electrophoresis < 4 g/24 h)

      In stage II, the MM cell mass is 0.6-1.2 × 1012 cells/m2 or more. The other values fit neither those of stage I nor those of stage III.

      In stage III, the MM cell mass is >1.2 × 1012 cells/m2, and all of the following are present:

      • Hemoglobin value < 8.5 g/dL
      • Serum calcium value >12 mg/dL
      • Advanced lytic bone lesions (scale 3) on radiographs
      • High M-component production rates (IgG value greater than 7 g/dL, IgA value greater than 5 g/dL, urine light-chain M component on electrophoresis greater than 12 g/24 h)

      Subclassification A includes relatively normal renal function (serum creatinine value < 2 mg/dL), whereas subclassification B includes abnormal renal function (serum creatinine value > 2 mg/dL)

      Median survival is as follows:

      • Stage I, >60 months
      • Stage II, 41 months
      • Stage III, 23 months

      Disease in subclassification B has a significantly worse outcome (eg, 2-12 mo survival in 4 separate series).

      International Staging System

      The International Staging System of the International Myeloma Working Group is also based on three stages.

      Stage I consists of the following:

      • Beta-2 microglobulin ≤3.5 g/dL and albumin ≥3.5 g/dL
      • CRP ≥4.0 mg/dL
      • Plasma cell labeling index < 1%
      • Absence of chromosome 13 deletion
      • Low serum IL-6 receptor
      • Long duration of initial plateau phase

      Stage II consists of the following:

      • Beta-2 microglobulin level ≥3.5 to < 5.5 g/dL, or
      • Beta-2 microglobulin < 3.5 g/dL and albumin < 3.5 g/dL

      Stage III consists of the following:

      • Beta-2 microglobulin of 5.5 g/dL or more

      Median survival is as follows:

      • Stage I, 62 months
      • Stage II, 44 months
      • Stage III, 29 months

      Revised International Staging System

      In the 2015 revision of the International Staging System (ISS) , stage I comprises all of the following:

      • ISS stage I  
      • Standard-risk chromosomal abnormalities by fluorescence in situ hybridization (FISH)(ie, no high-risk)
      • Serum lactate dehydrogenase (LDH) level at or below the upper limit of normal

      Stage II consists of all other possible combinations of ISS criteria, chromosomal abnormalities, and LDH other than those of stage I or III.

      Stage III consists of the following:

      • ISS stage III and 
      • High-risk chromosomal abnormalities by FISH (ie, presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)) or
      • Serum LDH level above the upper limit of normal          
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