Multiple Myeloma Workup

  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: May 8, 2012
 

Approach Considerations

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

The 2009 International Myeloma Workshop developed guidelines for standard investigative workup in patients suspected to have multiple myeloma. These guidelines included the following:[15]

  • 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
  • MRI
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Complete Blood Count

Perform a complete blood count (CBC) to determine if the patient has anemia, thrombocytopenia, or leukopenia. The CBC and differential may show pancytopenia, abnormal coagulation, and an increased erythrocyte sedimentation rate (ESR). The reticulocyte count is typically low. Peripheral blood smears may show Rouleau formation.

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Metabolic Panel

Obtain a comprehensive metabolic panel to assess levels of total protein, albumin and globulin, blood urea nitrogen (BUN), creatinine, and uric acid (uric acid will be high 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).

The 2011 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines on Oncology, Multiple Myeloma Version recommend the use of serum free light chain assay as well as fluorescence in situ hybridization (FISH) for 1q21 amplification as part of the initial diagnostic workup.[16]

Chemical screening, including calcium and creatinine SPEP, immunofixation, and immunoglobulin quantitation, may show azotemia, hypercalcemia, an elevated alkaline phosphatase level, and hypoalbuminemia. A high lactic 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

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.[12] (See Prognosis.) The prognosis of patients with MM and impaired renal function is reduced.

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C-Reactive Protein

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.[12] (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.

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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 patients, according to an International Myeloma Working Group consensus statement.[17]

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 lyRadiograph 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.

Conventional plain radiography can usually depict lytic lesions. Such lesions appear as multiple, rounded, punched-out areas found 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.[18, 19] 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.[19] 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.[17]

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.[20]

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 ofBone 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.

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 malignaBone 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.

Analysis of bone biopsy specimens may reveal plasmacytic, mixed cellular, or plasmablastic histologic findings. With the plasmacytic type, median survival is approximately 39.7 months. With the mixed cellular type, survival is 16.1 months, and with the plasmablastic type, survival is 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, 2 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.[21, 22]

Salmon-Durie staging system

The Salmon-Durie classification of MM is based on 3 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 greater than 10 g/dL
  • Serum calcium value less than 12 mg/dL (normal)
  • Normal bone structure (scale 0) or only a solitary bone plasmacytoma on radiographs
  • Low M-component production rates (IgG value less than 5 g/dL, IgA value less than 3 g/dL, urine light-chain M component on electrophoresis less than 4 g/24 h)

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

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

  • Hemoglobin value equal to 8.5 g/dL
  • Serum calcium value greater than 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 3 stages.

Stage I consists of the following:

  • Beta-2 microglobulin less than or equal to 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
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Contributor Information and Disclosures
Author

Karen Seiter, MD  Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Eisai Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching

Coauthor(s)

Dhaval Shah, MD  Fellow, Department of Hematology/Oncology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Sara J Grethlein, MD  Senior Attending Physician, Cancer Treatment Center, Bassett Healthcare Network

Sara J Grethlein, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Nothing to disclose.

Seema S Rizvi, MD  Associate Medical Director, Lutheran Care Center

Seema S Rizvi, MD is a member of the following medical societies: American Academy of Family Physicians and American Medical Association

Disclosure: Nothing to disclose.

Lilian M Thomas, MD  Fellow, Department of Hematology/Oncology, State University of New York Upstate Medical University

Lilian M Thomas, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Koyamangalath Krishnan, MD, FRCP, FACP  Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Harris Gellman, MD  Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami, Leonard M Miller School of Medicine

Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, and Arkansas Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

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Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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.
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.
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.
 
 
 
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