Diagnosis

An accurate diagnosis is one of the most important aspects of a person’s medical care. Obtaining a precise diagnosis will help the doctor to:

  • Estimate how the disease will progress
  • Determine the appropriate treatment

The results of blood tests that accompany periodic medical examinations may indicate the need for further evaluation for myeloma. These include an elevated protein level, anemia and abnormalities in kidney function or calcium levels.

Bone Marrow Tests. Your doctor tests your bone marrow to look for malignant plasma cells. Bone marrow testing involves two steps usually done at the same time in a doctor's office or a hospital:

  • A bone marrow aspiration to remove a liquid marrow sample
  • A bone marrow biopsy to remove a small amount of bone filled with marrow

Diagnostic Criteria for Myeloma  

The diagnosis of myeloma depends on three main findings:

  • Malignant plasma cells: Plasma cell level of >10% in a bone marrow biopsy sample 
  • Unusually large amounts of monoclonal protein (called an “M spike”)
    • Monoclonal proteins can be either intact monoclonal immunoglobulins or immunoglobulin light chains (Bence Jones proteins) found in the blood and/or urine.
  • Evidence of end-organ damage as defined by the CRAB criteria
    • If there are not CRAB signs and/or symptoms, 60% plasma cells in the bone marrow indicates a diagnosis. 

Revised International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma

Both of the following criteria must be met:

  • Malignant plasma cells in the bone marrow ≥ 10% or presence of bony or extramedullary plasmacytoma, confirmed by biopsy
  • Any one or more of the following myeloma-defining events:
    • Evidence of end-organ damage that can be attributed to the disease: (CRAB criteria)
      • Calcium elevation—serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
      • Renal dysfunction—creatinine clearance < 40 mL per minute or serum creatinine > 177 μmol/L (> 2 mg/dL)
      • Anemia—hemoglobin concentration of > 2 g/dL below the lower limit of normal, or a hemoglobin concentration of < 10 g/dL
      • Bone lesions—one or more osteolytic lesions found on x-ray, CT or PET‑CT scans
    • Clonal plasma cells in the bone marrow ≥ 60% with or without CRAB
    • Ratio of involved/uninvolved serum free light chain ratio ≥ 100 (involved free light chain levels must be ≥ 100 mg/L)
    • One or more focal lesions found on MRI studies (at least 5 mm in size)

Monoclonal Immunoglobulins (M Protein) and Light Chains (Bence Jones Protein)

In healthy individuals, plasma cells produce proteins called “polyclonal immunoglobulins.” These are a collection of antibodies that protect the body against all kinds of different invading viruses, bacteria or other infectious agents (antigens).

In myeloma, large amounts of a single antibody are noted as a “monoclonal immunoglobulin spike” or “monoclonal spike” (M spike), indicating that the protein came from cells that originally started as single, malignant cell. 

Monoclonal protein (M protein) levels can be measured in blood and/or urine samples, and these levels generally correlate with the extent of the myeloma.

A small number of patients with myeloma have either “oligosecretory disease,” in which the detectable level of monoclonal protein is low, or “nonsecretory disease,” in which no monoclonal protein can be detected. Some of these patients can be followed with a newer blood test that measures serum free light chains, which are a small fragment of the larger intact M protein.​

An intact immunoglobulin (Ig) molecule is composed of two larger pieces (heavy chains) and two smaller pieces (light chains) that are attached to each other. There are five types of heavy chains, and each type is represented by a specific letter: IgG, IgA, IgD, IgE and IgM. There are two types of light chains, referred to as “kappa (k)” and “lambda (λ).”

This whole (intact) immunoglobulin, made of the four chains, is usually too large to pass through the kidney. Thus, it is most often present in the blood but not in the urine. When the whole immunoglobulin is present in the urine, it is usually at a low level.

In many myeloma patients, the coordinated process of making and attaching light chains and heavy chains fails in the malignant plasma cells. Unattached, “free” light chains enter the blood and are excreted rapidly in the urine. The light chain is also called the “Bence Jones protein,” named for the doctor Henry Bence Jones who studied its characteristics. When excreted in large amounts, Bence Jones proteins (free light chains) can sometimes make the urine appear foamy and they can cause injury to the kidneys.

Each plasma cell produces one of five types of antibodies: IgG, IgA, IgM, IgE or IgD, and either kappa or lambda.

Myeloma cells produce many copies of its anibody. The most common type of myeloma is IgG kappa, occurring in approximately 52 % of patients. The next most common type is light chain myeloma in which no intact immunoglobulin is produced. 

Protein Electrophoresis Tests 

Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are tests in which proteins in blood and urine samples are separated so that individual antibodies can be identified and quantified. These tests are done in conjunction with immunofixation— for example, serum immunofixation electrophoresis (SIFE), which identifies immunoglobulins in blood samples. If present, an excessive production of a monoclonal immunoglobulin may be shown in laboratory test results as a spike on a graph (M spike). Most patients with untreated myeloma have a monoclonal immunoglobulin spike in serum, urine, or both.

Serum Free Light Chain (SFLC) Assay 

Serum free light chain testing provides complementary information to the two protein electrophoresis tests: SPEP and UPEP. The SFLC assay can detect abnormal levels of free light chains, which may be an indication of a plasma cell disorder. It can also detect changes in the ratio of kappa and lambda light chain production, which indicates an excess of abnormal plasma cells.

Additional Diagnostic Tests for Myeloma

Urine Test. In some patients, the myeloma cells do not make a complete monoclonal immunoglobulin molecule with two heavy and two light chains. Instead, they only make light chains. In these cases of “light chain myeloma,” serum test results may not show the characteristic increase of M protein (M spike), but there may be large amounts of monoclonal light chains in the urine.

Testing a 24-hour urine sample allows for an accurate measurement of the level of kidney function and can indicate possible kidney damage from myeloma. When there is damage to the kidneys, other proteins, such as albumin, may also be present in the urine. Also, the level of protein being excreted in the urine and the amount of light chains can be measured. All of these measurements provide information about the extent of the disease and are useful for monitoring response to treatment.

Complete Blood Count (CBC). This test measures the numbers of red blood cells, white blood cells and platelets in the blood. These measurements indicate the degree to which the myeloma cells in the marrow are affecting normal blood cell development. Sometimes a CBC with differential (CBC with diff), a test that also measures the number of the different types of white blood cells present in the blood, is ordered.

Blood Chemistry Tests. Abnormal levels of certain chemicals may indicate that an organ is not working properly or they may be caused by cancer or other health conditions. Tests are done to measure the levels of many different substances in the blood. 

Flow Cytometry. This is a test that determines whether abnormal plasma cells are present in a liquid sample of bone marrow aspirate or blood. Rarely, plasma cells can enter into the circulation and if they represent 20 percent or more of the blood cells, the condition is called “plasma cell leukemia.” Note that the percent of plasma cells in the bone marrow, assessed by flow cytometry, is not the value used in the diagnostic criteria above. That criteria is determined by a pathologist who reviews the bone marrow aspirate slides.

Cytogenetic Analysis. Fluorescence in situ hybridization (FISH) is a type of laboratory test that uses special dyes to identify mutations of specific chromosomes in cells. Chromosomal abnormalities play a crucial role in identifying cancerous cells and determining the risk of relapse. Approximately 40 percent of myeloma cases are characterized by the presence of trisomies (three copies of a chromosome) in the malignant plasma cells, while in most of the rest there is a translocation involving chromosome 14 (the site of a gene for the immunoglobulin heavy chain).

Next-Generation Sequencing (NGS). This is a broad term encompassing a number of modern technologies that increase the speed and reduce the cost of DNA sequencing to look for mutations. NGS can identify mutations present in the genes of the myeloma cells. Since the expression levels of these genes and how mutations in them, if present, influence the behavior of the myeloma cells, these techniques may be helpful in better predicting treatment outcomes and developing new and improved targeted therapies. Next-generation sequencing is being done now on a research basis but may soon be used in routine clinical practice. 

Imaging Tests. The following imaging tests are a very important part of the diagnosis, staging and management of myeloma:

  • Bone/skeletal survey (x-rays of all the bones in the body)
  • Magnetic resonance imaging (MRI) scan
  • Whole body low-dose computed tomography (CT) scan 
  • Positron emission tomography and computed tomography (PET-CT) scan 

If you're diagnosed with myeloma, you may need to undergo more tests during or after treatment to see how the myeloma cells are responding to therapy.

In addition, doctors stage myeloma to help them decide on the best treatment plan.

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