Newly Diagnosed Patients:

What Is Multiple Myeloma - Diagnosis


Diagnosis and Staging

The diagnosis of multiple myeloma is often made incidentally during routine blood tests for other conditions. For example, the existence of anemia and a high serum protein may suggest further testing.

If myeloma is suspected, a specialist experienced in treating myeloma should be consulted to further evaluate the disease and help develop a treatment plan. The MMRF can help you locate a National Cancer Institute (NCI) designated cancer center or a myeloma specialist in your area. Patients most commonly see a hematologist/oncologist. Hematologists specialize in blood diseases and disorders, and medical oncologists treat cancer using chemotherapy. Patients may also consult with a radiation oncologist (a doctor who treats cancer using radiation therapy).

Criteria for Diagnosis

A diagnosis of multiple myeloma is difficult to make on the basis of any single laboratory test result. Accurate diagnosis generally results from consideration of a number of factors, including physical evaluation, patient history, symptoms, and lab results.

A number of laboratory tests and medical procedures are used to help confirm a diagnosis of myeloma. These tests should be conducted on all patients as part of an initial evaluation. It is very important for patients to undergo all appropriate tests, as these tests help physicians determine treatment options. Many of these tests are also used to assess the extent of disease and to plan and monitor treatment.

Standards for diagnosis currently require confirmation of 1 major and one minor criteria or 3 minor criteria in a patient displaying symptoms of myeloma.

Major criteria:

  • A biopsy-proven plasmacytoma.

  • A bone marrow sample showing 30% plasma cells.

  • Elevated monoclonal immunoglobulin levels in the blood or urine

Minor criteria:
  • A bone marrow sample showing 10%-30% plasma cells.

  • Minor monoclonal immunoglobulin levels in blood or urine

  • Imaging studies revealing holes in bones due to tumor growth

  • Antibody levels (not produced by the cancer cells) in the blood are abnormally low.

The specific levels of normal for these lab values are explained below.

Blood and Urine Tests

  • A Complete Blood Count (CBC) measures the number of red blood cells, white blood cells, and platelets in the blood, as well as the number or relative proportion of the different types of white blood cells present, to detect if any of these are outside the normal range. The types of cells reported in a CBC and their normal ranges are listed in the table below.

Normal Range of Blood Cell Counts

Count Definition Normal Range*

Erythrocytes
(RBCs)

Number of red blood cells in the blood. Red blood cells bring oxygen from the lungs to the various tissues in the body and carry carbon dioxide back to the lungs. Low numbers of red blood cells or low hemoglobin or hematocrit indicate anemia, which can cause physical and mental fatigue

Female 4.1-5.1 x 1012/L
Male 4.5-5.3 x 1012/L

Hemoglobin
(Hb)

Oxygen-carrying substance in red blood cells

Female 12 - 16 g/dL
Male 13 - 18 g/dL

Hematocrit
(HCT)

Percentage of red blood cells in the blood.

Female 36 - 46%
Male 37 - 49%

Leukocytes
(WBCs)

Number of white blood cells in the blood; counts or percentages of the individual types of blood cells are also provided. White blood cells help fight infection and remove harmful substances from the body. A low number of white cells can increase the possibility of infection

Total 3.5 - 10.5 x 109/L
Neutrophils 1.7 - 7.0
Monocytes 0.3 - 0.9
Lymphocytes0.9 - 2.9
Basophils 0.0 - 0.3
Eosinophils 0.05 - 0.5

Platelets

Number of platelets in the blood. Because platelets help blood to clot, low counts can lead to excessive bleeding

150 - 450 x 109/L

*Normal ranges may vary.


  • A Chemistry profile checks levels of various blood components such as albumin, blood urea nitrogen (BUN), calcium, creatinine, and lactate dehydrogenase (LDH). Increased BUN and creatinine indicate decreased kidney function, while LDH levels help assess tumor cell burden.


  • Serum levels of beta-2 microglobulin (ß2-M) reflect the tumor mass and are now considered a standard measure of tumor burden.


  • C-reactive protein is a surrogate marker (meaning it follows the same pattern of increased or decreased levels) for IL-6, a growth factor for myeloma cells.


  • Quantitive immunoglobulins (QIGs) measure the levels of different types of antibodies (IgG, IgA, IgM).


  • Electrophoresis (EP) measures the levels of various proteins in the blood or urine. When performed on blood, it is called serum protein electrophoresis (SPEP). When performed on urine, it is called urine protein electrophoresis (UPEP). An additional test, called an immunoelectrophoresis (IEP) or immunofixation, may also be performed to provide more specific information about the type of abnormal antibody proteins present. Assessing changes and proportions of various proteins, particularly M protein, helps track the progression of myeloma disease and response to treatment. Myeloma is characterized by a large increase in M protein.

  • 24 hour urine protein and UPEP measure the amount of the urine for patients (about 50%) who show the presence of myeloma protein in the urine. These assessments help stage the patient and assess progression of the disease and response to treatment.

  • A serum-based assay called FREELITE™, which detects and quantifies free light chains (those not associated with intact immunoglobulin), has recently become available. Evidence suggests that this test may help predict the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.



Tests Conducted on the Bone

The following tests are performed on the bone:
  • X-rays and other imaging tests can assess changes in the bone structure and determine the number and size of bone lesions.

    • All patients should have a bone (skeletal) survey, which is a series of x-rays of the skull, spine, arms, ribs, pelvis, and legs (see x-ray).

    • Some patients may also require:


    Bone marrow aspiration or bone marrow biopsy can detect an increase in the number of plasma cells in the bone marrow. An aspiration requires a sample of liquid bone marrow, and a biopsy requires a sample of solid bone tissue. The procedure for doing these tests is similar except that a biopsy involves a larger needle. In both tests, samples are taken from the hip and are examined under a microscope. In rare cases, the bone marrow sample may have to be taken from the breast bone. The percentage of plasma cells present is determined. Multiple myeloma is probable if 10% or more of the cells in the bone marrow sample are plasma cells (see figure). Chromosomal analysis by conventional karyotyping and fluorescence in situ hybridization (FISH) will be performed in the plasma cells obtained from bone marrow aspiration. The proliferative capacity of plasma cells can be obtained from the same bone marrow sample either by labeling index or by plasma cell-cycle analysis.


    Classification and Staging

    A diagnosis of myeloma is made based on the presence of an increased number of plasma cells in the bone marrow and, in most cases, the presence of excess protein (M protein) in the blood or urine. At that point, patients are generally classified into categories based on their clinical and laboratory evaluation. Patients are also staged according to the severity of their disease based on a number of criteria.

    Classification of Myeloma

    Patients may be classified into one of three myeloma categories (MGUS, Asymptomatic, and Symptomatic) to help to determine treatment options. Patients in some categories do not have to receive treatment immediately, but may receive bisphosphonates if osteoporosis is present, or other supportive care for symptoms and complications. In these cases, postponing therapy may help avoid unnecessary side effects and the risk of complications associated with chemotherapy and may also delay development of resistance to chemotherapy. Knowing your classification is very important in deciding when it is appropriate to begin treatment. Participation in a clinical trial is also an option for many patients.

    Monoclonal Gammopathy of Undetermined Significance (MGUS)

    • MGUS is a common condition where a monoclonal protein is present. However, there are no symptoms, other criteria for myeloma diagnosis are absent, and no cause for the increased protein can be identified. MGUS occurs in about 1% of the general population and in about 3% of normal individuals over 70 years of age. MGUS itself is harmless but over many years approximately 16% of individuals with MGUS will progress to a malignant plasma cell disorder. Characteristics:

      • Serum M protein <3 g/dL

      • Bone marrow plasma cells <10%

      • Absence of anemia, renal failure, hypercalcemia, lytic bone lesions

      • Disease Management - observation

    Asymptomatic Multiple Myeloma

    Patients with asymptomatic multiple myeloma have a monoclonal protein and slightly increased numbers of plasma cells in the bone marrow. They may have mild anemia and/or a few bone lesions, but do not exhibit the renal failure and frequent infections that characterize active multiple myeloma. In these patients the myeloma is static and may not progress for months or years. Asymptomatic multiple myeloma includes both Smoldering Multiple Myeloma (SMM) and Indolent Multiple Myeloma (IMM).

    • Smoldering Multiple Myeloma (SMM)

      • Characteristics

        • Serum M protein >3 g/dL and/or bone marrow plasma cells ≥10%

        • Absence of anemia, renal failure, hypercalcemia, lytic bone lesions

      • Disease Management

        • Observation with treatment beginning at disease progression

        • Bisphosphonates

        • Supportive care

        • Participation in clinical trial

    • Indolent Multiple Myeloma (IMM)

      • Characteristics

        • Stable serum/urine M protein

        • Bone marrow plasmacytosis

        • Mild anemia or few small lytic bone lesions

        • Absence of symptoms

      • Disease Management

        • Monitoring every 3 months with treatment beginning at disease progression

        • Bisphosphonates

        • Supportive care

        • Participation in clinical trial

    Symptomatic Multiple Myeloma (MM)

    Patients who present with symptoms typically have a monoclonal protein and increased numbers of plasma cells in the bone marrow. They also have anemia, kidney failure, increased levels of calcium in the blood (hypercalcemia), or bone lesions. Patients with symptomatic myeloma require immediate treatment.

    • Characteristics

      • Presence of serum/urine M protein

      • Bone marrow plasmacytosis (>30%)

      • Anemia, renal failure, hypercalcemia, or lytic bone lesions

      Staging of Myeloma

      The process of staging myeloma is crucial to developing an effective treatment plan. The staging system most widely used since 1975 has been the Durie-Salmon system, in which clinical stage of disease (stage I, II, or III) is based on four measurements: levels of M protein, the number of lytic bone lesions, hemoglobin values (a measure of the number of red blood cells in the blood), and serum calcium levels. Stages are further divided according to renal (kidney) function (classified as A or B; Table 3).

      There is somewhat of an overlap between the various myeloma categories and stages. For example, both patients with smoldering myeloma and patients with Stage I disease do not require immediate treatment, and patients with Stage II and III disease have active, symptomatic myeloma. Increasingly, physicians are relying less on the Durie-Salmon staging system and more on biologically relevant markers as prognostic indicators when making treatment choices.

      A new, simpler, more cost-effective alternative is the International Staging System (ISS). The ISS is based on the assessment of two blood test results, beta 2-microglobulin (ß2-M) and albumin, which together showed the greatest prognostic power for multiple myeloma. This system has only recently been developed, but has already been proven more sensitive in discriminating between three stages of the disease, which indicate different levels of projected survival and suggest increasingly more aggressive treatment strategies.

      The following table summarizes the staging criteria.



      The Durie-Salmon Staging System

      Stage Durie-Salmon Criteria ISS Criteria

      I

      All of the following:

      • Hemoglobin value >10 g/dL

      • Serum calcium value normal or =12 mg/dL

      • Bone x-ray, normal bone structure (scale 0) or solitary bone plasmacytoma only

      • Low M-component production rate - IgG value <5 g/dL; IgA value <3 g/dL

      Bence Jones protein <4 g/24 h

      ß2-M < 3.5 mg/dL and albumin =3.5 g/dL

      II*

      Neither stage I nor stage III

      Neither stage I nor stage III

      III

      On or more of the following:

      • Hemoglobin value <8.5 g/dL

      • Serum calcium value >12 mg/dL

      • Advanced lytic bone lesions (scale 3)

      • High M-component production rate - IgG value >7 g/dL; IgA value >5 g/dL - Bence Jones protein >12 g/24 h


      ß2-M = 5.5 mg/dL

      Durie-Salmon sub classifications (either A or B)
      A: Relatively normal renal function (serum creatinine value <2.0 mg/dL
      B: Abnormal renal function (serum creatinine value =2.0 mg/dL

      *Stage II = ß2-M <3.5 or ß2-M 3.5 - 5.5 mg/dL, and albumin <3.5 g/dL