Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. Its prognosis, despite therapy, is generally poor, and treatment may involve chemotherapy and stem cell transplant. It is part of the broad group of diseases called hematological malignancies.

Clinical features

 Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions. Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.

 

Bone pain 

Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to proliferation of tumor cells and release of IL-6, also known as osteoclast activating factor (OAF), which stimulates osteoclasts to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show a "punched-out" resorptive lesions. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.

 Infection

 The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S pneumoniae, S aureus, and K pneumoniae, while common pathogens causing pyelonephritis include E coli and other gram-negative organisms. The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies.

 Renal failure

 Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

 Anemia

 The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

 Neurological symptoms

 Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.

  

Diagnosis

 Investigations

 The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein which is a urinary paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).

 In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).

 Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.

 

Workup

 The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull). Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas. 

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative. Cytogenetics may also be performed in myeloma for prognostic purposes. 

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and β2-microglobulin which provides prognostic information. On peripheral blood smear the rouleaux formation of red blood cells is commonly seen.

 The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.

 

Diagnostic criteria

 In 2003, the International Myeloma Working Group agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance):

     * Symptomatic myeloma:

         1. Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)

         2. A monoclonal protein (paraprotein) in either serum or urine

         3. Evidence of end-organ damage (related organ or tissue impairment, ROTI):

                o Hypercalcemia (corrected calcium >2.75 mmol/L)

                o Renal insufficiency attributable to myeloma

                o Anemia (hemoglobin <10 g/dL)

                o Bone lesions (lytic lesions or osteoporosis with compression fractures)

                o Frequent severe infections (>2 a year)

                o Amyloidosis of other organs

                o Hyperviscosity syndrome

    * Asymptomatic myeloma:

         1. Serum paraprotein >30 g/L AND/OR

         2. Clonal plasma cells >10% on bone marrow biopsy AND

         3. NO myeloma-related organ or tissue impairment

    * Monoclonal gammopathy of undetermined significance (MGUS):

         1. Serum paraprotein <30 g/L AND/OR

         2. Clonal plasma cells <10% on bone marrow biopsy AND

         3. NO myeloma-related organ or tissue impairment

 Related conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g. AL amyloidosis), and POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).

 

Staging

 International Staging System

 The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2003 :

     * Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL

    * Stage II: β2M < 3.5 and albumin < 3.5; or β2M between 3.5 and 5.5

    * Stage III: β2M > 5.5

 Durie-Salmon staging system

 First published in 1975, the Durie-Salmon staging system is still in use, but has largely been superseded by the simpler ISS:

     * stage 1: all of

          o Hb > 10g/dL

          o normal calcium

          o Skeletal survey: normal or single plasmacytoma or osteoporosis

          o Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA

          o Urinary light chain excretion < 4 g/24h

    * stage 2: fulfilling the criteria of neither 1 nor 3

    * stage 3: one or more of

          o Hb < 8.5g/dL

          o high calcium > 12mg/dL

          o Skeletal survey: 3 or more lytic bone lesions

          o Serum paraprotein >7g/dL if IgG, > 5 g/dL if IgA

          o Urinary light chain excretion > 12g/24h

 Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:

     * A: serum creatinine < 2mg/dL (< 177 umol/L)

    * B: serum creatinine > 2mg/dL (> 177 umol/L)

 

Pathophysiology

 Multiple myeloma develops in post-germinal center B lymphocytes.

 A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases. 

Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased.

The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.

 

Epidemiology

There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the average survival at diagnosis is about three years. 

Multiple myeloma is the second most prevalent blood cancer (10%) after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset. 

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.

 

 

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