Blood tests protein electropherogram showing a paraprotein (peak in the gamma zone) in a person with<unk>  The globulin level may be normal in established disease. A doctor may 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. 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. In theory,<unk>  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). People without evidence of a monoclonal protein may have "nonsecretory" myeloma (not producing immunoglobulins); this represents about 3% of all people with<unk> . Additional findings may include a raised calcium level (when osteoclasts are breaking down bone, releasing it into the bloodstream), raised serum creatinine level due to reduced kidney function, which is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin. Other useful laboratory tests include quantitative measurement of IgA, IgG, and IgM to look for immune paresis, and beta-2 microglobulin, which provides prognostic information. On peripheral blood smear, the rouleaux formation of red blood cells is commonly seen, though this is not specific. 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 MGUS to<unk> . This assay, the serum free light chain assay, has recently been recommended by the International Myeloma Working Group for the screening, diagnosis, prognosis, and monitoring of plasma cell dyscrasias. File:Multiple myeloma (2) HE stain.Bone marrow aspirate showing the histologic correlate of<unk>  under the microscope, H&E stain File:Plasmacytoma1.Plasmacytoma, H&E stain File:Cast nephropathy - 2 cropped - very high mag. Micrograph showing myeloma cast nephropathy in a kidney biopsy: Hyaline casts are PAS positive (dark pink/red – right of image). Myelomatous casts are PAS negative (pale pink – left of image), PAS stain. File:Dutcher and Russell bodies.Atypical plasma cell infiltrate with both Russell (cytoplasmic) and Dutcher (nuclear) bodies (H&E, 50x) File:Plasmacytoma_ultramini1.Micrograph of a plasmacytoma, H&E stain Histopathology 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 that express immunoglobulin in the cytoplasm and occasionally on the cell surface; myeloma cells are often CD56, CD38, CD138, and CD319 positive and CD19, CD20, and CD45 negative. Flow cytometry is often used to establish the clonal nature of the plasma cells, which will generally express only kappa or lambda light chain. Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific fluorescent in situ hybridization and virtual karyotype. The plasma cells seen in<unk>  have several possible morphologies. First, they could have the appearance of a normal plasma cell, a large cell two or three times the size of a peripheral lymphocyte. Because they are actively producing antibodies, the Golgi apparatus typically produces a light-colored area adjacent to the nucleus, called a perinuclear halo. The single nucleus (with inside a single nucleolus with vesicular nuclear chromatin) is eccentric, displaced by an abundant cytoplasm. Other common morphologies seen, but which are not usual in normal plasma cells, include: * Bizarre cells, which are multinucleated * Mott cells, containing<unk>  clustered cytoplasmic droplets or other inclusions (sometimes confused with auer rods, commonly seen in myeloid blasts) * Flame cells, having a fiery red cytoplasm Historically, the CD138 has been used to isolate myeloma cells for diagnostic purposes. However, this antigen disappears rapidly ex vivo. Recently, however, the surface antigen CD319 (SLAMF7) was discovered to be considerably more stable and allows robust isolation of malignant plasma cells from delayed or even cryopreserved samples. The prognosis varies widely depending upon various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART), which divides people into high-risk and standard-risk categories. People with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), t(14;20) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma. Medical imaging The diagnostic examination of a person with suspected<unk>  typically includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton, and proximal long bones. Myeloma activity sometimes appears as "lytic lesions" (with local disappearance of normal bone due to resorption). And on the skull X-ray as "punched-out lesions" (raindrop skull). Lesions may also be sclerotic, which is seen as radiodense. Overall, the radiodensity of myeloma is between −30 and 120 Hounsfield units (HU). Magnetic resonance imaging is more sensitive than simple X-rays in the detection of lytic lesions, and may supersede a skeletal survey, especially when vertebral disease is suspected. Occasionally, a CT scan is performed to measure the size of soft-tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of people with myeloma (no new bone formation; lytic lesions not well visualized on bone scan). File:Plasmozytom<unk>  Osteolysen Unterarm.X-ray of the forearm, with lytic lesions File:MMPlainSkull.Skull X-ray showing<unk>  lucencies due to<unk>  File:Emmentalersign<unk>  in the upper arm File:PathFracMMPlainMark.Pathological fracture of the lumbar spine due to<unk>  File:Multiple myeloma skull CT arrows.A CT of the brain revealed a lytic lesion in the left temporal bone (right side of image), and petrous temporal bones involving the mastoid segment of the facial nerve canal. Red arrows: lesion; green arrow: normal contralateral facial nerve canal. The lesions are consistent with a myeloma deposit. File:CT of osteoblastic lesions of<unk> .CT scan of the lower vertebral column in a man with<unk> , showing<unk>  osteoblastic lesions: These are more radiodense (brighter in this image) than the surrounding cancellous bone, in contrast to osteolytic lesions, which are less radiodense. Left femur with myeloma.Femur with<unk>  lesions Left femur before myeloma.Same femur before myeloma lesions for comparison Left humerus with myeloma.Humerus with<unk>  lesions Left humerus with subtle signs of myeloma.Same humerus before, with just subtle lesions Diagnostic criteria In 2003, the IMG agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma, and MGUS, which was subsequently updated in 2009: * Symptomatic myeloma (all three criteria must be met): *# Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma) *# A monoclonal protein (myeloma protein) in either serum or urine and it has to be more than 3g/dL (except in cases of true nonsecretory myeloma) *# Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, CRAB): *#*HyperCalcemia (corrected calcium >2.75 mmol/l, >11 mg/dl) *#* Renal failure (kidney insufficiency) attributable to myeloma *#* Anemia (hemoglobin 60% clonal plasma cells, a serum involved / uninvolved free light chain ratio ≥ 100 (the concentration of the involved free light chain must be ≥ 100 mg/l) and more than one focal lesion ≥ 5 mm by MRI. Together, these biomarkers and the CRAB criteria are known as myeloma-defining events (MDEs). A person must have >10 % clonal plasma cells and any MDE to be diagnosed with myeloma. The biomarker criteria were added so that smouldering people with<unk>  at high risk of developing<unk>  could be diagnosed before organ damage occurred, so they would therefore have a better prognosis. * Asymptomatic/smoldering myeloma: *# Serum M protein >30 g/l (3 g/dl) or *# Clonal plasma cells >10% on bone marrow biopsy and *# No myeloma-related organ or tissue impairment * Monoclonal gammopathy of undetermined significance (MGUS): *# Serum paraprotein 2 microglobulin (β2M) < 3.5 mg/L, albumin ≥ 3.5 g/dL, normal cytogenetics, no elevated LDH * Stage II: Not classified under Stage I or Stage III * Stage III: β2M ≥ 5.5 mg/L and either elevated LDH or high-risk cytogenetics t(4,14), t(14,16), and/or del(17p)
Multiple myeloma
Monoclonal gammopathy of renal significance  Monoclonal gammopathy of renal significance  1
Monoclonal gammopathy of undetermined significance
Monoclonal gammopathy of renal significance
Smouldering myeloma
Waldenström macroglobulinemia
AL amyloidosis
Plasma cell leukemia