Case 11 Presentation_final

8/4/2019 Case 11 Presentation_final

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Case 11

Qi Wang, Liz Croisant, KristinHarris, Nancy Mercier, Stefanie

Brown

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• Mrs. Jones, 54 yo, F

• Fell and injured right hip

• 6-month history of backache, lethargy, and weakness

• Postmenopausal, taking hormone replacement therapy

• 3 episodes of pneumococcal pneumonia in last 2 yrs.

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• Swollen, tender, and bruised right hip

• One inch of true shortening of the right leg

• Clinically anemic with pallor of her mucous

membranes and nailbeds

• Mild tachycardia

3



TESTS RESULTS X-ray of pelvis

and upper femurs Fracture of the neck of

femur througharea of decreased bonedensity

Red cell count 3.0 x 1012 /L

Hemoglobin 8.0 g/dL White cell count 3.6 x 109 /L Differential See photograph below

Platelet count 130 x 103 /mm3 ESR 32 mm/h BUN 30 mg/dL Creatinine 3 mg/dL Total protein 132 g/dL Serum albumin 2.6 g/dL Bilirubin (total) 0.8 mg/dL Alkalinephosphatase 150 U/L AP-1, 2 50 /L AP-2, 1 160 /L AP-3, 2 15 /L

Serum calcium 20 mg/dL 4



• Fracture in the neck of the femur (hip)

• Area of decreased bone density

• Decreased RBCs and hemoglobin (anemia)

• Decreased WBC - Diff shows plasma cell (may indicate

MM)

• Thrombocytopenia

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• Elevated BUN and creatinine, decreased serum albumin

(possible renal problems)

• Elevated ESR (inflammation - most likely due to broken bone)

• Extremely elevated total protein (indicates an increase of

immunoglobulins)

• Elevated alkaline phosphatase and serum calcium (due to hip

fracture)

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• Back pain

• Broken bones

• Weakness/lethargy

• Repeated

pneumococcal

pneumonia infections

• Elevated total protein

• Elevated calcium level

• Decreased WBC

• Plasma cell

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• Waldenstrom's Macroglobulinemia

• MGUS

• Smoldering MM

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• Serum Protein Electrophoresis• Basic principle: electrophoresis

• Charged molecules exposed to electric field, migrate towardanode (+) or cathode (-)

• Migratory direction and rate of migration dependent on size, shape,charge, voltage, buffer pH

• Method to separate and isolate different molecular species within asample

• Serum protein electrophoresis (SPE)

• Used to separate and isolate major protein fractions withinpatient serum sample (5)

• Albumin, alpha, alpha 2, beta, gamma

• Gamma region

• Immunoglobulins

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• SPE

• Procedure

• Agarose gel electrophoresis or cellulose acetateelectrophoresis may be performed

• Sample placed at cathode (-) end, voltage applied to system

• Alkaline buffer used (pH 8.6)

• Proteins net negative charge under alkaline conditions

• Serum proteins move toward anode

• 5 major serum protein fractions separated• Fractions fixed and stained

• Fractions quantitated using densitometer

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Normal Serum ProteinElectrophoresis

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• SPE

• Applications

• Detection of monoclonal immunoglobulin (M protein, paraprotein)

• Abnormal SPE pattern

• Monoclonal immunoglobulin appears as spike in gamma region

• Identical immunoglobulins from monoclonal plasma cells migrate to the

same position causing spike

• Monoclonal immunoglobulins the hallmark of Multiple Myeloma

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Mrs. Jones’ Abnormal

SPE pattern

Spike in gammaregion – M protein

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• Immunofixation electrophoresis (IFE)

• Qualitative technique that combines zone electrophoresis with

immunoprecipitation

• Procedure used to identify the paraprotein causing the sharp peak on serum

protein electrophoresis in the gamma region

• Sometimes the alpha2 or beta region

• Characterization of paraproteins is critical to the proper diagnosis of the

plasma cell disorder

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• IFE

• Separation of patient serum proteins using gel electrophoresis

• Application of IgG, IgA, IgM, kappa, and lambda antisera to the

electrophoresed samples in their respective lanes

• Precipitation of the antibodies complexed to their antigen occurs at

the region where the antigen (the IgA, IgG, IgM, etc proteins in the

patient’s serum) has migrated

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• Precipitated antigen-antibody complex is then visualized by

staining the precipitated bands

• A sharp band in the lane for a heavy chain class and a sharp

band in one of the light chain lanes indicates the presence

of a monoclonal immunoglobulin

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Mrs. Jones’ serum protein IFE

results

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• IFE: Results

• Excess IgA antibodies with lambda light chains are present in the

plasma of this patient

• Blood serum paraprotein levels of more than 30 g/L diagnostic of

multiple myeloma

• The presence of excessive IgA antibody is characteristic of this

disorder

• 20% of patients with multiple myeloma produce excessive IgA antibodies

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• Free Light Chains (FLC)

• Also known as Bence Jones Proteins (BJP)

• Monoclonal free kappa or lambda light chains of immunoglobulin

molecules

• Components of immunoglobulin molecules

• Single immunoglobulin monomer includes two light chains (either kappa or

lambda) and heavy chains

• FLC and Multiple Myeloma

• 60-70% of Multiple Myeloma patients excrete FLC in urine

• About 10% of Multiple Myeloma patients have only FLC20



• Testing for FLC

• Screening test – Heat Test for FLC in urine

• BJPs soluble at RT (in acidified urine),

• Precipitate at 40-60°C

• Resolubilize at 95-100°C

• *Note

• Other tests for protein in urine not very reliable for detecting FLC proteins, focus

primarily on albumin (urinalysis reagent strip)

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• Testing for FLC• Screening Test- a serum FLC assay (Freelite)

• A quantitative method to measure Kappa

light chains, Lambda light chains, and theserum free kappa:free lambda ratio

• Uses nephelometry to measure

• Very sensitive for detecting plasma cell

disorders• Significantly increased free light chain

production and abnormal kappa/lambdaratios indicate an increased risk of disease

progression 22



• Serum FLC

• SPE and IFE

• Urine FLC

• Urine Protein Electrophoresis (UPE) and IFE

• Concentrated 24 hour urine without preservative used

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Mrs. Jones’ urine IFE results

show free lambda lights chains

present in her urine 24



• Additional testing to confirm

diagnosis of Multiple Myeloma

• Bone marrow aspirate and biopsy

• Evaluate marrow for malignant

plasma cells

• Evaluate for increased numbers

of plasma cells in marrow

(>30%)

• X-ray, MRI, and CT

• Evaluate bone damage and

tumors (plasmacytoma)

• Peripheral blood smear

• May reveal plasma cells25



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• All three must be met

• Monoclonal plasma cells must be present in bone marrow ≥10%

and/or presence of biopsy-proven plasmacytoma

• Presence of monoclonal antibodies in serum and/or urine

• Myeloma-related organ dysfunction (one or more must be met)

• Calcium elevation in the blood (serum calcium >10.5 mg/L or

upper limit of normal)

• Renal insufficiency as evidenced by serum creatinine >2 mg/100

mL

• Anemia as evidenced by Hgb <10 g/100 mL or 2 g < normal

• Presence of lytic bone lesions or osteoperosis 27



• Lab findings supporting diagnosis of Multiple Myeloma• Decreased RBC and hemoglobin (anemia)• Decrease in WBCs• Plasma cells observed on peripheral blood film• Thrombocytopenia• Elevated BUN, creatinine, decreased serum albumin – renal dysfunction• Elevated total serum protein – elevated immunoglobulin levels• Hypercalcemia• Punched out lesions in skull• M spike in gamma region seen in SPE• Excess IgA antibodies with lambda light chains seen on IFE

• > 2.0 g/L serum IgA• Decrease in other immunoglobulins• < 600 mg/dL for IgG

• FLC in urine seen on IFE• >30% plasma cells seen in bone marrow

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• Plasma cell myeloma, Kahler's disease

• Cancer of the plasma cells in bone marrow

• Most common monoclonal gammopathy

• 2nd most common hematological malignancy

(10%)

• 1% of all cancers

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• Plasma cells: Type of WBC that helps the body fight

infection by producing proteins called antibodies

• MM: plasma cells grow out of control in bone marrow,

form tumors (plasmacytoma) in areas of solid bone

• These bone tumors make it harder for the bone marrow

to make healthy RBCs and platelets

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• Immune system keeps proliferation of B cells and

secretion of antibodies under tight control

• Control is lost when chromosomes and genes aredamaged, often through rearrangement

• Chromosomal translocation between the immunoglobulin

heavy chain gene and an oncogene is frequently

observed in patients with MM

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• Mutation results in dysregulation of the oncogene

(thought to be an important initiating event in the

pathogenesis of myeloma)

• Results in proliferation of a plasma cell clone and

genomic instability that leads to further mutations and

translocations

• Chromosome 13 and 14 abnormality - 50% cases

• Production of cytokines (IL-6) by the plasma cells causes

localized damage – osteoporosis 32



• Creates a microenvironment in which the malignant cells

thrive

• Angiogenesis (the attraction of new blood vessels) isincreased

• Produced antibodies are deposited in various organs -

leads to renal failure, polyneuropathy and various other

myeloma-associated symptoms

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• Precise etiology not yet been established

• Genetic

• Environmental/Occupational

• Significant exposures in agriculture, food, and petrochemicalindustries

• Increased risk in farmers, especially those who use herbicides andinsecticides

• Exposure to benzene and other organic solvents

• Long-term (>20 y) exposure to hair dyes

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• MGUS (~19% of patients develop MM within 2-19 yrs)

• Radiation (risk in atomic-bomb survivors exposed to > 50

Gy)

• Chronic inflammation (preexisting chronic inflammatory

diseases)

• Infection (HPV8 infection of bone marrow dendritic cells)

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• 4.3 cases per 100,000 white men

• 3 cases per 100,000 white women

• 9.6 cases per 100,000 black men

• 6.7 cases per 100,000 black women.• Median age is 68 years for men, 70 years for women

• 18% of patients <50 years, 3% of patients <40 years

• Male-to-female ratio ~ 3:2

• In U.S., African Americans are twice as likely asCaucasian

• Rare among people of Asian descent (1-2cases/100,000)

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• Many organs affected, symptoms and signs vary greatly

• CRAB: C = Calcium (↑), R = Renal failure, A = Anemia,

B = Bone lesions (common tetrad of MM)

• Symptoms• Severe bone pain - Pathologic fracture

• Easy fatigability - Anemia, possible amyloid

• Nausea, confusion - Hypercalcemia

• Nausea, fatigue - Renal failure

• Recurrent infections - Decrease in normal Ig

• Paraplegia - Spinal cord compression

• Confusion, blurred vision - Hyperviscosity (rare)

• Bleeding - Thrombocytopenia

• Skin Nodules - Plasma cell tumors

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• Major criteria

• Biopsy proven plasmacytoma

• >30% plasma cells in bonemarrow

• Monoclonal protein (M spike)• >3.5 g/dL of serum IgG or

• >2.0 g/dL of serum IgA or

• >1 g/24 h of lambda orkappa urinary L chains

• For diagnosis must have

• 1 major and 1 minor criteria or

• 3 minor criteria (must includefirst 2)

• Minor Criteria

• 10-30% plasma cells in bonemarrow

• M spike present but < levels

under major• Multiple lytic bone lesions

• Low normalimmunoglobulins

• IgM < 50 mg/dL

• IgA < 100

• IgG < 600

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• Based on 4 factors

• Amount of abnormal monoclonal immunoglobulin in the blood orurine

• Amount of calcium in the blood

• Severity of bone damage based on x-rays• Amount of hemoglobin in the blood

• Factors divide myeloma into 3 stages

• Stage I indicates the smallest amount of tumor, stage III

indicates the largest amount of tumor

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• Stage I• Hgb >10g/dL• Serum Calcium <12mg/dL• <2 lytic lesions on a skeletal survey• Small M spike (IgG <5g/dL or IgA <3.5g.dL or urine light chains

<4g/24h)• Stage II• Fits neither stage I or III

• Stage III• Hgb <8.5g/dL• Serum Calcium >12mg/dL• >=2 lytic bone lesions• Large M spike (Iga >7g/dL or IgA >5g/dL)

• Subclass• Subclass A: Creatinine level <2mg/dL• Subclass B: Creatinine level >2mg/dL

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• Stage 2, Subclass B

• Hemoglobin <8.5g/dL (8g/dL)

• Serum Calcium >12mg/dL (20mg/dL)

• >2 Lytic Bone Lesions (multiple)

• Large M spike: IgG > 7g/dL or IgA > 5g/dL (IgG=0.12g/dL,IgA=3.54g/dL)

• Creatinine >2mg/dL (3mg/dL)

• Fits ¾ criteria for stage III (since IgA is <5g/dL), so

defaults to stage II)

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• Developed ~ 1995

• Easier, more reliable

• Divides myeloma into 3 stages based only on the serum beta-2 microglobulin and serum albumin levels

• Stage I• Serum beta-2 microglobulin <3.5 mg/L and albumin level >3.5 g/L

• Stage II

• Neither stage I or III, meaning that either:

• The beta-2 microglobulin level is 3.5 - 5.5 mg/L (any albuminlevel)

• OR the albumin is <3.5g/L while beta-2 microglobulin is <3.5mg/L

• Stage III

• Serum beta-2 microglobulin >5.5mg/L

• Testing was not done to be able to stage in this system for our42



• Patient’s with a milder or slower progressing case may be carefully

watched without treatment.

• Medications used in treatment:

• Dexamethasone, melphalan, cyclophosphamide, doxil, thalidomide,

lenalidomide and bortezomib (alone or combined)

• Lenalidomide is an immunomodulatory drug, it slows or kills myeloma cells

an impacts blood vessels and surrounding substances that help cancer

cells.

• Bortezomib is known as a proteosome inhibitor and it is given43



• Bisphosphonates

• Reduce bone pain and prevent fractures

• Radiation therapy may be done to treat a bone tumor or give

bone pain relief.

• Bone marrow transplantation

• Autologous or stem cell

• Allogenic

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• Stay hydrated – preserves kidney function

• Stay active – helps preserve calcium in their bones

• Complications treated quickly

• Avoid X-ray test that use contrast dye

• Consider joining a support group

• Address stress of illness

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• Prognosis

• Survival is dependent upon age and stage

• Durie & Salmon Stage II ~ 41 months

• Some cases very aggressive• Some cases very slow progressing

• Conclusion:

• The patient was taken off of hormone replacement therapy to avoid

exacerbating bone lesion susceptibility

• Patient put on bisphosphonates to help prevent bone lesions

• The patient was given a bone marrow transplant

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