Proposal Chemistry

7/27/2019 Proposal Chemistry

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Topic: A comprehensive study of biochemistry of myeloma cells

Objectives: After the study following objectives can be full filled

Definition of myeloma cells Signs and symptoms Brief review of Diagnosis Pathophysiology An analysis of different available Treatments Prognosis

A detailed account of biochemistry of myeloma cells Comparative account of myeloma and normal cells

Research Method and Resources

This part of thesis envisages data collection from different sources of

information media, Google scholar, internet, various journals, magazines, and

many libraries.

Research is completely review based and coordination between different

aspects is made.

A group of doctors and medical students are also interviewed for the purpose.

In overall an Idea to generate awareness for early treatment and best available

treatments for a specific one are listed, so that both general reader and scholars

get benefited from the information compiled.

Multiple myeloma
http://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myeloma


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From Wikipedia, the free encyclopedia

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Multiple myeloma

Classification and external resources

Micrograph of a plasmacytoma, the histologic correlate

of multiple myeloma. H&E stain

ICD-10 C90.0

ICD-9 203.0

ICD-O: M9732/3

OMIM 254500

DiseasesDB 8628

MedlinePlus 000583

eMedicine med/1521

MeSH D009101

Multiple myeloma (from Greekmyelo-, bone marrow), also known as plasma cell myeloma or

Kahler's disease (afterOtto Kahler), is a cancerofplasma cells, a type ofwhite blood cell

normally responsible for producing antibodies.[1]

In multiple myeloma, collections of abnormal

plasma cells accumulate in thebone marrow, where they interfere with the production of normalblood cells. Most cases of myeloma also feature the production of aparaproteinan abnormal

antibody which can cause kidney problems. Bone lesions and hypercalcemia (high calcium

levels) are also often encountered.[1]
http://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/H%26E_stainhttp://en.wikipedia.org/wiki/International_Statistical_Classification_of_Diseases_and_Related_Health_Problemshttp://en.wikipedia.org/wiki/ICD-10http://en.wikipedia.org/wiki/ICD-10_Chapter_Chttp://apps.who.int/classifications/icd10/browse/2010/enhttp://en.wikipedia.org/wiki/International_Statistical_Classification_of_Diseases_and_Related_Health_Problemshttp://en.wikipedia.org/wiki/List_of_ICD-9_codeshttp://www.icd9data.com/getICD9Code.ashx?icd9=203.0http://en.wikipedia.org/wiki/International_Classification_of_Diseases_for_Oncologyhttp://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I97323/http://en.wikipedia.org/wiki/OMIMhttp://omim.org/entry/254500http://en.wikipedia.org/wiki/Diseases_Databasehttp://www.diseasesdatabase.com/ddb8628.htmhttp://en.wikipedia.org/wiki/MedlinePlushttp://www.nlm.nih.gov/medlineplus/ency/article/000583.htmhttp://en.wikipedia.org/wiki/EMedicinehttp://www.emedicine.com/med/topic1521.htmhttp://en.wikipedia.org/wiki/Medical_Subject_Headingshttp://www.nlm.nih.gov/cgi/mesh/2013/MB_cgi?field=uid&term=D009101http://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Hypercalcemiahttp://en.wikipedia.org/wiki/Kidneyhttp://en.wikipedia.org/wiki/Paraproteinhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Antibodyhttp://en.wikipedia.org/wiki/White_blood_cellhttp://en.wikipedia.org/wiki/Plasma_cellhttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Otto_Kahlerhttp://www.nlm.nih.gov/cgi/mesh/2013/MB_cgi?field=uid&term=D009101http://en.wikipedia.org/wiki/Medical_Subject_Headingshttp://www.emedicine.com/med/topic1521.htmhttp://en.wikipedia.org/wiki/EMedicinehttp://www.nlm.nih.gov/medlineplus/ency/article/000583.htmhttp://en.wikipedia.org/wiki/MedlinePlushttp://www.diseasesdatabase.com/ddb8628.htmhttp://en.wikipedia.org/wiki/Diseases_Databasehttp://omim.org/entry/254500http://en.wikipedia.org/wiki/OMIMhttp://www.progenetix.net/progenetix/I97323/http://en.wikipedia.org/wiki/ICD-Ohttp://en.wikipedia.org/wiki/International_Classification_of_Diseases_for_Oncologyhttp://www.icd9data.com/getICD9Code.ashx?icd9=203.0http://en.wikipedia.org/wiki/List_of_ICD-9_codeshttp://en.wikipedia.org/wiki/International_Statistical_Classification_of_Diseases_and_Related_Health_Problemshttp://apps.who.int/classifications/icd10/browse/2010/enhttp://en.wikipedia.org/wiki/ICD-10_Chapter_Chttp://en.wikipedia.org/wiki/ICD-10http://en.wikipedia.org/wiki/International_Statistical_Classification_of_Diseases_and_Related_Health_Problemshttp://en.wikipedia.org/wiki/H%26E_stainhttp://en.wikipedia.org/wiki/Histologyhttp://en.wikipedia.org/wiki/Plasmacytomahttp://en.wikipedia.org/wiki/Micrographhttp://en.wikipedia.org/wiki/File:Plasmacytoma_ultramini1.jpghttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myeloma


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Myeloma is diagnosed withblood tests (serumprotein electrophoresis, serum free kappa/lambda

light chain assay),bone marrow examination, urine protein electrophoresis, and X-rays of

commonly involved bones. Myeloma is generally thought to be incurable but highly treatable.Remissions may be induced with steroids, chemotherapy, proteasome inhibitors (e.g.

bortezomib), immunomodulatory drugs (IMiDs) such as thalidomide orlenalidomide, and stem

cell transplants.Radiation therapyis sometimes used to reduce pain from bone lesions.

[1]

Myeloma develops in 14 per 100,000 people per year. It is more common in men, and for

unknown reasons is twice as common in African-Americans as it is in European-Americans.With conventional treatment, median survival is 34 years, which may be extended to 57 years

or longer with advanced treatments. Multiple myeloma is the second most common

hematological malignancy in the U.S. (afternon-Hodgkin lymphoma), and constitutes 1% of allcancers.

[1]

Contents

1 Signs and symptomso 1.1 Bone paino 1.2 Infectiono 1.3 Renal failureo 1.4 Anemiao 1.5 Neurological symptoms

2 Diagnosiso 2.1 Investigationso 2.2 Workupo 2.3 Diagnostic criteriao 2.4 Staging

3 Pathophysiology

4 Treatmento 4.1 Initial therapyo 4.2 Maintenance therapyo 4.3 Relapse

5 Prognosiso 5.1 Genetic testing

6 Epidemiology 7 Other animals 8 See also 9 References 10 External links

Signs and symptoms

Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A

mnemonic sometimes used to remember the common tetrad (four parts) of multiple myeloma is

CRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.[2]

Myeloma
http://en.wikipedia.org/wiki/Stem_cell_transplanthttp://en.wikipedia.org/wiki/Stem_cell_transplanthttp://en.wikipedia.org/wiki/Stem_cell_transplanthttp://en.wikipedia.org/wiki/Radiation_therapyhttp://en.wikipedia.org/wiki/Radiation_therapyhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Mnemonichttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Non-Hodgkin_lymphomahttp://en.wikipedia.org/wiki/Hematological_malignancyhttp://en.wikipedia.org/wiki/White_Americanhttp://en.wikipedia.org/wiki/African-Americanhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Radiation_therapyhttp://en.wikipedia.org/wiki/Stem_cell_transplanthttp://en.wikipedia.org/wiki/Stem_cell_transplanthttp://en.wikipedia.org/wiki/Stem_cell_transplanthttp://en.wikipedia.org/wiki/Lenalidomidehttp://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Bortezomibhttp://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Glucocorticoidhttp://en.wikipedia.org/wiki/Bone_marrow_examinationhttp://en.wikipedia.org/wiki/Protein_electrophoresishttp://en.wikipedia.org/wiki/Blood_test


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has many possible symptoms, an

here in decreasing order ofincid

Bone pain

Illustration showing the most com

Bone pain affects almost 70% o

pain usually involves the spine a

indicate a pathologicalbone fraccompression. Myeloma bone dis

Nuclear Factor B Ligand (RA

which resorb bone. The resultantseen in plain radiographs, which

"pepper pot" appearance of the s

release ofcalcium into the blood

Infection

The most common infections arepathogens include S. pneumonia

causingpyelonephritis includeE

period for the occurrence of infechemotherapy.

[4]The increased r

immunoglobulin level is typicall

are ineffective monoclonal antib

d all symptoms may be due to other causes. Th

nce.

on site of bone lesions in vertebrae. Seefull anima

patients and is the most common symptom.[3]

d ribs, and worsens with activity. Persistent lo

ure. Involvement of the vertebrae may lead to sease is due to the overexpression of Receptor A

KL) by bone marrow stroma. RANKL activate

bone lesions are lytic (cause breakdown) in natmay show "punched-out" resorptive lesions (in

ull on radiography). The breakdown of bone al

, leading to hypercalcemiaand its associated sy

pneumonias andpyelonephritis. Common pne, S. aureus, andK. pneumoniae, while commo

. coli and othergram-negative organisms. The g

tion is in the initial few months after the start oisk of infection is due to immune deficiency. Al

elevated in multiple myeloma, the majority o

dies from the clonal plasma cell. A selected gr

y are presented

tion.

yeloma bone

alized pain may

pinal cordctivator for

s osteoclasts,

ure and are bestluding the

so leads to

ptoms.

moniapathogens

reatest risk

fthough the total

the antibodies

up of patients
http://en.wikipedia.org/wiki/Incidence_%28epidemiology%29http://en.wikipedia.org/wiki/Spinal_cord_compressionhttp://en.wikipedia.org/wiki/Spinal_cord_compressionhttp://en.wikipedia.org/wiki/Calciumhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Incidence_%28epidemiology%29http://blausen.com/index-wiki.php?word=Multiple+Myelomahttp://blausen.com/index-wiki.php?word=Multiple+Myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Spinal_cord_compressionhttp://en.wikipedia.org/wiki/Hypercalcemiahttp://en.wikipedia.org/wiki/Hypercalcemiahttp://blausen.com/index-wiki.php?word=Multiple+Myelomahttp://en.wikipedia.org/wiki/Spinal_cord_compressionhttp://en.wikipedia.org/wiki/Immunoglobulinhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Gram-negativehttp://en.wikipedia.org/wiki/Escherichia_colihttp://en.wikipedia.org/wiki/Pyelonephritishttp://en.wikipedia.org/wiki/Klebsiella_pneumoniaehttp://en.wikipedia.org/wiki/Staphylococcus_aureushttp://en.wikipedia.org/wiki/Streptococcus_pneumoniaehttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Pyelonephritishttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Hypercalcemiahttp://en.wikipedia.org/wiki/Calciumhttp://en.wikipedia.org/wiki/Skullhttp://en.wikipedia.org/wiki/Osteoclasthttp://en.wikipedia.org/wiki/RANKLhttp://en.wikipedia.org/wiki/Spinal_cord_compressionhttp://en.wikipedia.org/wiki/Spinal_cord_compressionhttp://en.wikipedia.org/wiki/Bone_fracturehttp://en.wikipedia.org/wiki/Multiple_myelomahttp://blausen.com/index-wiki.php?word=Multiple+Myelomahttp://en.wikipedia.org/wiki/File:Blausen_0656_MultipleMyeloma.pnghttp://en.wikipedia.org/wiki/File:Blausen_0656_MultipleMyeloma.pnghttp://en.wikipedia.org/wiki/Incidence_%28epidemiology%29


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with documented hypogammagl

therapy to reduce the risk of infe

Renal failure

Renal failure may develop both

The most common cause of rena

the light chains. Increased bonethereby contributing to the renal

Light chains produce myriad eff

tubular acidosis).

Other causes include hyperurice

oftumorcells.

Anemia

The anemia found in myeloma is

replacement of normal bone marblood cell production (hematopo

Neurological symptoms

Common problems are weaknes

changes and retinopathy may be

properties of theparaprotein. Ficontrol (due to involvement ofs

syndromeand otherneuropathiegive rise toparaplegia in late pre

Diagnosis

Investigations

Serum protein electrophoresis sho

multiple myeloma.

bulinemia may benefit from replacement imm

ction.[5]

cutelyand chronically.

failure in Multiple Myeloma is due to tubulop

esorption leads to hypercalcemia and causes nefailure. Amyloidosis is a distant third in the cau

cts which can manifest as the Fanconi syndro

ia, recurrent infections (pyelonephritis), and l

usually normocytic and normochromic. It resul

ow by infiltrating tumor cells and inhibition ofiesis) by cytokines.

, confusion and fatigue due to hypercalcemia.

the result ofhyperviscosity of the blood depen

ally, there may be radicular pain, loss ofbowelinal cord leading to cord compression) orcarpa

(due to infiltration ofperipheral nerves by amsenting cases.

ing a paraprotein (peak in the gamma zone) in a p

noglobulin

thic effects of

hrocalcinosissation.

e (type II renal

cal infiltration

ts from the

normal red

eadache, visual

ing on the

or bladderl tunnel

loid). It may

tient with
http://en.wikipedia.org/wiki/Renal_failurehttp://en.wikipedia.org/wiki/Renal_tubular_acidosishttp://en.wikipedia.org/wiki/Renal_tubular_acidosishttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Hematopoiesishttp://en.wikipedia.org/wiki/Carpal_tunnel_syndromehttp://en.wikipedia.org/wiki/Carpal_tunnel_syndromehttp://en.wikipedia.org/wiki/Paraplegiahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Acute_renal_failurehttp://en.wikipedia.org/wiki/Acute_renal_failurehttp://en.wikipedia.org/wiki/Chronic_renal_failurehttp://en.wikipedia.org/wiki/Hematopoiesishttp://en.wikipedia.org/wiki/Cytokineshttp://en.wikipedia.org/wiki/Cytokineshttp://en.wikipedia.org/wiki/Carpal_tunnel_syndromehttp://en.wikipedia.org/wiki/Renal_tubular_acidosishttp://en.wikipedia.org/wiki/Carpal_tunnel_syndromehttp://en.wikipedia.org/wiki/Protein_electrophoresishttp://en.wikipedia.org/wiki/File:Monoclonal_gammopathy_Multiple_Myeloma.pnghttp://en.wikipedia.org/wiki/File:Monoclonal_gammopathy_Multiple_Myeloma.pnghttp://en.wikipedia.org/wiki/Paraplegiahttp://en.wikipedia.org/wiki/Amyloidhttp://en.wikipedia.org/wiki/Peripheral_nerveshttp://en.wikipedia.org/wiki/Neuropathieshttp://en.wikipedia.org/wiki/Carpal_tunnel_syndromehttp://en.wikipedia.org/wiki/Carpal_tunnel_syndromehttp://en.wikipedia.org/wiki/Carpal_tunnel_syndromehttp://en.wikipedia.org/wiki/Spinal_cord_compressionhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Bowelhttp://en.wikipedia.org/wiki/Radicular_painhttp://en.wikipedia.org/wiki/Paraproteinhttp://en.wikipedia.org/wiki/Hyperviscosityhttp://en.wikipedia.org/wiki/Retinopathyhttp://en.wikipedia.org/wiki/Headachehttp://en.wikipedia.org/wiki/Hypercalcemiahttp://en.wikipedia.org/wiki/Fatigue_%28medical%29http://en.wikipedia.org/wiki/Confusionhttp://en.wikipedia.org/wiki/Weaknesshttp://en.wikipedia.org/wiki/Cytokineshttp://en.wikipedia.org/wiki/Hematopoiesishttp://en.wikipedia.org/wiki/Normochromichttp://en.wikipedia.org/wiki/Normocytichttp://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Pyelonephritishttp://en.wikipedia.org/wiki/Hyperuricemiahttp://en.wikipedia.org/wiki/Renal_tubular_acidosishttp://en.wikipedia.org/wiki/Renal_tubular_acidosishttp://en.wikipedia.org/wiki/Fanconi_syndromehttp://en.wikipedia.org/wiki/Chronic_renal_failurehttp://en.wikipedia.org/wiki/Acute_renal_failurehttp://en.wikipedia.org/wiki/Renal_failurehttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Immunoglobulinhttp://en.wikipedia.org/wiki/Hypogammaglobulinemia


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The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate(ESR), lytic bone lesions, elevatedbeta-2 microglobulin, and/or a high serumprotein (especially

raised globulins orimmunoglobulin) may prompt further testing. The globulin level may benormal in established disease. A doctor will requestprotein electrophoresis of the blood and

urine, which might show the presence of aparaprotein (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 immunoglobulinproduced 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 orheavy chains (the building blocks ofantibodies) may be secreted in isolation: - or-light chains or any of the five types of heavy chains (-, -, -, - or -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 is mainly due to casts of paraprotein deposition in the kidney, although the cast may also

contain complete immunoglobulins, Tamm-Horsfall protein and albumin.[6]

Bone marrow aspirate showing the histologic correlate of multiple myeloma under the

microscope. H&E stain.

Plasmacytoma. H&E stain.
http://en.wikipedia.org/wiki/Tamm-Horsfall_proteinhttp://en.wikipedia.org/wiki/Albuminhttp://en.wikipedia.org/wiki/Albuminhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/H%26E_stainhttp://en.wikipedia.org/wiki/H%26E_stainhttp://en.wikipedia.org/wiki/File:Cast_nephropathy_-_2_cropped_-_very_high_mag.jpghttp://en.wikipedia.org/wiki/File:Plasmacytoma1.jpghttp://en.wikipedia.org/wiki/H%26E_stainhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/File:Multiple_myeloma_(2)_HE_stain.jpghttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Albuminhttp://en.wikipedia.org/wiki/Tamm-Horsfall_proteinhttp://en.wikipedia.org/wiki/Kidneyhttp://en.wikipedia.org/wiki/Renal_functionhttp://en.wikipedia.org/wiki/Creatininehttp://en.wikipedia.org/wiki/Calciumhttp://en.wikipedia.org/wiki/Osteoclastshttp://en.wikipedia.org/wiki/Calciumhttp://en.wikipedia.org/wiki/Antibodieshttp://en.wikipedia.org/wiki/Immunoglobulin_heavy_chainhttp://en.wikipedia.org/wiki/Immunoglobulin_light_chainhttp://en.wikipedia.org/wiki/IgEhttp://en.wikipedia.org/wiki/IgDhttp://en.wikipedia.org/wiki/IgMhttp://en.wikipedia.org/wiki/IgAhttp://en.wikipedia.org/wiki/IgGhttp://en.wikipedia.org/wiki/Immunoglobulinhttp://en.wikipedia.org/wiki/Bence_Jones_proteinhttp://en.wikipedia.org/wiki/Paraproteinhttp://en.wikipedia.org/wiki/Protein_electrophoresishttp://en.wikipedia.org/wiki/Immunoglobulinhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Beta-2_microglobulinhttp://en.wikipedia.org/wiki/Erythrocyte_sedimentation_ratehttp://en.wikipedia.org/wiki/Kidneyhttp://en.wikipedia.org/wiki/Anemia


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Micrograph showing my

PAS positive (dark pink/

pink - left of image). PA

Atypical plasma cell infil

bodies (H&E, 50x).

Workup

A 59 year-old patient presented wi

of the brain was performed lookin

revealed a lytic lesion in the left te

petrous temporal bones confirmed

Red arrows: lesion; green arrow: n

many in the skull and is consistent

The workup of suspected multip

of the skull, axial skeleton and p"lytic lesions" (with local disapp

rayas "punched-out lesions" (pe

sensitive than simple X-ray in thespecially when vertebral diseas

the size of soft tissue plasmacyto

workup of myeloma patients (noscan).

Abone marrow biopsy is usuallby plasma cells. This percentage

Immunohistochemistry (staining

can detect plasma cells which excell surface; myeloma cells are t

loma cast nephropathy in akidney biopsy. Hyal

ed - right of image). Myelomatous casts are PA

stain.

trate with both Russell (cytoplasmic) and Dutc

h a left facial droop and a known history of multipl

for a cerebral cause. The brain appeared normal.

poral bone (right side of image), and focused reco

a lytic lesion involving the mastoid segment of the

rmal contralateral facial nerve canal. The lytic lesio

ith a myeloma deposit.

e myeloma includes a skeletal survey. This is a

oximal long bones. Myeloma activity sometimearance of normal bone due to resorption), and

per pot skull). Magnetic resonance imaging (

e detection of lytic lesions, and may supersedeis suspected. Occasionally a CT scan is perfor

mas. Bone scans are typically not of any additi

new bone formation; lytic lesions not well visu

performed to estimate the percentage of boneis used in the diagnostic criteria for myeloma.

particular cell types using antibodies against su

press immunoglobulin in the cytoplasm and occpically CD56, CD38, CD138 positive and CD1

ine casts are

S negative (pale

er (nuclear)

myeloma. A CT

lose inspection

nstructions of the

facial nerve canal.

n was one of

series ofX-rays

s appear asn the skull X-

RI) is more

keletal survey,ed to measure

nal value in the

alized on bone

arrow occupied

rface proteins)

asionally on the9 and CD45
http://en.wikipedia.org/wiki/PAS_stainhttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/PAS_stainhttp://en.wikipedia.org/wiki/PAS_stainhttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/CD45http://en.wikipedia.org/wiki/CD19http://en.wikipedia.org/wiki/CD138http://en.wikipedia.org/wiki/CD38http://en.wikipedia.org/wiki/CD56http://en.wikipedia.org/wiki/Immunohistochemistryhttp://en.wikipedia.org/wiki/Diagnostic_criteriahttp://en.wikipedia.org/wiki/Bone_marrow_biopsyhttp://en.wikipedia.org/wiki/Bone_scanhttp://en.wikipedia.org/wiki/CT_scanhttp://en.wikipedia.org/wiki/Vertebralhttp://en.wikipedia.org/wiki/Magnetic_resonance_imaginghttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/Axial_skeletonhttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/Skeletal_surveyhttp://en.wikipedia.org/wiki/Facial_nervehttp://en.wikipedia.org/wiki/Petrous_portion_of_the_temporal_bonehttp://en.wikipedia.org/wiki/Temporal_bonehttp://en.wikipedia.org/wiki/Cerebrumhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Computed_tomographyhttp://en.wikipedia.org/wiki/File:Multiple_myeloma_skull_CT_arrows.PNGhttp://en.wikipedia.org/wiki/File:Multiple_myeloma_skull_CT_arrows.PNGhttp://en.wikipedia.org/wiki/File:Russell_and_Dutcher_bodies.jpghttp://en.wikipedia.org/wiki/PAS_stainhttp://en.wikipedia.org/wiki/Kidney_biopsyhttp://en.wikipedia.org/wiki/Cast_nephropathyhttp://en.wikipedia.org/wiki/Micrograph


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negative.[citation needed][2]

Cytogenetics may also be performed in myeloma for prognostic purposes,

including a myeloma-specific FISH and Virtual Karyotype.

Other useful laboratory tests include quantitative measurement ofIgA, IgG, IgM

(immunoglobulins) to look for immune paresis, andbeta 2-microglobulin which provides

prognostic information. On peripheral blood smear the rouleaux formation ofred blood cells iscommonly 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 alsosuggests 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.[citation needed]

This assay, the serum free light chain assay, has recently been recommended by the InternationalMyeloma Working Groupfor the screening, diagnosis,prognosis, and monitoring of plasma cell

dyscrasias.

The prognosis of myeloma 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 patients into high-risk and standard-risk categories.

Patients with deletion ofchromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14),t(14;16) or17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or

more) are considered to have high-risk myeloma.

Diagnostic criteria

In 2003, the International Myeloma Working Group[2]

agreed on diagnostic criteria forsymptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of

undetermined significance), which was subsequently updated in 2009:[7]

Symptomatic myeloma:1. Clonal plasma cells >10% on bone marrowbiopsy or (in any quantity) in a biopsy from

other tissues (plasmacytoma)

2. A monoclonal protein (paraprotein) in either serum or urine (except in cases of truenon-secretory myeloma)

3. Evidence of end-organ damage felt related to the plasma cell disorder (related organ ortissue impairment, ROTI, commonly referred to by the acronym "CRAB"):

HyperCalcemia (corrected calcium >2.75 mmol/L) Renal insufficiency attributable to myeloma Anemia (hemoglobin


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amyloidosis should be considered as amyloidosis and not myeloma. CRAB like abnormalities

are common with numerous diseases, and it is imperative that these abnormalities are felt to be

directly attributable to the related plasma cell disorder and every attempt made to rule out otherunderlying causes of anemia, renal failure etc.

Asymptomatic (smoldering) myeloma:1. Serum paraprotein >30 g/L AND/OR

2. Clonal plasma cells >10% on bone marrow biopsy AND3. NO myeloma-related organ or tissue impairment

Monoclonal gammopathy of undetermined significance (MGUS):1. Serum paraprotein


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o Skeletal survey: normal or single plasmacytoma or osteoporosiso Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgAo Urinary light chain excretion < 4 g/24h

stage II: fulfilling the criteria of neither I nor III stage III: one or more of

o Hb < 8.5g/dLo high calcium > 12 mg/dLo Skeletal survey: Three or more lytic bone lesionso Serum paraprotein > 7g/dL if IgG, > 5 g/dL if IgAo Urinary light chain excretion > 12g/24h

Stages I, II, and III of the Durie-Salmon staging system can be divided into A or B depending on

serum creatinine:

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

Pathophysiology

B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they

mature and display different proteins on their cell surface. When they are activated to secrete

antibodies, they are known as plasma cells.

Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node

known as the germinal center. The normal cell line most closely associated with MM cells isgenerally taken to be either an activated memory B cell or the precursor to plasma cells, the

plasmablast.[10]

The immune system keeps the proliferation of B cells and the secretion of antibodies under tight

control. When chromosomes and genes are damaged, often through rearrangement, this control is

lost. Often, a promoter gene moves (or translocates) to a chromosome where it stimulates anantibody gene to overproduction.

A chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome14, locus q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11

[11]) 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 allcases of myeloma. Deletion of (parts of) chromosome 13 is also observed in about 50% of cases.

Production ofcytokines[12]

(especially IL-6) by the plasma cells causes much of their localised

damage, such as osteoporosis, and creates a microenvironment in which the malignant cellsthrive. Angiogenesis(the attraction of new blood vessels) is increased.
http://en.wikipedia.org/wiki/Plasmablasthttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Chromosome_14http://en.wikipedia.org/wiki/Chromosome_14http://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Angiogenesishttp://en.wikipedia.org/wiki/Angiogenesishttp://en.wikipedia.org/wiki/Angiogenesishttp://en.wikipedia.org/wiki/Osteoporosishttp://en.wikipedia.org/wiki/Interleukin_6http://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Oncogenehttp://en.wikipedia.org/wiki/Chromosome_14http://en.wikipedia.org/wiki/Chromosome_14http://en.wikipedia.org/wiki/Heavy_chainhttp://en.wikipedia.org/wiki/Chromosomal_translocationhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Plasmablasthttp://en.wikipedia.org/wiki/Memory_B_cellhttp://en.wikipedia.org/wiki/Germinal_centerhttp://en.wikipedia.org/wiki/B_lymphocyteshttp://en.wikipedia.org/wiki/B_lymphocytes


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The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy

and various other myeloma-associated symptoms.

Treatment

Treatment for multiple myeloma is focused on therapies that decrease the clonal plasma cellpopulation and consequently decrease the signs and symptoms of disease. If the disease is

completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population

but no end-organ damage), as in smoldering myeloma, treatment is typically deferred, orrestricted to clinical trials.

[13]

In addition to direct treatment of the plasma cell proliferation,bisphosphonates (e.g.pamidronateorzoledronic acid) are routinely administered to prevent fractures; they have also been observed

to have direct anti-tumor effect even in patients without known skeletal disease. If needed, red

blood cell transfusions orerythropoietin can be used for management of anemia.

Initial therapy

Initial treatment of multiple myeloma depends on the patients age and comorbidities. In recentyears, high-dose chemotherapy with autologous hematopoietic stem-cell transplantation has

become the preferred treatment for patients under the age of 65. Prior to stem-cell

transplantation, these patients receive an initial course of induction chemotherapy. The mostcommon induction regimens used today are thalidomidedexamethasone,bortezomib based

regimens, and lenalidomidedexamethasone.[14][15]

Autologous stem cell transplantation (ASCT),

the transplantation of a patients own stem cells after chemotherapy, is the most common type ofstem cell transplantation for multiple myeloma. It is not curative, but does prolong overall

survival and complete remission. Allogeneic stem cell transplantation, the transplantation of a

healthy persons stem cells into the affected patient, has the potential for a cure, but is onlyavailable to a small percentage of patients.

[11]Furthermore, there is a 510% treatment-

associated mortality rate.

Patients over age 65 and patients with significant concurrent illness often cannot tolerate stem

cell transplantation. For these patients, the standard of care has been chemotherapy with

melphalan and prednisone. Recent studies among this population[16]

suggest improved outcomeswith new chemotherapy regimens, e.g. withbortezomib.

[17]Treatment with bortezomib,

melphalan, and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide

plus low-dose dexamethasone an 82% survival at 2 years and melphalan, prednisone and

lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens

have not been performed.[18]

A 2009 review noted "Deep venous thrombosis and pulmonary embolism are the major side

effects of thalidomide and lenalidomide. Lenalidomide causes more myelosuppression, and

thalidomide causes more sedation. Peripheral neuropathy and thrombocytopenia are major side

effects of bortezomib."[19]
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Treatment of related hyperviscosity syndrome may be required to prevent neurologic symptoms

orrenal failure.[20][21]

Maintenance therapy

Sometimes after the initial treatment an ongoing maintenance therapy is offered. A 2009 reviewof maintenance therapy concluded "In younger patients, post-ASCT maintenance therapy with

thalidomide appears to increase tumor burden reduction further, which translates in[to]

prolonged PFS (Progression-free survival)."[22]

A different 2009 review stated "the role of maintenance therapy with thalidomide, lenalidomide,

or bortezomib for patients with multiple myeloma is not definitively established; such therapyshould be performed only in the context of a clinical trial."

[23]

Relapse

The natural history of myeloma is of relapse following treatment. Depending on the patient'scondition, the prior treatment modalities used and the duration of remission, options for relapseddisease include re-treatment with the original agent, use of other agents (such as melphalan,

cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second

autologous stem cell transplant.

Later in the course of the disease, "treatment resistance" occurs. This may be a reversible

effect,[11]

and some new treatment modalities may re-sensitize the tumor to standard therapy. Forpatients with relapsed disease,bortezomib (or Velcade) is a recent addition to the therapeutic

arsenal, especially as second line therapy, since 2005. Bortezomib is aproteasome inhibitor.

Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for

treating myeloma. More and more patients survive longer and longer, thanks to stem celltransplant (with their own or a donor's) and treatments combining Bortezomib (Velcade),

Dexamethasone (corticoid) and melphalan or cyclophosphamide (Endoxan).This seems to

maintain the monoclonal peak at a reasonable level. Survival expectancy is then rising, and newtreatments are being developed.

Renal failure in multiple myeloma can be acute (reversible) orchronic (irreversible). Acute renalfailure typically resolves when the calcium and paraprotein levels are brought under control.

Treatment of chronic renal failure is dependent on the type of renal failure and may involve

dialysis.

Prognosis

With high-dose therapy followed by autologous stem cell transplantation, the median survival

has been estimated in 2003 to be approximately 4.5 years, compared to a median of

approximately 3.5 years with "standard" therapy.[24]
http://en.wikipedia.org/wiki/Renal_failurehttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Progression-free_survivalhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Dialysishttp://en.wikipedia.org/wiki/Dialysishttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Medianhttp://en.wikipedia.org/wiki/Autologous_stem_cell_transplantationhttp://en.wikipedia.org/wiki/Dialysishttp://en.wikipedia.org/wiki/Chronic_renal_failurehttp://en.wikipedia.org/wiki/Acute_renal_failurehttp://en.wikipedia.org/wiki/Lenalidomidehttp://en.wikipedia.org/wiki/Proteasomehttp://en.wikipedia.org/wiki/Bortezomibhttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Progression-free_survivalhttp://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Renal_failurehttp://en.wikipedia.org/wiki/Hyperviscosity_syndrome


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The International Staging Syste

of 62 months for stage 1 disease,

disease.[8]

The prognoses for patients with

for everyone. The average age oserious diseases, which affect su

Genetic testing

Some myeloma centers now em

examining DNA, oncologists careturning quickly following treat

Cytogenetic analysis of myelom13, non-hyperdiploidy and the b

prognosis. The 11q13 and 6p21

Prognostic markers such as thes

that new treatment developmentrisk" disease.

SNP array karyotyping can detecmissed by a targeted FISH panel

cytogenetics informative in only

1. Virtual karyotyping identifi2.

del(12p13.31) is an indepe

3. amp(5q31.1) is a favorable4. The prognostic impact of a

patients who greatly benef

Array-based karyotyping cannot

MM. Therefore, FISH for this tr

detect genome-wide copy numb

Epidemiology

can help to predict survival, with a median sur

45 months for stage 2 disease, and 29 months

ultiple myeloma, as those with other diseases,

onset is 70 years. Older patients often are expevival. Younger patients might have much long

loy genetic testing, which they call a gene arr

determine if patients are high risk or low riskment.

cells may be ofprognostic value, with deletiolanced translocations t(4;14) and t(14;16) conf

ytogenetic abnormalities are associated with a

are always generated by retrospective analyses

will improve the outlook for those with traditi

t copy number alterations of prognostic signific.[25]

In MM, lack of a proliferative clone makes

~30% of cases.

d chromosomal abnormalities in 98% of MM cases

dent adverse markermarker

p(5q31.1) over-rides that of hyperdiploidy and als

it from high-dose therapy.

detect balanced translocations, such as t(4;14) s

nslocation should also be performed if using S

r alterations of prognostic significance in MM.

vival (in 2005)

or stage 3

are not the same

riencing otherr survival rates.

y. By

f the cancer

of chromosomerring a poorer

etter prognosis.

, and it is likely

nally "poor-

ance that may beconventional

o identifies

een in ~15% of

P arrays to
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Age-standardized death fromlymphomas and multiple myeloma per 100,000 inhabitants in 2004.[26]

no data

less than 1.8

1.83.6

3.65.4

5.47.2

7.29

910.8

10.812.6

12.614.4

14.416.2

16.218

1819.8

more than 19.8

Multiple myeloma, globally, resulted in about 74,000 deaths in 2010 up from 49,000 in 1990.[27]

There are approximately 71,213 people in the United States living with multiple myeloma andaccording to Surveillance Epidemiology and End Results data an estimated 21,700 new cases of

myeloma were diagnosed in 2012 in the United States. The age-adjusted incidence rate for

multiple myeloma is 5.8 per 100,000 per year.

Multiple myeloma is the second most prevalent blood cancer (10%) afternon-Hodgkin's

lymphoma.[28]

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[citation needed]

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 thelowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000African 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.

A familial predisposition to myeloma exists.[29]

Hyperphosphorylation of a number of proteins -

the paratarg proteins - a tendency which is inherited in an autosomal dominant manner appears a
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common mechanism in these familes. This tendency is more common in African American

patients with myeloma and may contribute to the higher rates of myeloma in this group.[29]

Other animals

Multiple myeloma affects many other species. The disease has been diagnosed in dogs,[30] cats,and horses.

[31]

In dogs, multiple myeloma accounts for around 8% of all haemopoietic tumors. Multiplemyeloma occurs in older dogs, and is not particularly associated with either males or females. No

species appear over represented in case reviews that have been conducted.[32]

Diagnosis in dogs

is usually delayed due to the initial non specificity and range of clinical signs possible. Diagnosisusually involves bone marrow studies, X-rays, and plasma protein studies. In dogs, protein

studies usually reveal the monoclonal gammaglobulin elevation to be IgA or IgG in equal

incidence.[32]

In rare cases the globulin elevation is IgM, which is referred to as Waldenstrm's

macroglobulinemia.[33]

The prognosis for initial control and return to good quality of life in dogs

is good. 43% of dogs started on a combination chemotheraputic protocol achieved completeremission. Long term survival is normal with a median of 540 days reported.

[32]Recurrence is

expected eventually, and although rescue protocols can be attempted, recurrences are oftenresistant to available chemotheraputics, and death commonly eventually follows from

complications such as renal failure, sepsis or pain related owner initiated euthanasia.

See also

Discovery and development of thalidomide and its analogs Waldenstrm macroglobulinemia Plasma cell leukemia, an aggressive form of MM Multiple Myeloma Research Consortium Multiple Myeloma Research Foundation International Myeloma Foundation Virtual Karyotype

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