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eMedicine Specialties > Hematology > Plasma Cell Disorders

Multiple Myeloma
Author: Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal
Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University
Coauthor(s): Lilian M Thomas, MD, Fellow, Department of Hematology/Oncology, State University of New York Upstate
Medical University
Contributor Information and Disclosures
Updated: Jun 28, 2010

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 Overview
 Differential Diagnoses & Workup
 Treatment & Medication
 Follow-up
 Multimedia

 References
 Keywords
 Further Reading

Introduction

Background
Multiple myeloma (see images below) is a debilitating malignancy that is part of a spectrum
of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to
plasma cell leukemia. First described in 1848, multiple myeloma is a disease characterized
by a proliferation of malignant plasma cells and a subsequent overabundance of
monoclonal paraprotein. An intriguing feature of multiple myeloma is that the antibody-
forming cells (ie, plasma cells) are malignant and, therefore, may cause unusual
manifestations.

Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue
cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are
(c) 2002 by the American Society of Hematology. All rights reserved.
Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma.
All images and text are (c) 2002 by the American Society of Hematology. All rights
reserved.
The presentation of multiple myeloma can range from asymptomatic to severely
symptomatic with complications requiring emergent treatment. Systemic ailments include
bleeding, infection and renal failure; local catastrophes include pathologic fractures and
spinal cord compression. Although patients benefit from treatment (ie, longer life, less pain,
fewer complications), currently no cure exists. Recent advances in therapy have helped to
lessen the occurrence and severity of adverse effects of multiple myeloma.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System
Center. Also, see eMedicine's patient education article Myeloma.
Pathophysiology
Multiple myeloma can cause a wide variety of problems. The proliferation of plasma cells
may interfere with the normal production of blood cells, resulting in leukopenia, anemia, and
thrombocytopenia. The cells may cause soft-tissue masses (plasmacytomas) or lytic lesions
in the skeleton. Feared complications of multiple myeloma are bone pain, hypercalcemia,
renal failure, and spinal cord compression. The aberrant antibodies that are produced lead
to impaired humoral immunity, and patients have a high prevalence of infection, especially
with encapsulated organisms such as Pneumococcus. The overproduction of these
antibodies may lead to hyperviscosity, amyloidosis, and renal failure.
Frequency
United States

The age-adjusted annual incidence of multiple myeloma is 4.3 cases per 100,000 white
men, 3 cases per 100,000 white women, 9.6 cases per 100,000 black men, and 6.7 cases
per 100,000 black women.

Mortality/Morbidity
Multiple myeloma affects the kidneys in several ways. The most common mechanisms of
renal injury are direct tubular injury, amyloidosis, or involvement by plasmacytoma. 1,2
Physicians manage the acute clinical condition with plasmapheresis to rapidly lower
circulating abnormal proteins. Data about this approach are limited, but a small randomized
study showed a survival advantage with the use of apheresis. 2 Conventional therapy may
take weeks to months to show a benefit. Renal impairment resulting from multiple myeloma
is associated with a very poor prognosis. A recent case series demonstrated that patients
with renal failure from myeloma may benefit from autologous stem cell transplants, and as
many as one third may demonstrate improvement in their renal function with this approach. 3

Spinal cord compression is one of the most severe adverse effects of multiple myeloma.
Reports indicate that as many as 20% of patients develop spinal cord compression at some
point during the course of their disease. Symptoms typically include back pain, weakness or
paralysis in the legs, numbness, or dysesthesias in the lower extremities. However,
depending on the level of involvement, patients may present with upper extremity
symptoms.

The mechanism of these symptoms may be the development of an epidural mass with
compression, a compression fracture of a vertebral body destroyed by multiple myeloma,
or, rarely, an extradural mass. The dysfunction may be reversible, depending on the
duration of the cord compression; however, once established, the dysfunction is only rarely
fully reversed.

A frequent complication of multiple myeloma is pathologic fractures. Bony involvement is

typically lytic in nature. Physicians should orthopedically stabilize (ie, typically pin) and
irradiate these lesions. Careful attention to a patient's bony symptoms, intermittent
radiographic surveys, and the use of bisphosphonates may be useful to prevent
fractures.4,5,6

Patients with multiple myeloma commonly develop hypercalcemia. The mechanisms include
bony involvement and, possibly, humoral mechanisms. Treatment for myeloma-induced
hypercalcemia is the same as that for other malignancy-associated hypercalcemia;
however, the dismal outcome observed with hypercalcemia in solid tumors is not observed
in multiple myeloma.

Race
Multiple myeloma accounts for 1.1% of the malignancies in white US residents and 2.1% of
the malignancies in black residents.

Sex
The male-to-female ratio of multiple myeloma is 3:2.

Age
The median age of patients with multiple myeloma is 68 years for men and 70 years for
women.

Clinical

History
Presenting symptoms of multiple myeloma include bone pain, pathologic fractures,
weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal cord
compression, or renal failure. Increasingly, physicians are identifying asymptomatic patients
through routine blood screening. Typically, a large gap between the total protein and the
albumin levels observed on an automated chemistry panel suggests a problem (ie, protein
minus albumin equals globulin).

 Bone pain
o This is the most common presenting symptom in multiple myeloma. Most
case series report that 70% of patients have bone pain at presentation.
o The lumbar spine is one of the most common sites of pain.
 Pathologic fractures and bone lesions
o Pathologic fractures are very common in multiple myeloma; 93% of patients
have more than one site of bony involvement.
o A severe bony event is a common presenting issue.
 Spinal cord compression
o This complication occurs in approximately 10-20% of patients with multiple
myeloma at some time during the course of disease.
o The symptoms that should alert physicians to consider spinal cord
compression are back pain, weakness, numbness, or dysesthesias in the
extremities.
o It is common for spinal cord compressions in multiple myeloma to occur at
multiple levels, so comprehensive evaluation of the spine is warranted.
o Patients who are ambulatory at the start of therapy have the best likelihood of
preserving function and avoiding paralysis.
 Bleeding
o Occasionally, a patient may come to medical attention for bleeding resulting
from thrombocytopenia.
o Rarely, monoclonal protein may absorb clotting factors and lead to bleeding.
 Hypercalcemia
o Confusion, somnolence, bone pain, constipation, nausea, and thirst are the
presenting symptoms of hypercalcemia.
o This complication may be present in as many as 30% of patients with multiple
myeloma at presentation. In most solid malignancies, hypercalcemia carries
an ominous prognosis, but in multiple myeloma, its occurrence does not
adversely affect survival.
 Infection
 o Abnormal humoral immunity and leukopenia may lead to infection.
o Pneumococcal organisms are commonly involved, but shingles (ie, herpes
zoster) and Haemophilus infections are also more common among patients
with multiple myeloma.
 Hyperviscosity
o Epistaxis may be a presenting symptom of multiple myeloma with a high
tumor volume. Occasionally, patients may have such a high volume of
monoclonal protein that their blood viscosity increases, resulting in
complications such as stroke, myocardial ischemia, or infarction.
o Patients may report headaches and somnolence, and they may bruise easily
and have hazy vision. Patients with multiple myeloma typically experience
these symptoms when their serum viscosity is greater than 4 times that of
normal serum.
 Neurologic symptoms
o Carpal tunnel syndrome is a common complication of myeloma.
o Meningitis (especially that resulting from pneumococcal or meningococcal
infection) is more common in patients with multiple myeloma.
o Some peripheral neuropathies have been attributed to multiple myeloma.
 Anemia
o Anemia, which may be quite severe, is the most common cause of weakness
in patients with multiple myeloma.

Physical

 Pallor from anemia may be present.

 Ecchymoses or purpura from thrombocytopenia may be evident.
 Bony tenderness is not uncommon in multiple myeloma, resulting from focal lytic
destructive bone lesions or pathologic fracture. Pain without tenderness is typical.
 Neurologic findings may include a sensory level change (ie, loss of sensation below
a dermatome corresponding to a spinal cord compression), weakness, or carpal
tunnel syndrome.
 Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells,
are not uncommon. Plasmacytomas have been described in almost every site in the
body. Although the aerodigestive tract is the most common location, reports also
describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal
lesions.
 Amyloidosis may develop in some patients with multiple myeloma. The characteristic
physical examination findings that suggest amyloidosis include the following:
o The shoulder pad sign is defined by bilateral swelling of the shoulder joints
secondary to amyloid deposition. Physicians describe the swelling as hard
and rubbery. Amyloidosis may also be associated with carpal tunnel
syndrome and subcutaneous nodules.
o Macroglossia is a common finding in patients with amyloidosis (see image
below).

 Amyloidosis infiltrating the tongue in multiple myeloma. All images
and text are (c) 2002 by the American Society of Hematology. All
rights reserved.

o Skin lesions that have been described as waxy papules or nodules may occur
on the torso, ears, or lips.
o Postprotoscopic peripalpebral purpura strongly suggests amyloidosis.
Patients may develop raccoonlike dark circles around their eyes following any
procedure that parallels a prolonged Valsalva maneuver. The capillary
fragility associated with amyloidosis may account for this observation. In the
 past, this correlation was observed when patients underwent rectal biopsies
to make the diagnosis.
 The most widely accepted schema for the diagnosis of multiple myeloma uses
particular combinations of laboratory, imaging, and procedure findings as diagnostic
criteria. The findings are as follows:
o I = Plasmacytoma on tissue biopsy
o II = Bone marrow with greater than 30% plasma cells
o III = Monoclonal globulin spike on serum protein electrophoresis, with an
immunoglobulin (Ig) G peak of greater than 3.5 g/dL or an IgA peak of greater
than 2 g/dL, or urine protein electrophoresis (in the presence of amyloidosis)
result of greater than 1 g/24 h
o a = Bone marrow with 10-30% plasma cells
o b = Monoclonal globulin spike present but less than category III
o c = Lytic bone lesions
o d = Residual IgM level less than 50 mg/dL, IgA level less than 100 mg/dL, or
IgG level less than 600 mg/dL
 The following combinations of findings are used to make the diagnosis of multiple
myeloma:
o I plus b, c, or d
o II plus b, c, or d
o III plus a, c, or d
o a plus b plus c
o a plus b plus d

Causes

 Genetic causes
o A study by the Mayo clinic found multiple myeloma in 8 siblings from a group
of 440 patients; these 8 siblings had different heavy chains but the same light
chains.
o Ongoing research is investigating whether human leukocyte antigen (HLA)-
Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma.
 Environmental or occupational causes: Case-controlled studies have suggested a
significant risk of developing multiple myeloma in individuals with significant
exposures in the agriculture, food, and petrochemical industries. Long-term (>20 y)
exposure to hair dyes has been tied to an excessive risk of developing multiple
myeloma.
 MGUS: Approximately 19% of patients with MGUS develop multiple myeloma within
2-19 years.
 Radiation
o Radiation has been linked to the development of multiple myeloma.
o In 109,000 survivors of the atomic bombing of Nagasaki during World War II,
29 died from multiple myeloma between 1950 and 1976; however, some
more recent studies do not confirm that these survivors have an increased
risk of developing multiple myeloma.
 o A recent study of workers at the Oak Ridge Diffusion Plant in eastern
Tennessee showed only a weak correlation of risk of multiple myeloma to
uranium exposure.7

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

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Multiple myeloma

Classification and external resources

Micrograph of a plasmacytoma, the histologic correlate

of multiple myeloma. H&E stain.
ICD - 10 C 90.0

ICD -9 203.0

M 9732/3
ICD-O:

OMIM 254500

8628
DiseasesDB

000583
MedlinePlus

med/1521
eMedicine

D009101
MeSH

Multiple myeloma (from Gk.myelo-, bone marrow), also known as MM, myeloma, plasma cell
myeloma, or as Kahler's disease (after Otto Kahler) is a cancer of the white blood cells known
as plasma cells.[1] A type of B cell, plasma cells are a crucial part of the immune system
responsible for the production of antibodies in humans and other vertebrates. They are produced
in the bone marrow and are transported through the lymphatic system. Due to the fundamental
nature of the system affected, multiple myeloma manifests systemic symptoms that make it
difficult to diagnose. Myeloma is generally thought to be incurable, but remissions may be
induced with steroids, chemotherapy, thalidomide and stem cell transplants.[2] Despite the name
myeloma, this form of cancer does not involve myeloid cells, as plasma cells are lymphoid, but is
so named because it mainly involves the myelum (bone marrow).
There were 15,271 cases diagnosed and 11,070 deaths in the United States in 2004, and an
incidence of 4/100,000 worldwide.[3] Median survival is 50–55 months.[4] Chromosome diagnosis
can separate patients into more or less favorable prognoses.
Myeloma is part of the broad group of diseases called hematological malignancies.

Contents
[hide]

 1 Signs and symptoms

o 1.1 Bone pain
o 1.2 Infection
o 1.3 Renal failure
o 1.4 Anemia
o 1.5 Neurological symptoms
 2 Diagnosis
o 2.1 Investigations
o 2.2 Workup
o 2.3 Diagnostic criteria
o 2.4 Staging
 3 Pathophysiology
 4 Treatment
o 4.1 Initial therapy
o 4.2 Relapse
 5 Prognosis
 6 Epidemiology
 7 Gallery
 8 See also
 9 References
 10 External links

[edit] 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 of multiple myeloma is CRAB: C =
Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.[5] Myeloma has many
possible symptoms, and all symptoms may be due to other causes. They are presented here in
decreasing order of incidence.

[edit] Bone pain

Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent
localized pain may indicate a pathological bone fracture. Involvement of the vertebrae may lead
to spinal cord compression. Myeloma bone disease is due to the overexpression of Receptor
Activator for Nuclear Factor κ B Ligand (RANKL) by bone marrow stroma. RANKL activates
osteoclasts, which resorb bone. The resultant bone lesions are lytic in nature and are best seen in
plain radiographs, which may show "punched-out" resorptive lesions (including the "pepper pot"
appearance of the skull on radiography). The breakdown of bone also leads to release of calcium
into the blood, leading to hypercalcemia and its associated symptoms.

[edit] 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 greatest risk
period for the occurrence of infection is in the initial few months after the start of chemotherapy.
[6]
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. A selected group of patients may benefit from replacement immunoglobulin
therapy to reduce the risk of infection.[7]

[edit] 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, also called
Bence Jones proteins, 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.

[edit] 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.

[edit] 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.

[edit] Diagnosis
[edit] Investigations

Serum protein electrophoresis showing a paraprotein (peak in the gamma zone) in a patient with
multiple myeloma.
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.

[edit] Workup

A 59 year-old patient presented with a left facial droop and a known history of multiple
myeloma. A CT of the brain was performed looking for a cerebral cause. The brain appeared
normal. Close inspection revealed a lytic lesion in the left temporal bone (right side of image),
and focused reconstructions of the petrous temporal bones confirmed a lytic lesion involving the
mastoid segment of the facial nerve canal. Red arrows: lesion; green arrow: normal contralateral
facial nerve canal. The lytic lesion was one of many in the skull and is consistent with a
myeloma deposit.
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. Bone scans are typically not of any additional value in the
workup of myeloma patients (no new bone formation, lytic lesions not well visualized on bone
scan).
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.[5] 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 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.[citation needed]
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.
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 of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14),
t(14;16) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or
more) are considered to have high-risk myeloma.

[edit] Diagnostic criteria

In 2003, the International Myeloma Working Group[5] agreed on diagnostic criteria for
symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of
undetermined significance), which was subsequently updated in 2009:[8]

 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(except in cases of
true non-secretory myeloma)
 3. Evidence of end-organ damage felt related to the plasma cell disorder (related
organ or tissue impairment, ROTI, commonly referred to by the acronym
"CRAB"):
 HyperCalcemia (corrected calcium >2.75 mmol/L)
 Renal insufficiency attributable to myeloma
 Anemia (hemoglobin <10 g/dL)
 Bone lesions (lytic lesions or osteoporosis with compression fractures)

Note: Recurrent infections alone in a patient who has none of the CRAB features is not sufficient
to make the diagnosis of myeloma. Patients who lack CRAB features but have evidence of
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 other
underlying causes of anemia, renal failure etc.

 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
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).

[edit] Staging

International Staging System

The International Staging System (ISS) for myeloma was published by the International
Myeloma Working Group in 2005:[9]

 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 >= 3.5 and < 5.5
 Stage III: β2M >= 5.5

Note that the ISS should be used only in patients who meet diagnostic criteria for myeloma.
Patients with MGUS and asymptomatic myeloma who have renal dysfunction from unrelated
causes such as diabetes or hypertension may have elevated β2M levels just from the renal
dysfunction and cannot be considered as stage III myeloma. This is one of the main drawbacks
of the ISS. It does not really quantify tumor burden or extent unlike staging systems used in other
cancers. It is more of a prognostic index rather than a true staging system. For this reason, it is
recommended that the ISS be used along with the Durie Salmon Staging System (see below)
Durie-Salmon staging system
First published in 1975, the Durie-Salmon staging system[10] is still in use:

 stage I: 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 II: fulfilling the criteria of neither I nor III
 stage III: one or more of
o Hb < 8.5g/dL
o high calcium > 12 mg/dL
o Skeletal survey: Three 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 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)

[edit] 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 is
generally taken to be either an activated memory B cell or the precursor to plasma cells, the
plasmablast.[11]
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 an
antibody gene to overproduction.
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[2]) 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[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 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.

[edit] Treatment

Treatment for multiple myeloma is focused on disease containment and suppression. If the
disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow
population but no end-organ damage), treatment may be deferred.
In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate
or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat
anemia.

[edit] Initial therapy

Initial treatment of multiple myeloma depends on the patient’s age and comorbidities. In recent
years, high-dose chemotherapy with 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 most common induction
regimens used today are thalidomide–dexamethasone, bortezomib based regimens, and
lenalidomide–dexamethasone.[13] Autologous stem cell transplantation, the transplantation of a
patient’s own stem cells after chemotherapy, is the most common type of stem cell
transplantation for multiple myeloma. It is not curative, but does prolong overall survival.
Allogeneic stem cell transplantation, the transplantation of a healthy person’s stem cells into the
affected patient, has the potential for a cure, but is only available to a small percentage of
patients. [2] Furthermore, there is a 5-10% 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[14] suggest improved outcomes
with new chemotherapy regimens. 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.[15]

[edit] Relapse

The natural history of myeloma is of relapse following treatment. Depending on the patient's
condition, the prior treatment modalities used and the duration of remission, options for relapsed
disease 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,
[2]
and some new treatment modalities may re-sensitize the tumor to standard therapy. For
patients with relapsed disease, bortezomib (or Velcade) is a recent addition to the therapeutic
arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor.
Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for
treating myeloma.
Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal
failure 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.

[edit] Prognosis
The International Staging System can help to predict survival, with a median survival of 62
months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.[9]
Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome
13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer
prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.
Prognostic markers such as these are always generated by retrospective analyses, and it is likely
that new treatment developments will improve the outlook for those with traditionally "poor-
risk" disease.
SNP array karyotyping can detect copy number alterations of prognostic significance that may be
missed by a targeted FISH panel.[16] In MM, lack of a proliferative clone makes conventional
cytogenetics informative in only ~30% of cases.

1. Virtual karyotyping identified chromosomal abnormalities in 98% of MM cases

2. del(12p13.31)is an independent adverse marker
3. amp(5q31.1) is a favorable marker
4. The prognostic impact of amp(5q31.1) over-rides that of hyperdiploidy and also identifies
patients who greatly benefit from high-dose therapy.

Array-based karyotyping cannot detect balanced translocations, such as t(4;14) seen in ~15% of
MM. Therefore, FISH for this translocation should also be performed if using SNP arrays to
detect genome-wide copy number alterations of prognostic significance in MM.
According to the Multiple Myeloma Research Foundation, some myeloma patients live for more
than 15 years after diagnosis.[citation needed]