CASE 19
Multiple Myeloma
IM-p
Topics bearing on
this case:
A malignancy of terminally differentiated
B lymphocytes,
of
- The develp@ment
B lymphocytéS'
Monospecificity
of
B-cell receptors
Malignant tumors result from the outgrowth of a single transformed cell.
can
Malignant tumors that result from the clonal outgrovfth of B lymphocytes
Structure Ofthe
antibody rholeéule
express clonotypic immunoglobulin molecules derived from the same
ureatrahgement
cells
occur at all stages of B-cell development (Fig. 19.1). These malignant B
immunoglobulin gene rearrangement, either on their surface or as secreted
monoclonal antl%ody.
Malignancies of plasma cells cause a disease called multiple myeloma. It is a
disease of bone because these plasma-cell tumors arise in the bone marrow.
As the tumor masses expand, they cause local erosions of the bone, and the
appearance on radiographs of multiple bone lesions (Fig.19.2).
gene
Immunoglobulin
B-cell tumors
Measurement of
immunoglobulins
iso peswithing
Case 19: Multiple Myeloma
Fig. 19.1 B-cell tumors represent clonal
outgrowths of B cells at various stages
of development. Each type of tumor cell
has a normal B-cell equivalent, homes to
similar sites, and has behavior similar to that
cell. Thus, myelomacells look much like the
plasma cells from which they derive, they
secrete immunoglobulin,and they are found
predominantlyin the bone marrow. Many
lymphomas and myelomas may go through
a preliminaryless aggressive
lymphoproliferativephase, and some mild
lymphoproliferationsappear to be benign.
Name ot tumor,
Chronic lymphocytic
Npkmal cell equivafeot
Lbcation
CD5 B-l cell
Blood
'Statu"ig
genes
Mutated
leukemia
Acute lymphoblastic
Unmutated
Lymphoid progenitor
Bone
leukemia
marrow
and
Pre-B cell leukemia
Mantle cell lymphoma
Unmutated
Pre-B cell
Unmutated
Resting naive B cell
Mutated,
intraclonal
variability
Follicular center cell
lymphoma
Mature B cell
Burkiffs lymphoma
Periphery
Mutated
Hodgkin's lymphoma
Germinal center B cell
intraclonal
variability
WaldenströmS
B cell
lgM-secreting
no variability
Mutated,
macroglobulinemia
Multiple myeloma
Plasma cell.
Various isotypes
(O
withinclone
Mutated,
no variability
withinclone
These myelomas secrete a staggering amount of monoclonal immunoglobulin,
which may be of the IgG or IgA,or very rarely IgD or IgE, isotype, bearing
either kappa (K)or lambda (X)light chains (Fig.19.3).The malignant plasma
cells asynchronously synthesize more light chains than heavy chains, so that
Fig. 19.2 Radiographs of the skull and a
long bone in a patient with multiple
myeloma. Note the 'punched out lesions in
the bones, where the accumulation of
malignantplasma cells has eroded the
normalcalcification.Courtesy of L. Shulman.
Case 19: Multiple Myeloma
lgG
lgM
Fig. 19.3 The structural organization of the main human
immunoglobulin isotype monomers. The choice of constant-region
gene detemines the class or isotype of the immunoglobulinmade.
Both lgM and lgE lack a hinge region but each contains an extra
lgD
lgA
lgE
of
heavy-chain C domain. The isotypes also differ in the distribution
N-linked carbohydrate groups, as shown in turquoise, and in the
distributionof disulfide bonds (black line).
immmunoglobulinlight chains are excreted in the urine in excessive
amounts. In 1846Dr Charles McIntyre, a physician practicing medicine in
London, made
a house callon a greengrocer residing in Devonshire Street.
Seeing this unfortunate man wasting away with fragile bone disease, it
occurred to Dr McIntyre that he might be losing excessive amounts of protein
Canimal matter') in his urine. He took a urine specimen back to his consulting
rooms and found that, upon heating, a precipitate formed in the urine
between 45 and 600C, and redissolved upon further heating of the urine to
boiling point. On the followingday, he sent a specimen of this urine to Dr
Henry Bence-Jones, Professor of Clinical Chemistry at Guys Hospital, with a
complete description of the bizarre characteristics of the abnormal protein
that precipitated, and a question: 'What is this?' The protein was thenceforth
known as a Bence-Jones protein. It took over 100 years to answer the question
but, eventually, Bence-Jones proteins were found to be immunoglobulin light
chains.
The case of Isabel Archer: the consequences of
unrestrained growth of an
B-cell clone,
Isabel Archer was a 55-year•oldhousewife in 1989, when she began to experience
excessive fatigue. She had been in good health her entire life. Her 57-year-old
husband, a successful lawyer, was also in good health, as were her three sons, all
in their 20s. At the time of a routine annual check-up at her physician she reported
to him how easily she became fatigued. He found no abnormalities on physical
examination.
A blood sample revealed that she had mild anemia; her red blood cell count was
3.5 x 106 PI-I (normal 4.2-5.0 x 106 PI-I ). Her white blood cell count was 3600 PI-I
(normal 5000 gJ-1). The sedimentation rate of her red blood cells was 32 mm h-l
(normal <20 mm tr i ). Unclotted whole blood from Mrs Archer was put in a narrowbore tube to determine how far the red blood cells would sediment in 1 hour.
easilyfatiy
11
Case 19: MultipleM e ma
Fig. 19.4 Electrophoresis indicates
whether serum immunoglobulins have
monoclonal components. An
electrophoretic patternof normal serum run
to
on an agarose gel (lane I) is shown next
the pattern obtained with a serum sample
2
from Mrs Archer (lane 2). The heterogeneous
immunoglobulins from normal serum stained
as a smear, whereas the monoclonal
componentof Mrs Archers serum ran as a
kite, elev._
levels
rise..
tight proteinband. The electrophoresis was
performedagain with normal serum (lanes 3
+ 5) and MrsArchers serum (lanes 4 + 6)
and this reacted with an antibody to chains
(lanes 3 + 4) and antibody to K chains
(lanes 5 + 6). The agarose gel was washed
to remove all proteins except for
antigen:antibodycomplexes. This shows
that Mrs Archers myeloma protein was
lgGK
by rouleaux formation, in which red
Sedimentation of the red blood cells is caused
hastened when the fibrinogen or lgG
blood cells stack on one another, and is
This elevated sedimentation rate prompted
content of the blood plasma is elevated.
immunoglobulins. The concentration of lgG was
the measurementof her serum
mg dl-l ), that of lgA 14 mg dl-l (normal
found to be 3790mg dl-l (normal 600-1500
dl-l (normal 75-150 mg dl-l ).
150-250 mg dl-l ) and that of lgM 53 mg
presence of a monoclonal protein, which
Electrophoresis of her serum revealed the
kappa light chains (Fig. 19.4).
on further analysis was found to be lgG with
any abnormality. No treatmentwas
Radiographs of all of her bones did not show
advised.
physician and on each occasion he
Mrs Archer returnedfor regular visits to her
was gradually increasing. In April
measured her serum lgG level and noticed that it
January 1992 it was 5100 mg dl-l . By
1991 her serum lgG was 4520 mg dl-l , and in
her red blood cell count had fallen
November 1992, her anemia had worsened and
blood
to 3.0 x 106 PI-I . At the same time her white
Pla5tøacyfama
al}horacic
•econ
-I G
al
levelieep5ti5iMY.
count had fallen to 2600 PI-I .
sudden onset of upper back pain.
In December 1992,Mrs Archer experienced the
radiograph of the thoracic spine
She was referredto a radiologist who performeda
reported to the internist
followed by a magnetic resonance imaging (MRI) scan. He
body with extrusion of a
that he found destructionof the second thoracic vertebral
plasmacytoma (a tumor of plasma cells) from the affected vertebral body
corticosteroid,
compressing the spinal cord. Mrs Archer was treated with the
her
decadron, and irradiationto her spine. Her symptoms improved. However,
serum lgG level reached 6312 mg dl-l and she required blood transfusions because
of her worsening anemia.She was treatedwith melphalan and prednisone.
In April 1993, furtherchemotherapywas given because of the persisting elevation
of her serum IgG. She was treated for 9 months with vincristine, adriamycin, and
decadron and her serum lgG fell from 6785 mg dl-l to 5308 mg dl-l . When her
serum lgG subsequently rose to 8200 mg dl-l she was treated with a course of
cyclophosphamide, etoposide, and decadron, which reduced her serum lgG level to
6000 mg dl--l .
In February 1995, Mrs Archer developed high fever and chest pain. On chest
radiograph she was found to have pneumonia of the lower lobe of the left lung.
She was treatedsuccessfully with antibiotics. She again experienced high fever,
$laking chills and chest pains in May 1995.
Because she was hypotensive (low blood pressure) she was admitted to the
intensive care unit and given antibiotics intravenously and cardiac pressors to
raise her blood pressure. Streptococcus pyogenes was cultured from her sputum
and blood. She recoveredfrom this episode in the hospital and remains fully
active. She requires occasional blood transfusions for her anemia and complains
at times of bone pain. Her serum lgG is stable at 6200 mg dl-l .
Case 19: Multiple Myeloma
Multiple myeloma.
if not most, of the typical features of
IsabelArcher presents us with many,
plasma cells. A single plasma cell
multiple myeloma, a malignant tumor of
progeny have disseminated to
has undergone malignanttransformation; its
producing prodigious quantities of a
many sites in the bone marrow and are
monoclonalimmunoglobulin.
to most cancer
Multiplemyeloma is a very malignant disease that is resistant
chemotherapy. Methylphenylalanine mustard (melphalan), which Mrs
been
Archer received,is one of the few chemotherapeutic agents that has
in
was
Archer
Mrs
effectivein the treatment of this disease. Although
relativelygood health as our case history ended, her outlook for survival is
verypoor. Recently,bone marrow transplants have been used to cure patients
with multiple myeloma.
Myelomaproteins have played an important part in the history of immunology. Subclasses of IgG were first recognized, for example, when a rabbit was
immunizedwith a single human myeloma protein and found to react with
80%of myeloma proteins but not with the other 20%. This led to the conclusion that the 80%that did react belonged to an IgG subclass (IgGl) capable of
generating subclass-specificantibodies in rabbits. Four subclasses of IgG
were distinguished by immunizing rabbitswith single myeloma proteins and
testing the antibodies generated for cross-reactivityto other myeloma
proteins. Korngoldand Lipari had already used this approach to classify
Bence-Jonesproteins into tvvogroups of proteins, subsequently calledkappa
and lambda light chains. Later on, a myeloma protein that was available in
abundant amounts as a homogenous protein became the first immuno-
globulin molecule for which a complete amino acid sequence was obtained.
Questions.
The serum lgG from Mrs Archer was assumed to be monoclonal
because it migrated as a tight band on electrophoresis in an agarose gel,
and because it reacted with antibodies to kappa but not to lambda
chains. What other evidence could be brought to bear to prove the
monoclonalityof this 146?
Mrs Archer became anemic (lowred blood cell count) and neutropenic (low white blood cell count). What was the cause of this?
As her diseee progressed, Isabel Archer became susceptible to
pyogenicinfections; for example, she had pneumonia twice in a short—
period. Whatis the basis of her susceptibilty to these infections?
Youmight conclude that it wouldbe useful to administer gamma
globulinintravenouslyto Mrs Archer to protect her from more pyogenic
11
Case 19: Multiple Myeloma
infections. Whywouldthis treatment be less successful than in the case
of X-Iinkedagammaglobulinemia?
A monoclonalimmunoglobulinin the serum is called an M-component
('M' for myeloma).Is the presence of an M-component in serum
diagnostic of multiple myeloma?
Very rarely an individual with multiple myeloma has two Mcomponents in the blood.Although these two M-components derive from
different constant-region genes, their antigen-binding regions are both
encoded by the same variable-regiongene. Can you hypothesize how this
happens?
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