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08 Clinical Lymphoma & Myeloma November 2005
IntroductionAmyloidosis is a generic term for hyaline eosinophilic
extracellular material deposited in various tissues, which shows
polarization birefringence after Congo red staining.1 The
extracellular deposits produce diverse clinical syndromes
depending on the site of organ deposition. Amyloid of all types
shares the same physical properties, including apple-green
birefringence after Congo red staining,2 characteristic fibrillar
appearance by electron microscopy, and -pleated sheet
conformation. Not all normal proteins have an -helical
secondary structure, and not all the -conformation proteins arepathologic (eg, keratin).3 Despite these similar physical
properties, the chemical composition of amyloid has been
shown to include 22 different proteins (Table 1). Virchow in
Berlin thought amyloid was a starch (amyloid), and Rokitansky
in Vienna thought it was fat (lardaceous). Both were incorrect.
Amyloidosis is a nonspecific term because it includes all
forms of systemic and localized amyloidosis. In the 19th
century, the most common form was the secondary systemic
form caused by chronic respiratory and bone infections,
tuberculosis, and leprosy. In the 20th century, inherited forms
of amyloidosis were recognized. The most common form of
systemic amyloidosis in the United States, however, is theimmunoglobulin light chain form (AL). Primary, or
immunoglobulin light chain, amyloidosis is structurally
unrelated to all other forms of amyloidosis, including
Alzheimers disease.4 Light chain amyloidosis is the systemic
amyloidosis with the shortest patient survival.
The structural subunit of primary amyloid fibrils is the
monoclonal light chain or fragment or monoclonal heavy chain
(very rare). It would be unusual for the entire immunoglobulin
light chain molecule to be found in an amyloid deposit. The
light chain found in amyloid is produced by a clonal population
of plasma cells in the bone marrow.5
Symptoms Associated with AmyloidosisSymptoms of amyloidosis include weight loss, edema, andfatigue. They are so nonspecific that amyloidosis would not
appear in the differential diagnosis of these symptoms.6 Patients
are referred to hematologists because they have been found to
have a monoclonal gammopathy or are thought to have
premyeloma,with symptoms not easily explained and bone
marrow with 10% plasma cells.7 Fluid retention, weight loss,
and fatiguerare in newly diagnosed myeloma but common in
amyloidosisshould be important clues to clinicians. However,
no single blood test, radiograph, or scan can diagnose
amyloidosis. Finding Howell-Jolly bodies in a peripheral blood
film of a nonsplenectomized patient is an important but
uncommon clue. Thus, maintaining a high index of suspicion is
essential for recognizing this disease.
The clinical presentation is broad. Patients with renal
amyloidosis generally develop nephrotic-range proteinuria and
may be treated empirically with prednisone before the diagnosis
is confirmed with renal biopsy findings. Before biopsy, common
diagnoses include membranous or membranoproliferative
glomerulonephropathy and minimal change glomerulonephritis.8
Amyloidosis: Diagnosis and Management
Morie A. Gertz, Martha Q. Lacy, Angela Dispenzieri, Suzanne R. Hayman
Amyloidosis is a rare plasma cell proliferative disorder. The annual incidence in Olmsted County, Minnesota, is 8 in 1,000,000 patients.
This is a difficult disorder to diagnose, because the symptoms at presentation are vague and include dyspnea, paresthesias, edema,
weight loss, and fatigue. The clinical syndromes at the time of presentation include nephrotic-range proteinuria with or without renal fail-
ure, cardiomyopathy, atypical multiple myeloma,hepatomegaly, and autonomic or peripheral neuropathy. The serum immunoglobulin
free light chain assay has been an important step forward in classifying systemic amyloidosis as an immunoglobulin light chain form and
in monitoring therapy. Recently, the importance of serum cardiac biomarkers in assessing outcome has been recognized. New therapies
developed over the past 5 years include high-dose chemotherapy with stem cell reconstitution, combinations of alkylating agents with
dexamethasone, and, most recently, thalidomide.
Clinical Lymphoma & Myeloma, Vol. 6, No. 3, 208-219, 2005
Key words:Amyloid, Monoclonal gammopathy, Multiple myeloma, Stem cell transplantation
Abstract
ComprehensiveReview
Address for correspondence: Morie A. Gertz, MD, Division of Hematology,Mayo Clinic, 200 First St SW, Rochester, MN 55905E-mail: [email protected]
Submitted: Apr 8, 2005; Revised: Jun 2, 2005; Accepted: Jun 27, 2005
Division of Hematology, Mayo Clinic, Rochester, Minnesota.
Electronic forwarding or copying is a violation of US and International Copyright Laws.Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group,ISSN #1526-9655, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Clinical Lymphoma & Myeloma November 2005 20
Hematologists who evaluate
patients with suspected
myeloma and light chain
proteinuria should be
attentive to dramatic increases
in serum cholesterol
concentration or marked
hypoalbuminemia, features of
nephrotic syndrome not seen
in light chain multiple
myeloma in which lipid levels
are normal and the serum
albumin level is usually only
mildly decreased.
Frequently, patients with
amyloid cardiomyopathy do
not develop cardiomegaly or
classic signs of pulmonary
edema because of the
restrictive nature of cardiac
involvement. The normal sizeof the heart and the normal
left ventricular ejection
fraction (LVEF) determined
echocardiographically often
make it difficult to decide
whether the patients fatigue
and dyspnea have a cardiac
basis.9 Many patients with cardiac amyloidosis are referred by
pulmonologists who initially evaluate the patient for
noncardiac dyspnea.Often, amyloid peripheral neuropathy is diagnosed initially as
chronic inflammatory demyelinating polyneuropathy or, moreimportantly, as peripheral neuropathy associated with
monoclonal gammopathy of undetermined significance
(MGUS) because diagnostic testing was not sufficient to
exclude amyloidosis as the underlying disease.10 The median
duration of neuropathic symptoms before the diagnosis of AL
amyloidosis is 2 years.11
Patients with amyloidosis presenting with hepatomegaly are
generally thought to have malignancy and undergo liver biopsy.
In amyloidosis, liver biopsy has a small risk of bleeding, and
rupture of the liver has been reported.12 By recognizing
amyloidosis and obtaining tissue at a lower risk site, this
potentially rare but catastrophic complication can be avoided.13
Physical findings in amyloidosis include the following:
enlargement of the tongue, periorbital purpura, and, rarely, extra-
articular deposits producing skeletal pseudohypertrophy (shoulder
pad sign). These physical findings are highly specific for
amyloidosis but are relatively insensitive because only 15% of
patients have them. The clinician needs to focus on organs that
become involved with amyloid and the nature of their
dysfunction. Amyloidosis should be in the differential diagnosis
for any adult patient with nephrotic-range proteinuria. Ten
percent of nondiabetic patients aged 44 years with nephrotic
syndrome have amyloidosis.14 Slightly more than one-half of
patients with amyloidosis have changes of infiltrative
cardiomyopathy as defined with echocardiography.15
Cardiac symptoms can range from minimal (eg, easy
fatigability or unexplained lower extremity edema) to frank
congestive symptoms. Electrocardiography demonstrates low-voltage QRS complexes in the limb leads or an infarction
pattern that is related to myocardial infiltration and unrelated to
coronary artery disease.16 The most common echocardiographic
finding is not a granular sparkling appearance, as frequently
assumed; instead, the ventricular wall is thickened, which is
usually misinterpreted as hypertrophy rather than infiltration.15
If a patient has echocardiographic evidence of wall thickening
but does not have a history of hypertension or cardiac valvular
disease, amyloidosis must be considered in the differential
diagnosis. Occasionally, patients with heart dysfunction
undergo catheterization and coronary angiography; however,
the evaluation is terminated when the angiographic findings are
found to be normal despite high right-sided filling pressures that
suggest the need for endomyocardial biopsy, a test that is 100%
sensitive. The complication rate is 3%, with none of the
complications being fatal or long term.17 All patients with an
unexplained heart problem or unexplained proteinuria should
have studies for possible light chain AL.
Approximately 15% of patients with amyloidosis have
clinically important liver involvement.13 Serum amyloid P
scanning component quite frequently identifies patients who
have liver involvement that has not produced biochemical
changes or hepatomegaly. The most common liver presentation
Primary; may be associated with myeloma
Primary; may be associated with myeloma
Secondary and familial; mediterranean fever
Native in senile systemic amyloid; mutant in familial amyloidosis
Inherited renal amyloidosis
Inherited hepatic amyloidosis
Familial amyloid neuropathy
Dialysis associated
Alzheimers disease
Diabetes; islet cells
Isolated atrial amyloidosis
Finnish familial amyloidosis
Hereditary cerebral hemorrhage with amyloidosis, Iceland
Creutzfeldt-Jakob disease
Medullary thyroid cancerIslet amyloidosis (degu)
Prolactinoma
Corneal dystrophy
Spongiform encephalopathies
Abbreviation Protein
Immunoglobulin light chain or fragment
Immunoglobulin heavy chain or fragment
Amyloid A
Transthyretin
Fibrinogen chain
Lysozyme
Apolipoprotein AI or AII
2-Microglobulin
-Protein precursor
Islet amyloid polypeptide
Atrial natriuretic factor
Gelsolin
Cystatin C
Scrapie protein
(Pro) CalcitoninInsulin
Prolactin
Lactoferrin
Prion
Clinical Phenotype
AL
AH
AA
ATTR
AFib
ALys
AApoA
A2M
A
AIAPP
AANF
AGel
ACys
ASCR
ACal
AINS
APro
Alact
APrPSC
Amyloid NomenclatureTable 1
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10 Clinical Lymphoma & Myeloma November 2005
Amyloidosis
is an unexplained increase in alkaline phosphatase (ALP) level orunexplained hepatomegaly. Typical liver symptoms of early
satiety, anorexia, and right upper quadrant fullness are generally
present but not specific. Radionuclide liver scans, computerized
tomographic scans, and magnetic resonance imaging do not
show any abnormality other than physical enlargement. These
patients are the most likely to have a hyposplenic peripheral
blood film. When evaluating patients who have unexplained
liver dysfunction, it is important to screen for infiltrative liver
disease with studies to detect monoclonal light chain
abnormalities in addition to performing studies to detect
hepatitis, cirrhosis, and biliary obstruction.
Peripheral neuropathy is present in 15% of patients with ALamyloidosis.11 Sensory changes precede motor changes, and the
lower extremities are affected before the upper extremities are.
Clues to recognizing amyloid neuropathy include the presence
of carpal tunnel syndrome (present in half the patients) in
association with autonomic neuropathy. Autonomic neuropathy
can be the presenting manifestation of amyloidosis. Clinical
manifestations of amyloid autonomic neuropathy include
gastrointestinal tract involvement, which can be manifest in the
upper gastrointestinal tract as nausea, vomiting, delayed gastric
emptying, and pseudo-obstruction, and in the lower
gastrointestinal tract as alternating diarrhea and constipation,
often to the point of incontinence. Autonomic failure of the
urinary tract includes delayed emptying, inability to void, and
spontaneous overflow incontinence. Autonomic failure may also
produce orthostatic hypotension with orthostatic syncope and
failure of a compensatory increase in heart rate when the patient
changes from a supine to standing position. Amyloid
neuropathy is typically dysesthetic, and the pain requires
treatment with analgesics, amitriptyline, and gabapentin as well
as narcotics. Without sufficient evaluation to exclude
amyloidosis, amyloid neuropathy may be misdiagnosed as
monoclonal gammopathyassociated peripheral neuropathy or
Waldenstrms macroglobulinemiaassociated neuropathy.18
Any patient with nephrotic-range proteinuria, nonischemic
cardiomyopathy, hepatomegaly, or peripheral neuropathy or
with an atypical myeloma presentation needs to have screeningtests for amyloidosis.19
Screening for AmyloidosisLight chain amyloid is composed of immunoglobulin light chain
or heavy chain fragments.20 Thus, by definition, AL amyloidosis is
a plasma cell dyscrasia. Virtually all patients have a clonal
population of plasma cells detectable in the bone marrow.7 Also,
most patients have a detectable immunoglobulin abnormality
defined as positive serum immunofixation for light chain,
positive urine immunofixation for light chain, or abnormal
serum immunoglobulin free light chain nephelometric assay.21
Screening with serum protein electrophoresis is inadequatebecause 50% of patients do not have an intact
immunoglobulin protein in the serum or have light chain
proteinemia, which will not produce a discrete band on the
electrophoretic pattern (Figure 1). Urine immunofixation is
important and complementary to serum immunofixation
(Figure 2). In a Mayo Clinic study of 110 consecutive patients
with light chain AL, serum immunofixation results were
positive in 69%, and urine immunofixation results were positive
in 74%. When immunofixation was used to screen serum and
urine, a monoclonal protein was found in 104 of the 110
patients (95%). The immunoglobulin free light chain assay was
abnormal in 100 patients (91%). When all 3 screening studies
were combined, 109 of the patients with AL amyloidosis were
identified correctly, a sensitivity of 99%. Conversely, when the
serum immunoglobulin free light chain assay was used in 52
patients with non-AL amyloidosis, all had a normal :ratio,
including 23 patients with localized, 16 with familial, 6 with
senile, and 3 with secondary amyloidosis, a specificity of
100%.22 Overall, serum and urine immunofixation and the serum
immunoglobulin free light chain assay constitute the best
noninvasive screening tests for patients who potentially have AL. A
positive finding justifies performing biopsy to confirm the
diagnosis. Serum amyloid P scanning also detects amyloid deposits
Serum Monoclonal Protein (g/dL)
Percentof
Patients
0 0.01-0.50 0.51-1.50 > 1.5
60
40
20
0
: = 1:3.1
G
D
o
M
AG
Biclonal
Results of serum protein electrophoresis and serum immunofixation in 219 patients with AL orlight-chain amyloidosis. A, G, M, D, immunoglobulin heavy chain; K, L, or
immunoglobulin light chain.
Serum Protein Electrophoresis and Immunofixationin Patients with Amyloidosis
Figure 1
Results of urine immunofixation and 24-hour urine total protein in 219 patients with AL or light-chain amyloidosis.
Urine Protein per Day
Numbe
rofPatients
< 1.0 1.0-2.9 3.0-5.9 > 6.0
80
60
40
0
21%
68%
Median3.5 per day
0
Biclonal
20
1%10%
Urine Immunofixation in Patients with AmyloidosisFigure 2
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Clinical Lymphoma & Myeloma November 2005 21
with a high level of sensitivity,23 but it is not widely available.
The possibility of nonlight chain AL in a patient with an
unrelated MGUS must be considered. Patients with MGUS can
have an abnormal serum free light chain ratio.24 Therefore,
amyloidosis with an immunoglobulin light chain must be
confirmed immunohistochemically for type to avoid the rare
patient with amyloid A (AA) or an inherited form of
amyloidosis, the transthyretin (TTR) type or fibrinogen (AFib)
type, with a low-level monoclonal gammopathy.
The 2 types of hereditary amyloidosis that are most likely to
be misdiagnosed as AL type are variants TTR and AFib because
of the frequent lack of family history. Important clues to the
possibility are the predominant neuropathic or cardiac
phenotype of variant TTR and the lack of extrarenal
involvement in AFib. Renal biopsies in patients with AFib show
massive glomerular amyloid deposition without interstitial or
vascular amyloid deposits.
How Is the Diagnosis of AmyloidosisConfirmed?
If a patient has a compatible clinical syndrome andimmunofixation or nephelometric testing subsequently
demonstrates an immunoglobulin light chain abnormality, the
diagnosis must be confirmed by biopsy. In patients with nephrotic
syndrome, cardiomyopathy, hepatomegaly, or neuropathy, amyloid
deposits can be demonstrated histologically in biopsy specimens
from kidney (Figure 3), heart, liver, or nerve, but this is generally
not required. In patients with amyloidosis, kidney and liver biopsies
have a risk of bleeding; rarely, catastrophic rupture of the liver or
spleen can occur.25 It is easier and safer to obtain a bone marrow
sample or a subcutaneous fat aspirate. In 220 consecutive patients
receiving high-dose therapy at Mayo Clinic, the bone marrow was
positive for amyloid deposits when stained with Congo red in 156of 213 patients (73%; 3 equivocal), and the subcutaneous fat
aspirate results were positive in 137 of 190 (72%; 7 equivocal).
Either the bone marrow sample or the fat aspirate results were
positive in 181 of 218 patients (83%). Obtaining the fat aspirate or
the bone marrow sample is convenient and less invasive and does
not cause any bleeding complication (in the absence of factor X
deficiency). Bone marrow biopsy is required for every patient with
AL amyloidosis to exclude overt multiple myeloma. Other centers
have reported the efficacy of biopsy of the minor salivary glands,26
gingiva, rectum, and skin, with all the biopsies causing minimal
morbidity. Amyloidosis has a very low prevalence in the general
population and, as a screening tool, fat aspiration has a very low
yield. It would be expected to produce more false-positive than
true-positive results if the prevalence of amyloidosis in the
population studied is expected to be low.27 False-positive results
from overstaining, thick fat particles trapping Congo red stain, and
nonspecific staining of elastin or collagen fibers in the fat.
Immunohistochemical verification of the type of amyloid
with and antisera is essential.28 Nonimmunoglobulin
amyloidosis and incidental MGUS are possibilities.29 Clinically,
distinguishing among AL, AA (secondary), AF (familial), and
SSA (senile systemic) types of amyloidosis is difficult. In our
experience, half of the patients with AF amyloidosis do not have
a positive family history. Patients with AA amyloidosis present
with renal amyloid nephrotic syndrome or gastrointestinal
involvement indistinguishable from AL amyloidosis.30 Patientswith AF amyloidosis can present with kidney involvement,
cardiomyopathy, or neuropathy31 indistinguishable from AL
amyloidosis. Senile systemic amyloidosis presents with amyloid
cardiomyopathy, and the clinical and echocardiographic features
are indistinguishable from those of AL amyloidosis.32
Immunohistochemical staining of tissues with commercially
available antisera is helpful. All forms of amyloid contain
amyloid P component, a glycoprotein representing 10% of the
fibril by weight. Positive immunochemical staining with P
component is a useful positive control.33 Transthyretin
antiserum that stains AF is highly reliable, and its absence should
make AF amyloidosis (as a result of TTR) unlikely. The sameapplies to the use of AA antiserum purchased commercially.
When and immunostaining is positive, it can be quite
specific, but it lacks sensitivity. Commercial antisera may not
recognize immunoglobulin light chain amyloid deposits because
the fibrils consist only of the N terminus of the light chain, thus
lacking the epitopes recognized by commercial antisera, or the
epitopes are hidden when the light chains fold into the -pleated
sheet conformation.34 Immunoelectron microscopy has been
used with immunogold to characterize the amyloid fibril.35
A specific form of inherited amyloidosis should be mentioned.
A mutation of the TTR molecule, isoleucine 122, results in
autosomally dominant inherited cardiac amyloidosis. This allele is
carried in 63 of 3376 (2%) of black Americans, or 700,000 black
Americans in the United States (2003 census data). Amyloid
cardiomyopathy in a black patient aged 70 years should
automatically be screened for this isoleucine 122 variant.36
Mutations in fibrinogen-A cause renal amyloidosis. The
fibrinogen origin of the amyloid deposit can be detected
immunochemically.37 In a landmark study, 10% of patients
referred to an amyloidosis center with the diagnosis of the AL
type had another form of amyloidosis, including 5% with AFib
and 4% with unrecognized mutations of TTR.28 Excluding
familial amyloidosis before therapy is initiated is important.
Sulfated alcian blue stain; 1000.
Vascular Amyloid Deposits in KidneyFigure 3
Morie A. Gertz et al
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12 Clinical Lymphoma & Myeloma November 2005
Amyloidosis
PrognosisThe most common cause of death of patients with AL
amyloidosis is cardiac failure or arrhythmia. The mechanism can
be progressive congestive cardiomyopathy or arrhythmic
death.38 The overall response rate and clinical outcome are
determined by the extent of cardiac involvement at diagnosis.
The method for accurately assessing the extent of cardiac
amyloidosis has evolved over the past 4 decades. In the early1960s, cardiac involvement was defined by clinical criteria such
as the presence of overt congestive heart failure. With these
clinical criteria alone, it is possible to detect a population of
patients whose median survival is only 3 months.39 In the 1970s
and 1980s, these clinical criteria were replaced by
echocardiographic criteria.
Echocardiography with Doppler studies, which assist in
measuring diastolic compliance, is useful in assessing all patients
with newly diagnosed AL amyloidosis. One-fourth of patients
without obvious heart symptoms have echocardiographically
detected cardiac amyloidosis.40 With echocardiography, the
LVEF and mean thickness of the ventricular septum can be
quantified. Left ventricular ejection fraction and septalthickness are important measures, although depression of the
LVEF is a very late phenomenon in amyloidosis because systolic
function is preserved until late in the disease. Doppler
echocardiography,9 however, allows measurement and
qualitative assessment of diastolic function with grades from I to
IV. These are accurate measures of ventricular diastolic
compliance. The stiffer the ventricle, the slower the relaxation
and the longer it takes blood to flow across the mitral valve. This
is measured by the deceleration time, which provides
information that correlates well with survival.40
Since the 1990s, cardiac biomarkers have supplemented
echocardiography in measuring sensitive changes in myocardialfunction. Serum biomarker studies are more reproducible and less
subject to interobserver variability than is echocardiography.
Serum troponin levels are more sensitive measures of ischemic
myocardial injury than the creatine kinase-MB fraction. Troponin
has been shown to be a powerful predictor of survival in patients
with AL amyloidosis, including those receiving conventional
treatment41 and those receiving high-dose therapy with stem cell
transplantation. Serum troponin T levels can be used to separate
patients into 3 subgroups of equal size with markedly different
survival rates: < 0.03 ng/mL, 0.03-0.1 ng/mL, and > 0.1 ng/mL.
The cardiac biomarkers N-terminal probrain natriuretic peptide
(NT-proBNP), which can be measured in stored frozen serum,
and brain natriuretic peptide (BNP) increase with atrial dilatation.
Increased NT-proBNP levels have been shown to predict survival
after the diagnosis of amyloidosis. A normal NT-proBNP level
excludes involvement of the heart with amyloid.42 The
combination of serum troponin T and NT-proBNP levels can be
used to classify patients into 3 groups43: those in whom troponin
T and NT-proBNP levels are increased (stage 3); both levels are
normal (stage 1); and the level of only 1 of the 2 markers is
increased (stage 2).44
Others have shown that serum 2-microglobulin is
prognostically important in AL amyloidosis45,46 and the
number of organs involved with amyloid appears to predict
outcome after stem cell transplantation.
For all patients with AL amyloidosis, our routine is to measure
serum troponin T, NT-proBNP, BNP, and 2-microglobulin
levels, count the number of organs involved, and perform
echocardiography.
Assessing the Therapeutic EffectOftentimes, assessing the response to therapy can be difficult.
Unlike multiple myeloma, in which the majority of patients
have a quantifiable monoclonal protein that can be used as a
surrogate for reduction in tumor mass, interpreting the response
of patients with amyloidosis is more complex. The majority of
patients with AL amyloidosis do not have a measurable
monoclonal protein (Figure 1). Because so many of the patients
have only light chain proteinemia, quantification has been
difficult until recently. Only 10% of patients with amyloidosis
have a serum monoclonal protein level > 1.5 g/dL.
Quantification of the urinary light chain is equally difficult
because a high proportion of patients have marked albuminuria
that overwhelms the monoclonal protein peak (Figure 2).Patients with AL amyloidosis have an average of 5% plasma cells
in the bone marrow. This degree of plasmacytosis is recognized
as abnormal. Amyloid can often be identified in bone marrow
biopsy samples. To convincingly demonstrate a reduction in
bone marrow plasmacytosis is difficult because of interobserver
variability and sampling variation.
Despite these limitations, a hematologic response for
amyloidosis has been defined by a 50% reduction in the
precursor monoclonal protein.47 The effect of a 50% decrease in
the monoclonal protein level in a cohort of patients receiving
high-dose therapy followed by stem cell transplantation is
shown in Figure 4. The nephelometric serum immunoglobulinfree light chain assay has become important in quantifying
hematologic responses in patients with amyloidosis. As
mentioned earlier, the light chain assay was used as a sensitive
and specific marker for AL amyloidosis. In addition to
classifying of the type of amyloid, this test provides a new
quantification method for confirming hematologic responses.48
The most important clinical endpoint in amyloidosis is organ
response. It has been assumed that the amyloid in organs cannot
resolve until production of the precursor light chain has been
interrupted. After this interruption occurs, the amyloid
deposits, as determined by serum amyloid P component
scintigraphy, will slowly resolve if the organ has not been
damaged irrevocably by the deposits or toxic intermediates.
Biopsy verification of amyloid resolution is rare. A hematologic
response to therapy correlates well with subsequent organ
response49 and survival (Figure 4). Therefore, a 50% reduction
in the serum or urine (or both) monoclonal protein or the
nephelometric serum free light chain assay is a reasonable
surrogate for response and will ultimately lead to functional
organ improvement, defined as reduction in urinary protein in
patients with renal amyloidosis, echocardiographic
improvement in patients with cardiac amyloidosis, and decrease
in liver span and serum ALP level in patients with hepatic
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Clinical Lymphoma & Myeloma November 2005 21
amyloidosis if irrevocable organ damage has not occurred. The
immunoglobulin serum free light chain level and light chain
ratio are measured in all patients who are receiving therapy andare monitored serially. A 50% decrease is accepted as a
hematologic response. Eradication of the monoclonal protein
from the serum and urine by immunofixation and normalization
of the serum free light chain ratio would be considered a
complete hematologic response. A diagnostic pathway for
considering, recognizing, and confirming AL amyloidosis and
assessing the prognosis of patients is given in Table 2. Remember
that therapy is not to be initiated until it is certain that the
amyloid is of light chain origin.
Nonsystemic Amyloidosis
Patients may be referred with localized forms of amyloidosis.These patients generally do not require systemic therapy, and
management can be supportive or localized. The location of the
amyloid deposits can be a clue to its localized nature. When
amyloid is detected in the ureter, bladder, urethra, or prostate, it is
generally localized.50,51 Most forms of cutaneous amyloidosis are
also localized, and macular amyloidosis is virtually always
localized.52 Nodular amyloidosis may be a component of systemic
AL amyloidosis.53 Tracheobronchial amyloidosis54 and nodular
pulmonary amyloidosis are localized and generally not associated
with a plasma cell dyscrasia.55,56 Soft tissue deposits of amyloid
and amyloid lymphadenopathy may not be associated with
systemic disease.57 Patients who present with localized amyloidosis
do not have a demonstrable monoclonal protein in the serum or
urine nor do they have bone marrow plasmacytosis.
A therapeutic strategy designed to dissolve the amyloid deposits
or to prevent their accumulation would be optimal. If the amyloid
deposits could be solubilized, the patients would not sustain brain
damage. No effective means is known for solubilizing amyloid
deposits. The approach has been to reduce precursor protein
production by cytotoxic chemotherapy. All therapies have been
derived from the treatment of multiple myeloma and are directed
at the small clonal population of plasma cells responsible for the
synthesis of the amyloidogenic light chain.
TherapyConventional TherapyThe first reports on cytotoxic chemotherapy for AL
amyloidosis are > 30 years old.58 Melphalan/prednisone is
effective treatment.59,60 A difficulty with this regimen is the
difficulty distinguishing between patients in whom therapy will
fail and those in whom the response will be delayed. Reports
have indicated that nearly a year is needed to detect a response
to melphalan/prednisone therapy. In addition to a low response
rate, oral melphalan can cause late myelodysplasia or acute
leukemia, and myelodysplasia can develop in nearly 7% of
exposed patients.61,62 The response rate to melphalan/
prednisone does not exceed 30%. However, this therapy issuitable for even the most severe disease and can be an option if
other regimens are considered excessively toxic.
The best responses to melphalan/prednisone occur in
patients with single-organ nephrotic syndrome without renal
insufficiency. The response rate for all patients treated with
melphalan/prednisone is 18%.47 If the ALP level is > 4 times
normal or the serum creatinine level is > 3 mg/dL, responses to
melphalan/prednisone are rare. Responses have been seen in
patients with advanced cardiomyopathy, and modest
prolongation of survival has been seen in patients with amyloid
congestive heart failure. Of 153 patients treated with
melphalan/prednisone, the 5-year survival rate of responders
was 78%. For 810 patients, the 10-year survival rate was 4.7%,
and all 10-year survivors received melphalan/prednisone.63 Of
the 10-year survivors, 14 of 30 exhibited a complete
hematologic response. Prospective randomized studies have
shown that melphalan/prednisone is superior to colchicine.64,65
In one study, survival in the melphalan/prednisone group was
17 months, and, in another study, it was 12.2 months.
Continuous oral daily melphalan has been used as single-agent
therapy for cardiac amyloidosis. In 30 such treated patients, 7
of the 13 evaluable after 3-4 months of therapy exhibited a
partial hematologic response, and 3 exhibited a complete
Survival Months
Nonresponders (n = 68)Responders (n = 151)
Survival(%)
100 20 30 40 50 60 70 80 90 100 110
100
80
40
60
20P< 0.001
Survival After Stem Cell Transplantation in Amyloidosis:Comparing Hematologic Responders with Nonresponders(N = 219)
Figure 4
1.Consider AL amyloidosis in differential if patient has:
Nondiabetic nephrotic syndrome
Nonischemic cardiomyopathyechocardiography shows leftventricular hypertrophy
Hepatomegaly with no scan defects
Chronic inflammatory demyelinating polyneuropathy
Atypical myelomaurine monoclonal light-chainpositive and bonemarrow plasmacytosis
2.Perform immunofixation serum, urine, and immunoglobulin serum- free light-chain assay; if results are positive, AL is a likely explanation
3.Biopsy bone marrow and subcutaneous fat, and stain with Congo red;kidney or liver biopsy is usually not required; electron microscopydemonstrates fibrils
4.Assess prognosisechocardiography with Doppler, serum troponin,NT-proBNP or BNP, 2-microglobulin
5.Initiate therapy
Diagnostic Pathway for AL AmyloidosisTable 2
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hematologic response.66 Reports of improvement in organ
function after treatment of AL with colchicine are rare.67
Dexamethasone-Based RegimensOf the first 4 patients who received treatment with
vincristine/doxorubicin/dexamethasone (VAD), 2 had a 50%
decrease in serum monoclonal protein. Vincristine is not a good
choice for patients with amyloid peripheral neuropathy, and
doxorubicin should be avoided if patients have severe
cardiomyopathy. Three of 4 patients with amyloid nephrotic
syndrome treated with VAD exhibited a partial response and were
alive and in remission for 4-9 years.68 VAD has been used in an
induction scheme to reduce the amyloid burden and to enhance
stem cell transplantation outcome.69 According to one study,
clinical improvement after VAD did not reduce transplantation-
related mortality.70
Among 92 patients treated at the AmyloidosisCenter in Great Britain, 4 cycles of VAD led to an organ response
in 39 patients (42%), with a treatment-related mortality rate of
7%.48 In the first report on dexamethasone therapy for
amyloidosis, 9 patients received dexamethasone 40 mg on days
1-4, 9-12, and 17-20, every 5 weeks. Improvement in AL organ
involvement was seen in 8 of these patients. Of 7 patients with
nephrotic syndrome, 6 had a 50% reduction in proteinuria.71 In 2
separate studies, we have reported on 44 patients with
amyloidosis.72,73A large proportion of these patients had cardiac
amyloidosis, and this may have affected outcome. The survival of
this cohort is shown in Figure 5.
Dexamethasone toxicity is substantial. Fluid retention occurs in
patients with nephrotic syndrome and heart failure. Dose
reductions are common. In the largest study (92 patients in the
Southwest Oncology Group study), 24% of patients had
hematologic complete remissions, and 45% had improvement in
amyloid-related organ dysfunction.74 Median survival for the
group was 31 months, and the overall 2-year survival rate was
60%. Heart failure and an increased 2-microglobulin level
predicted adverse outcome. Patients with cardiomyopathy had a
low response rate. The median time to hematologic response was
103 days. Improved survival was reported for patients with organ
response. Toxicity was linked to the number of organs involved.
However, according to the statistical analysis, only heart failure
predicted excessive toxicity. Patients in the Southwest Oncology
Group study received maintenance interferon therapy, but its
effect on outcome could not be determined.
The Italian Amyloidosis Group also reported on
dexamethasone therapy.49 The same group has also combined
dexamethasone with melphalan. The hematologic response rate
was 67% at a median of 4.5 months, with a 33% complete
response rate and a 48% organ response rate. Treatment-related
mortality was 4%, and one-half the patients had improved
organ function. Heart failure resolved in 19% of patients. The
use of oral melphalan and dexamethasone is viable alterative
therapy for patients with amyloidosis.75
In a report from Boston University Medical Center, pulsed low-
dose melphalan was administered intravenously to patients
ineligible for stem cell transplantation because of severe cardiac
involvement or poor performance status.76 The dose of melphalan
ranged from 17.5 mg/m2 to 25 mg/m2 every 4-6 weeks for 3-4
cycles. All patients received growth factor support, and the
melphalan dose was adjusted for granulocytopenia and
thrombocytopenia. Fifteen patients (median age, 55 years)received a median of 3 cycles of low-dose melphalan. Eight of 10
evaluable patients had more than a 50% decrease in serum free
light chain levels, and 2 exhibited normal serum free light chain
levels. Of the 15 patients treated, 2 survived 6 months and 24
months after treatment and 13 died. Median survival was 2
months. Ten patients died within 35 days after starting treatment.
Myelosuppression was the major toxic effect, suggesting that
the dose of 17.5 mg/m2 to 25 mg/m2 may have been excessive.
Pulsed low-dose melphalan given intravenously induced
hematologic responses, but long-term survival was poor, which
is typical of patients with advanced cardiac amyloidosis.
For 144 patients, the National Amyloidosis Treatment Centercombined the intermediate dose of melphalan at 25 mg/m2with
dexamethasone 20 mg for 4 days every 21-28 days.77 The median
follow-up was 13 months. Median number of cycles was 3. Fifty-
one patients did not receive dexamethasone. The treatment-related
mortality rate was 2%. Of the patients, 23% had normalization of
the serum free light chain, 31% had a 50% decrease in serum free
light chain, and 46% were thought to be nonresponders. The
response rate was higher among melphalan-treated patients who
also received dexamethasone. Clinical responses were evident
within 2 cycles in almost all the patients who eventually had a
response. Median survival for responders was 44 months
compared with 18 months for nonresponders. Amyloid organ
dysfunction improved in 14% of patients and was stable in 51%.
Parenteral melphalan and oral dexamethasone is a reasonable
therapeutic strategy, but, in our opinion, the initial dose of
parenteral melphalan should be approximately 16 mg/m2.
Thalidomide
For 16 patients enrolled in a thalidomide study, the median
maximum tolerated dose was 300 mg. Fifty percent of the
patients experienced grade 3/4 toxicity, 25% had to discontinue
taking the drug, and 25% had a reduction in light chain
proteinuria but not in total urinary protein.78 In a Mayo Clinic
Months
Surviv
al(%)
100 20 30 40 50 60 70 80 90 100 110
100
80
40
60
20
Survival of 44 Amyloidosis Patients Treated withDexamethasone at Mayo Clinic
Figure 5
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Clinical Lymphoma & Myeloma November 2005 21
report on 12 patients treated with thalidomide, 75% of patients
had a drug-related toxic effect.79 Progressive renal insufficiency
developed in 5 patients, and deep venous thrombosis and
syncope developed in 2 patients. The median time of
thalidomide treatment was 72 days; patients were intolerant of
the drug. The Italian Amyloidosis Group reported on
thalidomide and dexamethasone therapy in 31 patients.80 Only
11 patients tolerated 400 mg per day for a median of 5.7 months.
Twenty patients experienced severe grade 3 or greater toxicity. The
National Amyloidosis Treatment Center administered
thalidomide81 at a median dose of 100 mg per day. Although this
treatment had to be discontinued for 31% of patients, the
hematologic response rate was 55%. Thalidomide and
dexamethasone warrant further investigation in the treatment of
AL amyloidosis, but the thalidomide dose likely should be limited
to 100 mg per day. Irreversible peripheral neuropathy and skin
rash are common side effects of thalidomide.
Stem Cell Transplantation
Although no prospective randomized studies have compared
stem cell therapy with conventional therapy, many centers aroundthe world are using stem cell therapy for AL patients who are
thought to be sufficiently robust to withstand its toxic effects.82 In
a case-matched control series matching patients for age, organ
involvement, and extent of cardiac involvement, patients who
received high-dose therapy had a survival advantage.83 The
rationale for high-dose therapy is derived from data on multiple
myeloma that unequivocally demonstrate a survival advantage for
patients given high-dose therapy. Currently, most patients are not
eligible for stem cell transplantation. In our experience,
approximately one-fourth of patients are candidates. The mortality
rate of 12% is high compared with that of autologous stem cell
transplantation for hematologic neoplasia.82
There is selectionbias. Patients eligible for stem cell transplantation have better
cardiac function and do not have advanced liver or kidney
failure.84 Patients with marked organ dysfunction are at higher risk
for complications, including sudden cardiac death and
gastrointestinal tract bleeding.85
We have completed stem cell transplantation in 219 patients.86
The ratio of -to-amyloid was 1:3.1 (Figure 1). The kidney was
involved in 67% of patients, the heart in 50%, and the liver in
20%, and 15% of patients had peripheral neuropathy.
Conditioning used at Mayo Clinic is risk adjusted. Patients with
advanced cardiac amyloidosis receive a melphalan dose of 140
mg/m2, as do elderly patients or those who have a marked decrease
in creatinine clearance.87 Twenty percent of our patients had an
LVEF < 0.60 when they received a stem cell transplant.
Another group has used a similar risk-adapted approach to
dosing and has added dexamethasone and thalidomide as
posttransplantation therapy.88 Patients at high risk were given 2
cycles of melphalan 40 mg/m2without stem cell replacement. If
patients did not exhibit a complete response, they received 9
months of dexamethasone/thalidomide therapy. Also, 31
patients who had stem cell transplantation received melphalan
at the following doses: 5 patients at 100 mg/m2, 16 at 140
mg/m2, and 10 at 200 mg/m2. The treatment-related mortality
rate was only 7.4%. Six patients died of progressive disease at a
median of 5.5 months. Fifty-nine percent of patients had a
response to treatment. Seven patients had objective
improvement in amyloid-related organ function. There was an
association between a persistently abnormal serum free light
chain ratio and an increased risk of death. Risk-adapted dosing
of melphalan can decrease the treatment-related mortality rate.
There may be a role for maintenance dexamethasone therapy
following high-dose therapy.
In our experience, a hematologic response has a profound
effect on outcome. Our response rate is 68%,86 and responders
do exceedingly well (Figure 4). (Organ responses are defined in
the section on assessing therapeutic effect.) Nonresponders have
a median survival of 12.6 months. Although we frequently
reduce the dose of melphalan, we have not found a survival
difference among responders on the basis of the conditioning
dose; however, higher doses appear to produce higher response
rates. Treatment-related mortality is directly associated with the
number of organs involved as well as the serum creatinine level
before transplantation. Recently, we have recognized that weight
gain during growth factorprimed mobilization is a powerfulpredictor of treatment-related mortality. Patients who, during
mobilization, gain > 3% of their pretransplantation body weight
appear to have a higher treatment-related mortality rate even if
measures are taken to return their weight to the
pretransplantation level before conditioning chemotherapy is
initiated.89 The median survival for patients with > 2 organs
involved at the time of transplantation is 21.5 months. The
most common cause of death was sudden cardiac death, but we
have also observed fatal liver failure, exsanguinating
gastrointestinal tract hemorrhage, and postconditioning renal
insufficiency with multiorgan failure.90
We have not administered cytoreductive chemotherapybefore stem cell transplantation because patients have only
5%-10% plasma cells. The value of preconditioning
cytoreductive therapy has not been proven. According to a
report from Boston University, 2 cycles of melphalan and
prednisone before transplantation did not provide survival
benefit, and the delay often led to progression.91 For 312
patients treated at Boston University, the median survival was
4.6 years.92 A complete hematologic response was seen in
40% of patients, and this led to prolonged survival. Their
reported treatment-related mortality rate was 13%, with
mortality greatest among patients with cardiomyopathy. The
criteria for administering melphalan 200 mg/m2 were the
following: age, < 65 years; LVEF by echocardiography, > 0.45;
and > 2.5 million stem cells. At Mayo Clinic, the current goal
for stem cells is 4 million, but transplantation is performed if
the yield is only 2 million, with median time to 500 neutrophils
on day 13 and 20,000 platelets on day 13.
The group at Princess Margaret Hospital has emphasized how
selection criteria affect outcome. Of 80 patients referred to
Princess Margaret Hospital, 48 had AL amyloidosis without
myeloma. Twenty-six of these patients were thought to be
candidates for stem cell transplantation, and 20 underwent the
procedure.93 Over 5 years, treatment-related mortality has
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16 Clinical Lymphoma & Myeloma November 2005
Amyloidosis
decreased from 50% to 20%. Intent-to-treat organ responses
were kidney 46%, heart 25%, and liver 50%. The 3-year
survival rate was 56%. Improved outcome was predicted by
performance status, ALP level, nephrotic syndrome, and the
absence of hypotension. For patients with marked hypotension
or poor performance status, treatment-related mortality was
high. These patients should not receive a stem cell transplant.
The German Myeloma Group evaluated VAD induction
chemotherapy before stem cell mobilization with high-dose
melphalan.94 The VAD regimen produced grade 3/4 toxicity in
25% of patients, with a mortality rate of 7%. Stem cell
transplantation was performed in 86% of patients. An additional
benefit of pretransplantation induction therapy increasing the
posttransplantation hematologic response rate was not shown.
The mortality rate after stem cell transplantation was 13%. At the
time the results were reported, the 1-year survival rate from the
time of diagnosis was 75%, and the 3-year survival rate was 71%.
The survival rate was lower for patients with involvement of > 2
organs (60%) and was lower still for those with cardiac
involvement (40%). In the cohort of 24 patients who received
high-dose melphalan, a complete hematologic response wasobserved in 11. There were 3 treatment-related deaths (13%) and
1 death from progressive disease (4%).
The optimal conditioning regimen for amyloidosis has not
been studied. Most centers use melphalan alone. The use of total
body irradiation has been reported, but it did not appear to lower
treatment-related mortality.95 Tandem transplantation has been
attempted, but only a few patients, on an intent-to-treat basis,
completed a second planned transplantation. However, for those
who had the second procedure, the response rate increased.96
One of the worst complications we have observed is
postconditioning renal insufficiency. The serum creatinine level
increased in 19% of 80 patients. The risk factors were age,hypoalbuminemia, proteinuria, diuretic use, and increased
urine sediment score. Patients who develop postconditioning
renal insufficiency often require dialysis and have a low 12-
month survival rate. The renal insufficiency appears temporally
related to the infusion of melphalan.89 Ongoing tubular injury
may be a prerequisite for the development of postconditioning
renal insufficiency.
After stem cell transplantation, clonal responses range
between 50% and 60%, twice that reported with the use of
melphalan and prednisone.83,93 The selection bias inherent in
administering high-dose therapy may contribute partly to this
improved outcome. Eligibility for stem cell transplantation is a
predictor of improved survival.84 Stem cell transplantation does
produce kidney, heart, and liver responses. Currently, a
prospective randomized French trial is comparing stem cell
transplantation with oral melphalan/dexamethasone therapy. A
randomized trial begins in the United States in 2005.
Solid organ transplantation has been performed to manage
amyloidosis.25,97We have performed kidney transplantation in
patients with AL amyloidosis. Two strategies have been used. In
the first strategy, patients received high-dose therapy while on
dialysis in an effort to eliminate precursor light chain
production, followed by renal transplantation. The disadvantage
of this strategy was that patients on dialysis received a reduced
dose of melphalan, only 140 mg/m2, which may have
compromised the hematologic response rate. The complexities
of performing stem cell transplantation in patients on dialysis
are also increased. In the second strategy, high-dose therapy was
attempted within 6 months after patients received an allograft
kidney. Complication rates are high because these patients were
receiving long-term immunosuppressive therapy with
cyclosporine, prednisone, and tacrolimus and were at higher risk
for infection because of their chronically low CD4 cell counts.
Of our 8 patients, 5 of whom had end-stage renal disease by the
time of kidney transplantation, 1 died shortly after kidney
transplantation from causes unrelated to the procedure, and 1
has delayed stem cell transplantation. Of the 6 patients who
received stem cell transplantation, 1 died after transplantation,
but 5 are alive, and 3 have exhibited a complete hematologic
response. One patient developed a posttransplantation
monoclonal gammopathy. Immunosuppression did not
interfere with engraftment. Renal allograft function did not
decline with high-dose therapy.
Investigational Therapies
Etanercept has been used to treat advanced amyloidosis in 16
patients.98 The median duration of treatment was 42 weeks, and
objective improvement was noted in 50% of patients. The
estimated median survival was 24.2 months. Etanercept
warrants further study in the management of AL amyloidosis.
Dendritic cell idiotype vaccines have been attempted for
managing AL amyloidosis. Dendritic cell precursors were
purified from peripheral blood mononuclear cells and incubated
ex vivo with the patients serum containing the amyloid protein
precursors adjusted to a concentration of 10 g/mL. After 2
days of ex vivo expansion, the antigen-sensitized dendritic cellswere infused at 2, 4, and 16 weeks. No toxic effects were
observed. One patient had a reduction in proteinuria from 1400
mg to 60 mg per day. One patients neuropathy improved. Two
patients have died. The patients who had a clinical response had
a specific T-cell proliferative response to idiotype.99
An attempt to destabilize the amyloid fibril by interfering with
its sulfated glycosaminoglycan structure has been attempted.
Phase II trials with NC-531 were under way in October 2002.
Because all forms of amyloid have a high content of
glycosaminoglycans, particularly heparan sulfate proteoglycan,
such an agent could hold promise as a treatment.100A murine
antihuman light chain monoclonal antibody has been developed
that recognizes an epitope common to all AL fibrils. One
antibody, 11-1F4, was given to mice bearing AL amyloidomas
induced by the subcutaneous injection of human AL extracts.
Their tumor masses rapidly decreased. The antibody is now
being chimerized into a human form. Administration of the
chimerized reagent in mice bearing human AL tumors has
produced a marked reduction in amyloid burden with no
toxicity. Phase I trials of 11-1F4 are expected to begin.101,102
All forms of amyloid contain P component, and inhibitors of
P component have been developed in an attempt to destabilize
the amyloid fibril.103A compound has been shown to deplete P
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Clinical Lymphoma & Myeloma November 2005 21
component from the serum and, according to scanning results,
is capable of depleting P component from amyloid deposits.
The cross-linked P component is removed by liver clearance. It
is hoped that the amyloid fibril will be destabilized.
ConclusionAmyloidosis should be considered in any patient with nephrotic
syndrome, cardiomyopathy, unexplained hepatomegaly,
peripheral neuropathy, or atypical myeloma.Initial evaluation
includes immunofixation of serum and urine and a serum
immunoglobulin free light chain nephelometric assay. Biopsy is
required to substantiate the diagnosis, but examination of a
subcutaneous fat aspirate and bone marrow will lead to the
diagnosis in 80% of patients. Biopsy of the heart, kidney, or
liver is rarely required. Prognosis of amyloidosis can be
accurately assessed with troponin T and NT-proBNP.
Echocardiography is helpful in all cases.
No optimal treatment has been established for AL amyloidosis.
The most commonly used is cytotoxic chemotherapy, oral
melphalan, low-dose parenteral melphalan, or high-dose
melphalan with stem cell reconstitution. Dexamethasone isfrequently given in combination with oral and intermediate-dose
melphalan and has been used alone successfully. Thalidomide
and the new analogue lenalidomide are being studied. A phase
III trial by the French Myeloma Study Group is expected to
answer the question of whether high-dose therapy provides
survival benefit for patients with amyloidosis.
AcknowledgementThis work was supported in part by the Hematologic
Malignancies Fund, Mayo Clinic.
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