107 Immunoglobulin Light Chain Amyloidosis

Question 1

Common to all forms of amyloidosis, the deposits bind _______ dye and demonstrate ______ birefringence under polarized light.

Answer 1

Congo red dye

Green birefringence

Question 2

Amyloid deposits are always (intracellualr, extracellular) and, under the light microscope, appear amorphous

Answer 2

Extracellular

They appear pink when viewed with standard hematoxylin and eosin staining.

Under the electron microscope, they are rigid, linear, nonbranching fibrils of 9.5-nm diameter.

Question 3

Inherited forms of amyloidosis are generally composed of _________________ but can also be a consequence of point mutations in apolipoprotein, fibrinogen, and gelsolin.

Answer 3

Mutant transthyretin (TTR)

AA amyloidosis (secondary) can be the consequence of sustained inflammation but can also be inherited as it is in familial Mediterranean fever.

Question 4

Previously referred to as senile systemic amyloidosis, primarily a cardiac disorder, caused by deposition of wild-type transthyretin as amyloid material in predominantly male patients over the age of 60 years

Answer 4

ATTRwt (wild-type)

Question 5

The only form responsive to chemotherapy

Answer 5

AL amyloidosis

Question 6

Nomenclature of Amyloidosis: Subunit Protein

AL or AH:
AA:
ATTR (wild type):
ATTR (mutant):
A lect 2:
A Ins:
A fib:
A B-2M:

Answer 6

AL or AH: Immunoglobulin heavy or light chain
AA: Secondary serum amyloid A
ATTR (wild type): Senile systemic transthyretin
ATTR (mutant): Familial transthyretin
A lect 2: Leukocyte chemotactic factor; No mutation found
A Ins: Insulin localized to injection sites
A fib: Fibrinogen Aα-2 mutation
A B-2M: β2 microglobulin, Chronic dialysis

Question 7

Nomenclature of Amyloidosis: Clinical Organ Involvement

AL or AH:
AA:
ATTR (wild type):
ATTR (mutant):
A lect 2:
A Ins:
A fib:
A B-2M:

Answer 7

AL or AH: Heart, Kidney, Liver, Nerve
AA: Kidney, Gastrointestinal, Thyroid
ATTR (wild type): Heart, Carpal tunnel
ATTR (mutant): Heart, Nerve
A lect 2: Kidney
A Ins: Skin
A fib: Kidney
A B-2M: Soft tissue, joints, Spine

Question 8

Light-chain amyloidosis represents approximately _____% of all amyloid patients seen at the Mayo Clinic, and immunoglobulin heavy-chain amyloidosis represents ______% of all patients.

Answer 8

Light-chain amyloidosis 52%

Heavy-chain amyloidosis <1%

The immunoglobulin light chains found in amyloid deposits usually range from 8 kD–15 kD.

In light-chain amyloidosis, the κ to λ ratio is 1:3

Question 9

Subgroup of light chains found exclusively in patients with light-chain amyloidosis.

Answer 9

λVI

Question 10

TRUE OR FALSE

Overt myeloma with true CRAB criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions) is common in light-chain amyloidosis.

Answer 10

FALSE

Overt myeloma with true CRAB criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions) is uncommon in light-chain amyloidosis.

Patients with AL amyloidosis are classified into those patients with myeloma and those without myeloma.

The percentage of plasma cells present in the marrow at the time of diagnosis is prognostic and predicts outcome in patients with AL amyloidosis.

Patients who do not have myeloma at presentation have little chance of developing myeloma later in the course of the disease.

Question 11

Genetic abnormality seen in half of amyloidosis patients and appears to confer bortezomib resistance and an inferior outcome

Answer 11

translocation t(11;14)

The plasma cells in the marrow of patients with AL amyloidosis tend to be nonproliferative and frequently lack the genetic abnormalities that are typically seen in myeloma

Question 12

TRUE OR FALSE

Only 1% of patients with AL amyloidosis are under the age of 40 years.

Answer 12

TRUE

Only 1% of patients with AL amyloidosis are under the age of 40 years.

This age group regularly can be seen with secondary systemic amyloidosis

The majority of patients with light-chain amyloidosis are males (66%), unlike myeloma, where the male-to-female ratio is 52:48.

Question 13

Frequently cited as a diagnostic finding and, when present, is useful but is only seen in 15% of patients

Answer 13

Periorbital purpura

Enlargement of the tongue is seen in approximately one person in eight

Hepatomegaly is seen in approximately 20% of patients and is caused by direct infiltration of the liver

Question 14

Periarticular infiltration of the shoulders is called the

Answer 14

Shoulder pad sign

Question 15

Screening for light-chain amyloidosis

Answer 15

• Immunoelectrophoresis and immunofixation of both serum and urine
• Immunoglobulin free light-chain assay (both κ and λ) of serum

Systemic AL amyloidosis is a plasma cell neoplasm, and 99% of patients will have a detectable abnormality of one of these three tests, reflecting their synthesis by a clonal population of plasma cells in the marrow

Question 16

Screening for light-chain amyloidosis is recommended when a patient is seen with any of the following clinical syndromes:

Answer 16

• Nephrotic-range proteinuria with any serum creatinine level;
• Infiltrative cardiomyopathy or heart failure with preserved ejection fraction. A normal ejection fraction does not exclude AL amyloidosis. The only symptom may be exertional fatigue;
• Hepatomegaly or alkaline phosphatase elevation without specific imaging abnormalities;
• A mixed axonal demyelinating peripheral neuropathy, sensory and/or motor and/or autonomic, particularly when associated with a monoclonal gammopathy; and/or
• A patient with myeloma or MGUS with unusual symptoms that are not typical or consistent with myeloma CRAB criteria, particularly unexplained fatigue.

Question 17

If a systemic plasma cell neoplasm and an immunoglobulin light chain cannot be confirmed, the three possibilities are:

Answer 17

• The patient does not have amyloidosis,
• The patient does not have systemic AL amyloidosis, or
• The amyloidosis is not immunoglobulin light chain in type and reflects a different protein subunit, the most common being ATTRwt cardiac amyloidosis.

Question 18

Most commonly involved organ in amyloidosis

Answer 18

Kidney

2nd: Heart

Question 19

A critically important screening test used for prognostication and staging

Answer 19

Free light-chain assay

Question 20

TRUE OR FALSE

A screening serum protein electrophoresis is insufficient as a screening technique because a visible M-spike is seen in less than half of patients because of the high prevalence of light-chain proteinemia.

Answer 20

TRUE

A screening serum protein electrophoresis is insufficient as a screening technique because a visible M-spike is seen in less than half of patients because of the high prevalence of light-chain proteinemia.

Finding a monoclonal protein in the serum or in the urine of a patient with heavy albuminuria often obviates the need for a renal biopsy.

Question 21

A patient with a free light chain in the serum or urine and proteinuria can have only one of three disorders:

Answer 21

(1) myeloma cast nephropathy
(2) light-chain amyloidosis, or
(3) Randall-type immunoglobulin deposition disease (κ)

Question 22

Required to confirm the diagnosis of AL amyloidosis before therapy can commence

Answer 22

Biopsy

Although imaging of amyloid deposits with various radionuclides, most notably antiserum amyloid P component, continue to be explored and used in practice, they are not a substitute for histologic confirmation of the presence of AL amyloidosis

Question 23

Biopsy of choice in AL

Answer 23

Subcutaneous fat aspiration
Marrow biopsy

The fat aspiration is positive in three-fourths of patients with amyloidosis.

Congo red staining of marrow blood vessels can detect amyloid deposits in half of patients with AL amyloidosis.

At the Mayo Clinic, combining the two techniques (marrow and fat-pad aspirate), enables the diagnosis in 85% of cases.

If the clinical suspicion of AL amyloidosis is strong and these biopsies are negative, it is appropriate to biopsy the affected organ.

Question 24

Test to determine the protein subunit involved

Answer 24

Laser capture of the amyloid deposit followed by mass spectroscopic analysis

For patients who have ATTR amyloidosis, is that tissue mass spectroscopy not only identifies the protein in most instances, but may also indicate whether the protein is wild-type or mutant

Question 25

Forms of systemic amyloidosis for which **systemic chemotherapy is contraindicated**

Answer 25

Fibrinogen A-α amyloidosis, amyloid caused by apolipoprotein-A1, apolipoprotein-A4, and gelsolin

Question 26

**Kidney involvement** is seen in _____% of patients with **immunoglobulin light-chain amyloidosis**

Answer 26

61% ## Footnote It is conspicuously absent in the majority of patients with ATTR amyloidosis until late in the disease. Universal in systemic **AA amyloidosis** as well as **ALect2 amyloidosis, Alipoprotein and A-fibrinogen α amyloidosis**.

Question 27

**Renal** involvement is virtually **universal** in what types of amyloidosis

Answer 27

* Systemic AA amyloidosis * ALect2 amyloidosis * Alipoprotein amyloidosis * A-fibrinogen α amyloidosis

Question 28

Typical feature of renal amyloidosis

Answer 28

**Nephrotic syndrome:** nephroticrange proteinuria, hypoalbuminemia, hyperlipidemia, and edema

Question 29

# TRUE OR FALSE One-half of patients with renal amyloidosis will ultimately require renal replacement therapy

Answer 29

FALSE **One-third** of patients with renal amyloidosis will ultimately require **renal replacement therapy**

Question 30

The best predictor of which patients are most likely to require dialysis

Answer 30

Estimated GFR (eGFR) and level of urinary protein loss at the time of presentation

Question 31

The best method for prevention of dialysis

Answer 31

Effective therapy of the underlying plasma cell neoplasm

Question 32

# TRUE OR FALSE The correlation between the amount of amyloid seen in a renal biopsy and the degree of renal dysfunction is poor.

Answer 32

TRUE The correlation between the amount of amyloid seen in a renal biopsy and the degree of renal dysfunction is poor. ## Footnote *Patients who progress to ESRD but who achieve complete hematologic response can be candidates for renal transplantation*

Question 33

The most common cause of death in patients with renal amyloidosis

Answer 33

Progressive cardiac dysfunction from amyloid cardiomyopathy

Question 34

Type of cardiomyopathy in cardiac amyloidosis

Answer 34

Restrictive cardiomyopathy ## Footnote Restrictive cardiomyopathy caused by amyloid infiltration results in **poor relaxation (so-called “stiff heart syndrome”) and poor filling during diastole**, so that the ventricular chamber has a low end-diastolic volume, which results in reduced stroke volume and a reduced cardiac output. This represents a classic example of **heart failure with preserved ejection fraction.**

Question 35

Cardiac amyloid is found in about **45%** of patients at diagnosis and is responsible for nearly _____% of deaths.

Answer 35

90%

Question 36

Diagnosis of cardiac amyloid Most useful test for the imaging and diagnosis of amyloid

Answer 36

Echocardiography with doppler flow studies and cardiac strain studies ## Footnote It is not particularly useful in terms of the serial monitoring of patients for response or progression after treatment.

Question 37

Echocardiographic clues of cardiac amyloidosis

Answer 37

Thickening of the right ventricle, atrial systolic failure, and reduction in left ventricular chamber size Late consequences of cardiac involvement include valvular thickening and valvular regurgitation. ## Footnote It is important to recognize that surgical repair of a valve will not result in meaningful improvement in the patient’s aerobic capacity.

Question 38

When light-chain testing is negative, the possibility of __________________ should be considered.

Answer 38

ATTRwt cardiac amyloidosis ## Footnote Patients **over the age of 60 years**, predominantly **men**, **half of whom will also have bilateral carpal tunnel syndrome**

Question 39

Imaging in ATTRwt cardiac amyloidosis

Answer 39

Echocardiography, magnetic resonance imaging (MRI), or technetium pyrophosphate scanning

Question 40

A septal thickness greater than ____ mm would be rare with hypertensive cardiomyopathy and would be limited to either **amyloidosis or hypertrophic cardiomyopathy**

Answer 40

15 mm ## Footnote Interestingly, the degree of cardiac infiltration in ATTRwt amyloidosis and familial amyloid cardiomyopathy is substantially greater than that seen in AL amyloidosis **AL amyloidosis**: larger than **18 mm** will generally have **significant disability** related to cardiac failure **ATTR amyloidosis**, both mutant and wildtype, will frequently have septal thicknesses in the range of **25 mm** with **minimal symptomatology.**

Question 41

Highly sensitive in the diagnosis of cardiac amyloidosis

Answer 41

Endomyocardial biopsy ## Footnote If **five specimens** are taken, recognition of the diagnosis is virtually certain

Question 42

The mainstay of management for cardiac amyloidosis

Answer 42

Diuretic therapy

Question 43

Gene involved in **familial amyloid cardiomyopathy**

Answer 43

TTRVal122Ile

Question 44

Play an important role in the prognosis of cardiac amyloidosis as well as in its functional assessment

Answer 44

Cardiac biomarkers: B-natriuretic peptide and troponin ## Footnote All patients who present with amyloidosis, regardless of whether cardiac disease is suspected, should have cardiac biomarkers performed.

Question 45

# Cardiac amyloidosis **Mayo (2012) staging** involves the assignment of a point for any of the following characteristics:

Answer 45

* Difference between the involved and uninvolved free light chain of **greater than 180 mg/L** * A high sensitivity **(hs) cardiac troponin T level >40 ng/L** * An NT-proBNP of **greater than 1800 pg/mL**.

Question 46

Marker used to define **response and progression** and have **supplanted the use of serial echocardiography** to assess changes over time, both in following the natural history as well as assessing response to therapeutic interventions

Answer 46

NTproBNP

Question 47

MRI finding specific for cardiac amyloidosis

Answer 47

Delayed subendocardial enhancement

Question 48

A sensitive marker for the presence of ATTR amyloidosis

Answer 48

Technetium pyrophosphate

Question 49

Presentation of patients with liver amyloidosis

Answer 49

Hepatomegaly and elevation of the serum alkaline phosphatase, with normal or near-normal transaminases and bilirubin ## Footnote Liver infiltration caused by amyloid can be seen in up to **15%** of patients with light-chain amyloidosis. **Half** of the patients with **hepatic amyloidosis** have **renal amyloidosis**, which dominates the clinical syndrome. Portal hypertension and ascites are uncommon.

Question 50

Diagnosis of liver amyloidosis

Answer 50

Fat aspiration and marrow biopsy ## Footnote But a **liver biopsy is safe** and **does not have a higher risk of bleeding** complications than in other patients with liver disease.

Question 51

Amyloid deposits in what part of the nervous system

Answer 51

Vasa nervorum ## Footnote Causes a **mixed axonal and demyelinating peripheral neuropathy**. The neuropathy is **symmetric**, tends to **ascend beginning in the toes**, and eventually involves the upper extremities

Question 52

# Nervous System Amyloidosis Approximately **half** of the patients will have an associated ____________________ , and approximately **one-fourth** will have associated ________________________

Answer 52

Carpal tunnel syndrome Autonomic features

Question 53

The progression of amyloid neuropathy is **slow**, and it is common to have delays of ____ years before a diagnosis is established.

Answer 53

2–3 years

Question 54

# TRUE OR FALSE Electromyography is not particularly useful in the early diagnosis because amyloid preferentially affects the small unmyelinated fibers of the extremities, which are not well assessed with standard electrodiagnostic studies.

Answer 54

TRUE **Electromyography is not particularly useful** in the early diagnosis because amyloid preferentially affects the **small unmyelinated fibers of the extremities**, which are not well assessed with standard electrodiagnostic studies.

Question 55

Location of localized AL

Answer 55

* Bladder * Larynx * Skin * Bronchi

Question 56

The prognosis in amyloidosis is determined by two factors

Answer 56

* Extent of cardiac involvement * Plasma cell burden ## Footnote Cardiac involvement measured by the use of **cardiac biomarkers**. Plasma cell burden: **difference between the involved and uninvolved light chains in the serum (dFLC)**

Question 57

Parameters used to stage amyloidosis

Answer 57

NT-proBNP, troponin, and free light chain * hs troponin T level **equal to or greater than 40 ng/L** * NT-proBNP **greater than 1800 pg/mL** * dFLC **greater than 180 mg/L** ## Footnote Alternatively, one can use the **Mayo 2014 system with the European modification**, which also gives four groups, but **uses only the troponin and the NT-proBNP.** The **Mayo 2004 system** is especially helpful for **predicting the risk of early death.**

Question 58

Two parameters to assess response

Answer 58

* Hematologic response * Organ function

Question 59

Hematologic response

Answer 59

* **Complete remission** : negative immunofixation of serum and urine and a normal immunoglobulin free light-chain ratio * **Very good partial response** : dFLC less than 40 mg/L * **Partial response** : 50% decrease from baseline in the dFLC * **Failure to respond** ## Footnote **Light-chain assessment** is not only the ideal method for measuring response because of the rapid decline in levels, but it is better than the intact immunoglobulin as a measure of response when both are present.

Question 60

Renal response

Answer 60

* **Partial renal response**: 31% to 60% decrease in 24-hour urine protein volume * **Very good partial response**: more than 60% reduction in proteinuria * **Complete renal response**: less than 200 mg protein lost within 24 hours * **Progression**: 50% increase in urinary protein loss to at least 1 g/day or a 25% worsening of creatinine clearance

Question 61

Cardiac response

Answer 61

* **Partial response:** A 31% to 60% reduction in the NT-proBNP— a minimum of 300 ng/L in patients whose baseline NT-proBNP is greater than 650 ng/L * **Very good partial response**: more than a 60% reduction * **Complete cardiac response:** NT-pro BNP lower than 400 pg/mL * **Cardiac progression** : 30% increase in NT-proBNP, a minimum increase of 300 ng/dL ## Footnote An improvement in the New York Heart Association class **by two stages** from a IV to II or III to I also is considered a response.

Question 62

Liver repsonse

Answer 62

* **Response**: 50% reduction in the abnormal alkaline phosphatase value * **Progression** : 50% increase of alkaline phosphatase above the lowest recorded value ## Footnote *Currently, consensus criteria to define response in soft tissues such as the gastrointestinal tract, the tongue, the lung, or peripheral nerves do not exist for lightchain amyloidosis.*

Question 63

Standard of therapy for amyloidosis

Answer 63

Melphalan and prednisone Melphalan and dexamethasone ## Footnote Melphalan and prednisone: the response rate never exceeded 25% **Melphalan and dexamethasone: very low therapy-related mortality** and can be administered to patients with **cardiac and renal failure as well as the to the physically frail** ***Melphalan should be avoided in transplant-eligible patients because it may impair stem cell collection***

Question 64

# TRUE OR FALSE Autologous stem cell transplant been proven to be superior to conventional chemotherapy

Answer 64

FALSE Autologous stem cell transplant has not been proven to be superior to conventional chemotherapy

Question 65

# Autologous stem cell transplant in Amyloidosis To reduce treatment-related mortality, relatively stringent inclusion criteria should be adopted

Answer 65

* Biologic age less than 70 years * Serum creatinine lower than 1.8 mg/dL * Hs troponin T less than 75 ng/L * Systolic blood pressure higher than 90 torr ## Footnote To optimize stem cell collection, transplant candidates **should not be exposed to melphalan** beforehand, and stem cells are frequently mobilized without using cytotoxic chemotherapy.

Question 66

Although it is common practice not to use induction chemotherapy before stem cell transplantation, patients with **high plasma cell counts in the marrow (>10%)** merit pretransplantation induction chemotherapy, typically with

Answer 66

CyBorD

Question 67

Predictors of outcome after stem cell transplantation

Answer 67

Cardiac biomarkers, NTproBNP, and troponin

Question 68

Immunomodulator drug that can increase the level of NT-proBNP and may actually aggravate heart failure

Answer 68

Lenalidomide ## Footnote The typical dose of lenalidomide used to treat myeloma is n**ot well tolerated** by patients with AL amyloidosis and treatment should be initiated at **no more than 15 mg daily**.

Question 69

PI that resulted **36% cardiac toxicity** but has been reported to be beneficial in patients with **AL amyloidosis neuropathy**

Answer 69

Carfilzomib