- AL amyloidosis is characterized by abnormal light chains produced by plasma cells that misfold and deposit as amyloid in tissues like the heart, kidneys, liver, and nervous system. This can cause organ dysfunction. - Cardiac involvement is common and causes restrictive cardiomyopathy. Symptoms include heart failure, arrhythmias, and conduction abnormalities. Biomarkers, echocardiogram, cardiac MRI, and endomyocardial biopsy are used in diagnosis. - Prognosis is poor if cardiac involvement is present, with median survival of less than 2 years with heart failure symptoms. Treatment involves chemotherapy and stem cell transplantation to suppress the plasma cell disorder causing amyloid deposition.

1. MULTIPLE MYELOMA AND
AL AMYLOIDOSIS
Jerry Estep M.D, FACC, FASE
Medical Director, Heart Transplant and LVAD Program

2. DISCUSSION GOALS
• Overview of immunoglobin light chain (AL) cardiac
amyloidosis
• Define multiple myeloma in the context of AL
amyloidosis
• Highlight current therapeutic options

3. LIGHT CHAIN AMYLOIDOSIS
• AL amyloidosis is characterized
by a clonal population of bone
marrow plasma cells that produce
a monoclonal light chain Kappa
(κ) or Lambda (λ)type
• The light chain protein misfolds
and forms a Beta-pleated sheet
(in stead of alpha helical
configuration)
• Increased serum free light chains
precedes the development of
disease for many years

4. PATHOPHYSIOLOGY OF
CARDIAC AL AMYLOIDOSIS
• Light chain amyloid proteins
can be directly toxic to
cardiomyocytes 1
• Precursor soluble
intermediates have toxic
effects and contribute to
organ dysfunction2
• Major sites of clinically
important deposition: heart,
kidneys, liver, and nervous
system
1. Sikkink, L. A. et al. Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture. Cell Death Dis. 1, e98 (2010).
2. Levinson, R. T. et al.. Role of mutations in the cellular internalization of amyloidogenic light chains into cardiomyocytes. Sci. Rep. 3, 1278 (2013)
-Diastolic dysfunction
_Conducting system/
Rhythm disturbances
-Intramyocardial and
epicardial coronaries/Ischemia
Heart

5. INSOLUBLE PROTEIN EXTRACELLULAR
DEPOSITION
• AL incidence in the U.S. ~8.9 per
million person-years (up to 3000 new
patients/year)1
• AL amyloidosis is the most common
type of cardiac amyloidosis2
– 0.3 cases per 100,000 people in the
general population
– >50% have cardiac involvement
• Identified on biopsy specimens3
– Ability to bind Congo red (leading
to green birefringence -polarized
light)
– Characteristic appearance on EM1. Kyle RA et al. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45-59.
2. Gertz, M. et al. Pathophysiology and treatment of cardiac amyloidosis. Nat. Rev. Cardiol. 12,91-102 (2015)
3. Gertz, M. Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatement. Am. J. Hematol. 89:1133-1140, 2014.

6. OVERLAP WITH MULTIPLE
MYELOMA
• Affected patients may have
amyloidosis alone 1
– Most do not have multiple
myeloma
– Average bone marrow plasma cell
count ~ 5-7%
• In association with other plasma cell
dyscrasias2
– Multiple myeloma
– Waldenstrom macroglobulinemia
Clonal plasma cell disorder
1. Kourelis, T. V. et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients
with immunoglobulin light chain amyloidosis. J. Clin. Oncol. 31, 4319–4324 (2013).
2. Gertz, M. Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatement. Am. J. Hematol. 89:1133-1140, 2014.

7. MULTIPLE MYELOMA
(DISEASE DEFINITION)
• All criteria must be met except as noted1,2:
– Clonal bone marrow plasma cells > 10% or
biopsy proven plasmacytoma, and
– Evidence of end organ damage that can be
attributed to the underlying plasma cell
proliferative disorder
• Hypercalcemia: Serum calcium > 11.5 mg/dL
or
• Renal insufficiency: Serum Cr > 1.73 mmol/dl
or eGFR < 40 ml/min
• Anemia: Normochromic, normocytic with Hg
value > 2 g/dl below the lower limit of normal
or a Hg value < 10 g/dL
• Bone lesions: Lytic lesions, severe
osteopenia or pathologic fractures
– In the absence of end-organ damage: Clonal
bone marrow plasma cells > 60%
Lytic lesions in the radius
1. Rajkumar SV, Merlini G, San Miguel JF. Redefining myeloma. Nat Rev Clin Oncol 2012;9:494–496
2. The International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and
related disorders: A report of the International Myeloma Working Group. Br J Haematol 2003;121:749–757
Bone marrow aspirate smear

8. AMYLOIDOSIS
PRESENTATION
HIGHLIGHTS
• Two-thirds of patients are men1
• Median age at presentation ~ 67 years1
• 80% of patients will have λ light chains rather than
κ light chains
• Systemic disorder observations1, 2:
– ~50% of patients have renal involvement
– 16% have liver involvement
– 10 % have neurological involvement
– Study of 131 patients with + endomyocardial biopsy,
73% also had + results in non-cardiac tissues
1. Kyle RA et al. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45-59.
2. Fine, N. M. et al. Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac amyloidosis. Am. J. Cardiol. 113, 1723–1727 (2014).

9. WHEN TO SUSPECT
AL AMYLOIDOSIS
• Nonischemic cardiomyopathy
with “hypertrophy” on echo
• Nondiabetic nephrotic syndrome
• Hepatomegly or increased
alkaline phosphatase with no
imaging abnormality of the liver
• Chronic inflammatory
demyelinating polyneuropathy
with a monoclonal protein
• Monoclonal gammopathy with
unexplained fatigue, edema,
weight loss, or paresthesias ASE Chamber Guidelines JASE 2015

10. SYSTEMIC AL AMYLOIDOSIS
(DISEASE DEFINITION)
• All four criteria must be met:
– Presence of an amyloid-related systemic syndrome (such as
renal, liver, heart, gastrointestinal tract, or peripheral nerve
involvement)
– Positive amyloid staining by Congo red in any tissue (e.g., fat
aspirate, bone marrow, or organ biopsy)
– Evidence that amyloid is light-chain related established by
direct examination of the amyloid
• Mass Spectrometry (MS)-based proteomic analysis, or
• Immunoelectron microscopy
– Evidence of a monoclonal plasma cell proliferative disorder
(serum or urine M protein, abnormal free light chain ratio, or
clonal plasma cells in the bone marrow).
Rajkumar SV et al. Redefining myeloma. Nat Rev Clin Oncol 2012;9:494–496

11. EVALUATION OF SUSPECTED AL
CARDIAC AMYLOIDOSIS
• Clinical features
• ECG
• Serum BNP and
troponins
• Imaging
-Low voltage
found in ~46%
-Pseudoinfarct
~47%
AL
1. Kyle RA et al. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45-59.
2. Gertz, M. et al. Pathophysiology and treatment of cardiac amyloidosis. Nat. Rev. Cardiol. 12,91-102 (2015)
3. Mohty, Dania et al. Cardiac amyloidosis: Updates in diagnosis and management. Archives of CV Disease 2013; 106,528-540.

12. • Includes right-sided HF, including peripheral
edema and hepatomegaly (nephrotic syndrome may
contribute to edema and amyloid infiltration of liver
to hepatomegaly).
• Angina, jaw claudication. Involved arteries are small
and intramyocardial.
• Pre/syncope
– Exertional syncope marker for restrictive CM.
– Postural hypotension-autonomic neuropathy.
– Ventricular arrhythmia
– AV block
• Hypotension
• Cardiac murmur
• Renal dysfunction from low cardiac output
CLINICAL SYMPTOMS AND SIGNS-AL
CARDIAC AMYLOIDOSIS

13. CARDIAC BIOMARKERS AND
AL AMYLOIDOSIS
• Troponin T and NT-
proBNP are sensitive
indicators of the
presence of cardiac
amyloidosis and
survival1
– Troponin T > 0.025 ng/ml
– NT-proBNP > 1800 pg/ml
• An important feature of
the staging system for
AL amyloidosis2
1. Chaulagain, C. P. & Comenzo, R. L. New insights and modern treatment of AL amyloidosis. Curr. Hematol. Malig. Rep. 8, 291–298 (2013).
2. Dispenzieri, A. et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary
systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 104, 1881–1887 (2004)

14. Non-Invasive Imaging Examined in
AL Cardiac Amyloidosis
Echocardiography
• 2D (LVEF, LV wall thickness, LV mass)
• Spectral and Tissue Doppler (Diastolic grading and estimation of LV
filling pressure)
• Strain and strain rate imaging based on TDI and speckle tracking
Cardiac Magnetic Resonance (CMR)
• Late gadolinium enhancement (extravascular contrast)
• T1 mapping techniques –Noncontrast testing based on myocardial T1
relaxation times
• Direct quantification of myocardial extracellular volume fraction
Radionuclide Imaging
• Bone scintigraphy using 99m technetium-hydroxymethylene
disphosphonate and SPECT-CT

15. ECHOCARDIOGRAPHY
AND AL AMYLOIDOSIS
• LVEF tends to remain normal until the
amyloidosis is far advanced
• Normal or small ventricular volume
• LV hypertrophy ( > 1.2 cm) with “brilliant”
speckled appearance
• Impaired relation
• Left atrial enlargement
• Elevated estimated LV filling pressure at
later stages
• Elevated systolic pulmonary pressure
• RV wall thickness >7mm, elevated RA
pressure
1. Gertz, M. et al. Pathophysiology and treatment of cardiac amyloidosis. Nat. Rev. Cardiol. 12,91-102 (2015)
2. Quarta et al. Left Ventricular Structure and Function in TTR-Related versus AL Cardiac Amyloidosis Circ 2014

16. ADVANCED ECHOCARDIOGRAPHIC
TECHNIQUES AND CARDIAC
AMYLOIDOSIS
• Myocardial Deformation-(volume of
the ventricular wall remains the
same during the cardiac cycle and,
thus, deforms in three dimensions):
– Longitudinal shortening
– Circumferential shortening
– Radial thickening.
1.Kusunose K. et al.. Images in cardiovascular medicine: cardiac magnetic resonance imaging and 2-dimensional speckle tracking
echocardiography in secondary cardiac amyloidosis. Circ J. 2010;74:1494–496.
2. Sun JP et al. Differentiation of hypertrophic cardiomyopathy and cardiac amyloidosis from other causes of ventricular wall thickening by
two-dimensionalstrain imaging echocardiography. Am J Cardiol. 2009;103:411–415.

17. GREATER RESTRICTION OF BASAL
COMPARED TO APICAL MOVEMENT
Apical function
Basal function
S. M. Banypersad et al. Updates in Cardiac Amyloidosis: A Review. J Am Heart Assoc. 2012

18. SPECKLE TRACKING ECHO
CHARACTERISTICS OF 172 PATIENTS
WITH CARDIAC AMYLOIDOSIS
Quarta et al. Left Ventricular Structure and Function in TTR-Related versus AL Cardiac Amyloidosis Circ 2014
Relative Apical
Sparing in both
AL and ATTR
Prevalence of Frequency of Abnormal Indices
Speckle
tracking
strain
parameters
were the most
sensitive

19. Ischemic Nonischemic
• Idiopathic Dilated
Cardiomyopathy
• Myocarditis
• Hypertrophic Cardiomyopathy
• Right ventricular pressure
overload (e.g. congenital heart
disease, pulmonary HTN)
• Sarcoidosis, Myocarditis, Anderson-Fabry, Chagas
A. Subendocardial Infarct
B. Transmural Infarct
A. Mid-wall HE
B. Epicardial HE
C. Global Endocardial HE
• Amyloidosis, Systemic Sclerosis, Post cardiac transplantation
• Sarcoidosis
• Myocarditis
• Anderson-Fabry
• Chagas Disease
Shah et al. In: Edelman RR, et al., eds. Clinical
Magnetic Resonance Imaging, 2005.

20. S. Banypersad et al. J Am Heart Assoc. 2012
CLASSIC AMYLOID CMR
FINDING

21. CARDIAC MAGNETIC
RESONANCE IMAGING
Selvanayagam, J. B. et al. J Am Coll Cardiol 2007;50:2101-2110Ruberg F, Berk J. Circulation 2012; 126:1286
-Increasing experience that the pattern of LGE can be atypical and
patchy, especially during early disease

22. LGE-CARDIAC MRI DETECTION OF
CARDIAC AMYLOIDOSIS
• Austin et al. Delayed hyperenhancement
MRI provides incremental diagnostic and
prognostic utility in suspected cardiac
amyloidosis. JACC Cardiovasc Imaging
2009
– Sensitivity ~ 88%
– Specificity ~ 95%
– PPV ~ 93%
– NPV ~ 90%
Patients with biopsy proven Amyloidosis

23. SCREENING FOR
AL CARDIAC AMYLOIDOSIS
• Immunofixation of the
serum
• Immunofixation of the
urine
• Serum Ig free light chain
(FLC) assay
– Comparing the ratio of κ FLCs to λ
FLCs in a person's serum against
reference ranges (0.26-1.65) ~ 1: 1.5
or indicates whether that person may
have a plasma cell dyscrasia such as
multiple myeloma or AL amyloidosis.
High frequency of lambda light chain proteinemia
is a hallmark of AL amyloidosis
2 light
chains
Antibody Molecule

24. Biopsy of the iliac crest bone marrow combined with abdominal subcutaneous
fat aspiration will identify amyloid deposits in 85% of patients with amyloidosis

25. MASS SPECTROSCOPY IDENTIFIES
FIBRIL/SUBUNIT
1. Gertz, M. et al. Pathophysiology and treatment of cardiac amyloidosis. Nat. Rev. Cardiol. 12,91-102 (2015).

26. “The major determinant of
outcome in amyloidosis is the
extent of cardiac involvement”
American Journal of Hematology. 86:181-186, 2011

27. PROGNOSIS AND AL
CARDIAC AMYLOIDOSIS
1. Felker GM et al. The New England journal of medicine 2000;342(15):1077-1084
2. Gertz MA et al. Hematology/oncology clinics of North America 1999;13(6):1211-1233, ix
3. Klein et. al. Doppler and Cardiac Amyloidosis Circulation 1991
4. Koyama et. al. JACC Imaging Vol.3.No4,2010

28. AL CARDIAC
AMYLOIDOSIS TREATMENT
• Supportive
– Diuretics mainstay
– Beta blockers may not be tolerated
– Unclear value of amiodarone
– ICD use not associated survival benefit
– Anticoagulation management not defined
Amyloid Treatment
• Cytotoxic chemotherapy
• Autologous stem cell transplantation (ASCT)
• Heart transplantation followed by ASCT

29. CONVENTIONAL SYSTEMIC
CHEMOTHERAPY
• Melphalan-dexamethasone is effective in almost
2/3 of patients with median survival ~ 5 years1
• Bortezomib2
– -inhibits proteasomes, enzyme complexes which
regulate protein homeostasis within the cell.
– Up to 71- 80% of patients can have a hematologic
response1. Merlini, G., Seldin, D. C. & Gertz, M. A. Amyloidosis: pathogenesis and new therapeutic options. J. Clin. Oncol. 29, 1924–
1933 (2011).
2. Mikhael, J. R. et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete
hematologic response in patients with AL amyloidosis. Blood 119, 4391–4394 (2012).

30. CARDIAC RISK FACTORS FOR
STEM CELL TRANSPLANT
• Patients with a troponin T
level > 0.06 ug/l
• NT-proBNP > 5,000 ng/l
• LVEF < 60%
• Clinical HF syndrome
1. Gertz, M. et al. Troponin T level as an exclusion criterion for stem cell transplantation in
light-chain amyloidosis. Leuk. Lymphoma 49, 36–41 (2008).
2. Gertz, M. A. et al. Trends in day 100 and 2-year survival after auto-SCT for AL amyloidosis:
outcomes before and after 2006. Bone Marrow Transplant. 46, 970–975 (2011).

31. IMPROVED OUTCOME WITH
SEQUENTIAL HEART TRANSPLANT
AND ASCT
• United Kingdom National Amyloidosis Centre 1 -5 patients with AL
– ASCT 13 months (range 10-24 months) post heart transplant
– 60% (3/5 patients) survival rate at a median follow up 7.5 years
• The Mayo Clinic Group 2 -11 patients with AL amyloidosis
– ASCT 6 months post heart transplant
– Survival rate of 82% and 65% at 1 and 5 year respectively
• MGH Group 3 -9 patients with cardiac amyloidosis
– 8 patients ASCT ~7 months (median time) post heart transplant
– 62.5% survival (5/8 patients) at a median follow-up 4.6 yrs
• Stanford Group 4 -6 patients with AL amyloidosis
– 3 patients ASCT ~8 months(6.9 to 9.9 months) post heart transplant
– 100% survival at 1year
1. Gillmore JD et al. Blood 2006;107(3):1227-1229.
2. Lacy et.al J Heart Lung Transplant 2008;27(8):823-829.
3. Dey BR et al. Transplantation; 2010; 90(8):905-911.
4. Varr BC et al. J Heart Lung Transplant 2012;31(3):325-331.

32. Now up to ~12 with 88% one year survival

33. HOUSTON METHODIST
EXCLUSION CRITERIA
• GI-Mucosal amyloid deposition (relative) with
clinical signs or mal-absorption (absolute)
• Liver-positive liver biopsy with evidence of
portal hypertension (absolute)
• Renal-GFR < 30 ml/min or UA > 2 g
protein/day (absolute)
• Neurologic-Severe lifestyle limiting peripheral
neuropathy on exam (absolute)
• Hematologic-Symptomatic myeloma
independent of % of plasma cells (MM Stage
2 and 3).
• Pulmonary-Persistent and significant
pleural effusion(s) not felt to be HF
mediated.

34. MULTIPLE MYELOMA
• bone pain in the back or ribs
• weakness and fatigue
• weight loss
• broken bones
• recurrent infections
• weakness in the legs
• nausea/vomiting
Clincal Symptoms/Review of symptoms

35. A MULTI-CENTER, INTERNATIONAL REGISTRY OF
CARDIAC TRANSPLANTATION FOR LIGHT CHAIN (AL) AND
TRANSTHYRETIN (TTR) AMYLOIDOSIS
Massachusetts General Hospital,
Columbia University Medical Center,
Stanford University Medical Center,
Houston Methodist
Newark Beth Israel Medical Center,
University of Padova,
Boston University Medical Center
Marc Semigran MD, Lauren Gilstrap MD, Emily Niehaus BA, Mathew
Maurer MD, Ron Witteles MD, Jerry Estep MD, Giuseppe Feltrin MD,
Mark Zucker MD, David Baran MD, David Seldin MD

36. CONCLUSIONS
• AL cardiac amyloidosis is part of a systemic
disease due to misfolding of clonal immunoglobin
light chains and is associated with a poor
prognosis.
• Suspicion and initial screening of AL cardiac
amyloidosis is based in part on echocardiography
and measurements of immunoglobulin free light
chains
• Supportive treatment is limited
• Early referral to an amyloid treatment center is
recommended for consideration chemotherapy,
ASCT, and heart transplantation.