MULTIPLE MYELOMA AND

AL AMYLOIDOSIS

Jerry Estep M.D, FACC, FASE

Medical Director, Heart Transplant and LVAD Program

DISCUSSION GOALS

• Overview of immunoglobin light chain (AL) cardiac

amyloidosis

• Define multiple myeloma in the context of AL

amyloidosis

• Highlight current therapeutic options

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

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

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 EM

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. Gertz, M. Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatement. Am. J. Hematol. 89:1133-1140, 2014.

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.

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

AL CARDIAC

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).

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

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

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.

• 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

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)

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

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

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.

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

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

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.

S. Banypersad et al. J Am Heart Assoc. 2012

CLASSIC AMYLOID CMR

FINDING

CARDIAC MAGNETIC

RESONANCE IMAGING

Selvanayagam, J. B. et al. J Am Coll Cardiol 2007;50:2101-2110 Ruberg F, Berk J. Circulation 2012; 126:1286

-Increasing experience that the pattern of LGE can be atypical and patchy, especially during early disease

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

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

Biopsy of the iliac crest bone marrow combined with abdominal subcutaneous

fat aspiration will identify amyloid deposits in 85% of patients with amyloidosis

MASS SPECTROSCOPY IDENTIFIES

FIBRIL/SUBUNIT

1. Gertz, M. et al. Pathophysiology and treatment of cardiac amyloidosis. Nat. Rev. Cardiol. 12,91-102 (2015).

“The major determinant of

outcome in amyloidosis is the

extent of cardiac involvement”

American Journal of Hematology. 86:181-186, 2011

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

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

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

response

1. 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).

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).

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.

Now up to ~12 with 88% one year survival

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.

•

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

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

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.