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Multiple myeloma and al amyloidosis

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Multiple myeloma and al amyloidosis

  1. 1. MULTIPLE MYELOMA AND AL AMYLOIDOSIS Jerry Estep M.D, FACC, FASE Medical Director, Heart Transplant and LVAD Program
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 20. S. Banypersad et al. J Am Heart Assoc. 2012 CLASSIC AMYLOID CMR FINDING
  21. 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. 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. 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. 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. 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. 26. “The major determinant of outcome in amyloidosis is the extent of cardiac involvement” American Journal of Hematology. 86:181-186, 2011
  27. 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. 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. 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. 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. 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. 32. Now up to ~12 with 88% one year survival
  33. 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. 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. 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. 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.

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