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The Role of Transplant and New Treatments in Amyloidosis:

A Focus on Minimizing Toxicity

Jonathan L. Kaufman, MD Associate ProfessorHematology & OncologyWinship Cancer Institute of Emory University

Amyloidosis• Protein Conformation/Deposition

Disorder

• AL Amyloidosis

• Hereditary Amyloidosis– Transthyretin

– Fibrinogen Aα

– Apolipoprotein AI and AII

– Lysozyme

• Secondary Amyloidosis

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The cascade of molecular events leading to amyloidosis.

Merlini G et al. JCO 2011;29:1924-1933

©2011 by American Society of Clinical Oncology

Clinical Manifestations of Amyloidosis

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AL Amyloidosis

• Monoclonal plasma cell disorder

• 3,000 cases annually in the USA

• 10% of patients are < 50 years old

• Presenting symptoms are varied

• Delays in diagnosis are common

Comenzo and Gertz, Blood, 15 June 2002, Vol. 99, No. 12, pp. 4276-4282

• Clonal plasma cell disorder

• λ to κ ratio ~ 3:1

• Plasma cells less than 30%

• Low proliferation

• Small portion of light chains are amyloidogenic

• Certain variable regions more likely

AL Amyloidosis

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Clinical Manifestations of AL Amyloidosis

Merlini and Bellotti N Engl J Med. 2003 Aug 7;349(6):583-96

Merlini and Stone, Blood 2006

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Establishing the Clinical Diagnosis

Assay% Positive

(CI)1

FLC / ratio 91 (84–96)

Serum IFE 69 (60–78)

Urine IFE 83 (74–89)

Serum IFE + urine IFE 95 (90–99)

FLC / ratio + urine IFE 91 (84–96)

FLC / ratio + serum IFE 99 (95–100)

All 3 assays 99 (95–100)

Clinical Chemistry 51: 878-881, 2005.

Establishing the Diagnosis by “non-invasive” testing

Fat+ Marrow+ 62%

Fat+ Marrow– 11%

Fat– Marrow+ 15%

Fat– Marrow– 13%

Gertz, M. A. et al. Hematology 2004;2004:257-282

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Diagnostic algorithm for systemic amyloidosis.

Merlini G et al. JCO 2011;29:1924-1933

©2011 by American Society of Clinical Oncology

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Prognosis

• Cardiac involvement

• Age

• Number of organs involved

• Cardiac Biomarkers

• Serum Free Light Chain

• Fluid retention during mobilization

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Prognosis

• Cardiac involvement

• Age

• Number of organs involved

• Cardiac Biomarkers

• Serum Free Light Chain

• Fluid retention during mobilization

Dispenzieri, A. et al. J Clin Oncol; 22:3751-3757 2004

Cardiac Biomarkers are Prognostic

Copyright© American Society of Clinical Oncology

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Cardiac Biomarker Staging System

Dispenzieri A, J Clin Oncol. 2004 Sep 15;22(18):3751-7.

Stage INormal Troponin and NT-ProBNP

26 months

Stage IIEither Troponin-T >0.03ng/L or NT-ProBNP >36 pMol/L

10 months

Stage III Both abnormal3.5 months

Cardiac Biomarker are Prognostic Even in Patients without a Clinical Suspicion of Cardiac Involvement

Dispenzieri, A. et al. J Clin Oncol; 22:3751-3757 2004

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Troponin T as Predictor of TRM

Principles of Treatment:The Overflowing Sink Theory

• Unclog the drain (impair assembly, prevent filament formation, dissolve fibrils)

• Turn off the faucet (cytoreduction of plasma cells)

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Targeting the Plasma Cell Clone

Kyle et al. 336 (17): 1202, Figure 1 April 24, 1997

MP versus Colchicine

Median Survival for MP was 18 months

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Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

Palladini, G. et al. Blood 2007;110:787-788

Melphalan and Dexamethasone is an effective therapy for patients with Amyloidosis

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Dispenzieri, A. et al. Blood 2004;103:3960-3963

Patients treated with transplant fare better than case matched controls

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Skinner Ann Intern Med. 2004 Jan 20;140(2):85-93

But, High Mortality in Patients with Cardiac Involvement

Careful Patient Selection for High Dose Therapy

Gertz, M. A. et al. Hematology 2004;2004:257-282

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Sanchorwala, IMW, 2009

New Therapies: Targeting the Clone

• Lenalidomide

• Bortezomib

• Mel/Dex/Bortezomib

• CyBorD

• Carfilzomib

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Lenalidomide

• Lenalidomide: Highly active derivative of thalidomide. Effective alone and with dexamethasone for patient with myeloma

• Two independent phase II studies. The combination of dex plus lenalidomide improved response rates

Sanchorwala et al; Blood. 2006 Sep 7 Dispenzieri et al; Blood. 2006 Sep 28;

Progression-free survival in patients with hematologic CR.

Sanchorawala V et al. Blood 2010;116:1990-1991

©2010 by American Society of Hematology

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Lenalidomide: Conclusions

• Toxicity significant at 25mg 21/28 days

• Starting dose should be at most 15mg 21/28 days

• Should be used in combination with dex if possible

Single Agent Bortezomib

Reece et al, Blood

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Reece et al; Blood 2011

Bortezomib: Evidence of Hematologic and Organ Response

Copyright ©2007 Ferrata Storti Foundation

Kastritis, E. et al. Haematologica 2007;92:1351-1358

Bortezomib and Dexamethasone is Associated with Rapid Response

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Survival of patients according to (A) hematologic and (B) proBNP response

Kastritis E et al. JCO 2010;28:1031-1037©2010 by American Society of Clinical Oncology

Bortezomib Mel Dex

• Patient Population: newly diagnosed and relpased

• Hematologic Response: ORR 83%; CR%

• Organ Response: 50%

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Treatment algorithm for immunoglobin light chain amyloidosis.

Merlini G et al. JCO 2011;29:1924-1933

©2011 by American Society of Clinical Oncology