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Disclosures

Sharing knowledge. Sharing hope. Janet Brunner, PA-C • I have no relevant conflicts of interest to disclose.

Angela Dispenzieri, MD Forms Revision: • I have no relevant conflicts of interest to disclose. Myeloma Changes J. Brunner, PA-C and A. Dispenzieri, MD February 2013

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Objectives:

1) Understand why the Myeloma & Amyloid Forms were combined into one Disorder (PCD)- Pre-HCT Data 2) Complete the revised Pre/Post-HCT Plasma Cell Disorder (PCD) forms accurately Form 2016

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Subsequent HCT Plasma Cell Disorders (PCD)

Additional options have been added: • Additional sub-types have been added • Same disease subtype, but without a prior disease • Osteosclerotic myeloma / POEMS syndrome insert completed (begin with Q1) • Light chain deposition disease (LCDD)

• Same disease subtype, but there has been a • Question about preceding / concurrent PCD relapse or progression (begin with Q188- Was • (symptomatic) therapy given?) • Smoldering myeloma (asymptomatic) • of unknown significance • Same disease (begin with Q233) (MGUS)

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How to report Myeloma and Amyloidosis How to report Myeloma & Amyloidosis

• Scenario 1 • Scenario 2 • Patient has smoldering myeloma (asymptomatic) & • Patient has symptomatic myeloma & amyloidosis amyloidosis. • Report symptomatic myeloma as the primary • Report amyloidosis as the primary diagnosis for HCT diagnosis for HCT (question 1) (question 1). • Report amyloidosis as a concurrent diagnosis • Report smoldering myeloma as a concurrent diagnosis (question 6) (question 6)

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Bone marrow Blood stream Fight Immunoglobulins infection

Harmful Use MyelomaPlasma cellscells a.k.a. Myeloma: Monoclonal Poison kidneys M-protein Amyloid: Deposit in Eat away at bones M-spike various organs Crowd bone marrow Myeloma protein causing disease causing anemia Immunoglobulin LCDD Ig Similar to amyloid CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT

Asymptomatic vs. Symptomatic Myeloma Bone marrow Blood stream Criteria for Spectrum of MGUS  MM Myeloma protein Oligosecretory

Monoclonal Little protein M-spike No gammopathy secreted No ≥ 3 g/dL (MGUS) OR BMPC Non-IgM Inactive MM Light chain ≥ 10% ? Monoclonal End Organ Yes (smoldering secreted (no Most Damage?* Myeloma protein MM) cells heavy chain) myeloma cases Active or Yes symptomatic No protein MM secreted

End organ damage without other explanation Non-secretory Bence Jones Or light chain Calcium Renal Anemia Bones Other myeloma CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT Intern. Myeloma Working Group, Br J Haem 121, 749-57, 2003

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Light chain only myeloma vs. LCDD Kidney & Plasmaproliferative Disorders Glomerulus Glomerulopathies Tubulointerstitial Light chain only myeloma is merely a type Distal of MM (no heavy chain). It may cause tubule • AL amyloidosis • Cast nephropathy (myeloma kidney) light chain cast nephropathy (renal failure) • Light chain Proximal deposition disease tubule

Light chain deposition disease (LCDD) • Type II cryo (diffuse • Acquired is actually very similar to amyloidosis MPGN) Fanconi’s except looks slightly different under • Fibrillary GN syndrome Light chains + microscope Tamm Horsfall Protein = light chain cast nephropathy CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT

Staging of Myeloma International Staging System

• Durie-Salmon Staging Stage Criterion • Requires hemoglobin, serum calcium, monoclonal protein & bone survey findings Stage I 2M < 3.5 mg/L and alb  3.5 g/dL

• International Staging System (ISS) Stage II Not Stage I or III • Requires β microglobulin & albumin 2 Stage III 2M  5.5 mg/L

CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT Greipp P R et al. JCO 2005;23:3412-3420

Durie Salmon Staging System International Durie Salmon

Stage I Stage III Staging System Staging System All of the following One or more of the following Hemoglobin > 10.0 g/dL Hemoglobin < 8.5 g/dL Serum calcium < 12 mg/dL Serum calcium > 12 mg/dL On radiograph, normal bone structure or Advanced lytic bone lesions solitary bone only IIA 909/1759 58 (54,61) Low M-component production rates High M-component rates IgG < 5 g/dL, IgA < 3 g/dL, or urine IgG > 7 g/dL, IgA > 5 g/L, or urine light M spike on electrophoresis < 4 g/24 chain M spike > 12 g/24 hrs hrs Stage II Fitting neither stage I or III

A: Serum creatinine < 2 mg/dL B: Serum creatinine  2 mg/dL

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Cytogenetics IFM Tandem Transplant 513 Pts Risk by FISH and beta-2 microglobulin

B2M FISH • FISH LT4 Nml LT4 13 • Conventional GT4 Nml GT4 13 LT4 4;14; 17p

GT4 4;14, 17p

CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT Avet-Loiseau, H. et al. Blood 2007;109:3489-3495 Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

Metaphase Cytogenetics FISH for t(11;14) Genetic Risk in Multiple Myeloma

Standard Risk* Intermediate High Risk

t(11;14) del17p FISH t(6;14) t(4;14) t(14;16) Hyperdiploid t(14;20)

Cytogenetic deletion 13 Other All others Or hypodiploidy GEP High Risk Signature Or PCLI>3%

CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110 http://msmart.org/ v7 Revised and updated: Jan 2011

Laboratory Studies

This section has been expanded to include: • Gene Expression Profile

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Gene Expression Profiling (GEP) Gene expression patterns can distinguish risk groups in training cohort.

• Measures activity (the expression) of thousands of genes at once, to create a global picture of cellular function.

• GEP can distinguish between cells that are actively dividing, or show how the cells react to a particular treatment.

Shaughnessy J D et al. Blood 2007;109:2276-2284

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©2007 by American Society of Hematology

Amyloidosis Section Amyloidosis

• Cardiac biomarkers (revised form) • Cardiac biomarkers (current) • Brain natriuretic peptide (BNP) • Brain natriuretic peptide (BNP) and/or N-terminal • N-terminal prohormone brain natriuretic peptide (NT- prohormone brain natriuretic peptide (NT-proBNP) proBNP) • Troponin • Troponin I • Troponin T • High sensitivity troponin T

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Cardiac Biomarkers Significance of Cardiac Biomarkers in AL

Troponin T < 0.035 ug/L* (N=127) • BNP- secreted by the ventricles of the heart in (N=182) NT-proBNP < 332 ng/L* response to excessive stretching of heart muscle (N=174) cells (cardiomyocytes) Stage 1: Neither high • Troponin- integral to muscle contraction in skeletal Stage 2: Either high & cardiac muscle. It is the most specific & sensitive Stage 3: Both high laboratory markers of myocardial cell injury

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*Dispenzieri et al J Clin Oncol. 2004 ;22(18):3751-7 Kumar et al, Mayo Clinic Proc, 2011 86(1):12-8.

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Validation of the criteria of response to treatment in AL Pre-HCT Therapy amyloidosis Palladini G, Dispenzieri A, Gertz MA, et al. New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival Outcomes. Journal of clinical oncology. Added common regimens: 2012;30(36):4541-4549. 1.0 1.0 • VCD (Bortezomab, cyclophosphamide, 0.9 0.9 p=0.01 dexamethasone) 0.8 0.8 p<0.001 0.7 p<0.001 0.7 • RVD/VRD (Bortezomab, lenilidomide, 0.6 0.6 dexamethasone) 0.5 0.5 p<0.001 p<0.001 0.4 0.4 • DVD/VDD (Bortezomab, liposomal doxirubicin, Proportion survivingProportion Proportion surviving 0.3 0.3 CR (97 patients, 3.6 deaths/100 py) dexamethasone) 0.2 VGPR (233 patients, 9.6 deaths/100 py) 0.2 NT-proBNP progression (at least 300 ng/L and 30% increase), 169 patients 0.1 PR (140 patients, 23.7 deaths/100 py) 0.1 NT-proBNP stable, 108 patients NR (179 patients, 47.2 deaths/100 py) NT-proBNP response (at least 300 ng/L and 30% decrease), 100 patients 0.0 0.0 0 122436480 12243648 Time (months) Time (months) Survival of 377 patients with baseline NT- Survival of 649 patients based proBNP ≥650 ng/L according to NT-proBNP on hematologic response at 6 months response and progression at 6 months CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT

Best Response to Therapy

• Near Complete Remission (nCR) added • Serum & urine M-protein detectable by Plasma Cell Disorder (PCD) Post-HCT Data immunoelectrophoresis (IFE) • Negative SPEP & UPEP Form 2116 • <5% plasma cells in bone marrow.

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Disease Specificity Determination Laboratory Studies Section

• Q1- Was the recipient transplanted for or do they have a history of amyloidosis? • Lab Studies at Time of Best Response to HCT If yes, go to Q2 • Questions 5-33 If no, go to Q3 (best response question) • Completed for both Amyloidosis & Multiple Myeloma

• Q2- Did the recipient have features of multiple myeloma? If yes, go to Q3 If no, go to Q5 (lab studies at best response)

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Hematologic & Organ Evaluation Section Post-HCT Therapy

• Questions 32-59 • Not using ‘planned’ vs. ‘not planned’ terminology • Completed for Amyloid only patients; or • Q60- Was therapy given since the date of last • Multiple Myeloma patients with a history of or report for reasons other than relapse or progressive concurrent diagnosis of Amyloid disease? (include any maintenance and consolidation therapy)

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Questions

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