Forms Revision: Myeloma Changes

CENTER FOR INTERNATIONAL BLOOD & MARROW RESEARCH TRAINING & DEVELOPMENT

Sharing knowledge. Sharing hope.

Forms Revision: Myeloma Changes J. Brunner, PA-C and A. Dispenzieri, MDFebruary 2013


Disclosures

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

Angela Dispenzieri, MD• I have no relevant conflicts of interest to disclose.


Objectives:

1) Understand why the Myeloma & Amyloid Forms were combined into one

2) Complete the revised Pre/Post-HCT Plasma Cell Disorder (PCD) forms accurately


Plasma Cell Disorder (PCD)-Pre-HCT Data

Form 2016


Subsequent HCT

Additional options have been added:• Same disease subtype, but without a prior disease

insert completed (begin with Q1)

• Same disease subtype, but there has been a relapse or progression (begin with Q188- Was therapy given?)

• Same disease (begin with Q233)


Plasma Cell Disorders (PCD)

• Additional sub-types have been added• Osteosclerotic myeloma / POEMS syndrome• Light chain deposition disease (LCDD)

• Question about preceding / concurrent PCD• Multiple myeloma (symptomatic)• Smoldering myeloma (asymptomatic)• Monoclonal gammopathy of unknown significance

(MGUS)


How to report Myeloma and Amyloidosis

• Scenario 1• Patient has smoldering myeloma (asymptomatic) &

amyloidosis. • Report amyloidosis as the primary diagnosis for HCT

(question 1). • Report smoldering myeloma as a concurrent diagnosis

(question 6)


How to report Myeloma & Amyloidosis

• Scenario 2• Patient has symptomatic myeloma & amyloidosis• Report symptomatic myeloma as the primary

diagnosis for HCT (question 1)• Report amyloidosis as a concurrent diagnosis

(question 6)



AntibodiesImmunoglobulins

Plasma cells

Bone marrowFight infection

a.k.a. Monoclonal antibody

M-proteinM-spike

Myeloma proteinImmunoglobulin

Ig

HarmfulUse

Myeloma:Poison kidneysAmyloid:Deposit in various organscausing disease

LCDDSimilar to amyloid

Eat away at bonesCrowd bone marrow

causing anemia

Myeloma cells

Blood stream


Criteria for Spectrum of MGUS MM

End Organ Damage?*

Non-IgMMonoclonal

protein

End organ damage without other explanation

Calcium Renal Anemia Bones Other

M-spike ≥ 3 g/dL

OR

BMPC ≥ 10% ?

No

Active or symptomatic

MMYes

Monoclonal gammopathy

(MGUS)No

Inactive MM (smoldering

MM)Yes

Intern. Myeloma Working Group, Br J Haem 121, 749-57, 2003

Asymptomatic vs. Symptomatic Myeloma


Myeloma protein

Myeloma cells

No protein secreted

Non-secretory

OligosecretoryLittle protein secreted

Bence JonesOr light chain

myeloma

Light chain secreted (no

heavy chain)Most

myeloma cases

Bone marrow Blood stream


Light chain only myeloma vs. LCDD

Light chain deposition disease (LCDD) is actually very similar to amyloidosis except looks slightly different under microscope

Light chain only myeloma is merely a type of MM (no heavy chain). It may cause light chain cast nephropathy (renal failure)


Kidney & Plasmaproliferative Disorders

Glomerulopathies• AL amyloidosis• Light chain

deposition disease

• Type II cryo (diffuse MPGN)

• Fibrillary GN

Tubulointerstitial• Cast nephropathy

(myeloma kidney)

• Acquired Fanconi’s syndrome

Glomerulus

Proximal tubule

Distaltubule

Light chains +Tamm HorsfallProtein = light chain cast nephropathy


Staging of Myeloma

• Durie-Salmon Staging• Requires hemoglobin, serum calcium, monoclonal

protein & bone survey findings

• International Staging System (ISS)• Requires β2 microglobulin & albumin


International Staging System

Stage Criterion

Stage I 2M < 3.5 mg/L and alb 3.5 g/dL

Stage II Not Stage I or III

Stage III 2M 5.5 mg/L

Greipp P R et al. JCO 2005;23:3412-3420


Durie Salmon Staging System

Stage I Stage III 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

solitary bone plasmacytoma only Advanced lytic bone lesions

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

hrs chain M spike > 12 g/24

hrs Stage II Fitting neither stage I or III

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


Greipp P R et al. JCO 2005;23:3412-3420

International Durie Salmon Staging System Staging System

IIA 909/1759 58 (54,61)


Cytogenetics

• FISH

• Conventional


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

Avet-Loiseau, H. et al. Blood 2007;109:3489-3495

B2M FISHLT4 NmlLT4 13

GT4 NmlGT4 13LT4 4;14; 17p

GT4 4;14, 17p

IFM Tandem Transplant 513 PtsRisk by FISH and beta-2 microglobulin


FISH for t(11;14)Metaphase Cytogenetics


Standard Risk* Intermediate

t(11;14)t(6;14)

Hyperdiploidt(4;14)

All othersCytogenetic deletion 13

Or hypodiploidyOr PCLI>3%

FISH

Other

High Risk

del17pt(14;16)t(14;20)

GEP High Risk Signature

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110v7 Revised and updated: Jan 2011 http://msmart.org/

Genetic Risk in Multiple Myeloma



Laboratory Studies

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


Gene Expression Profiling (GEP)

• 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.


Gene expression patterns can distinguish risk groups in training cohort.

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

©2007 by American Society of Hematology


Amyloidosis Section

• Cardiac biomarkers (current)• Brain natriuretic peptide (BNP) and/or N-terminal

prohormone brain natriuretic peptide (NT-proBNP)• Troponin


Amyloidosis

• Cardiac biomarkers (revised form)• Brain natriuretic peptide (BNP)• N-terminal prohormone brain natriuretic peptide (NT-

proBNP)• Troponin I• Troponin T• High sensitivity troponin T


Cardiac Biomarkers

• BNP- secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells (cardiomyocytes)

• Troponin- integral to muscle contraction in skeletal & cardiac muscle. It is the most specific & sensitive laboratory markers of myocardial cell injury


Significance of Cardiac Biomarkers in AL (N=127)

(N=182)

(N=174)

Kumar et al, Mayo Clinic Proc, 2011 86(1):12-8.

Troponin T < 0.035 ug/L*

NT-proBNP < 332 ng/L*

Stage 1: Neither highStage 2: Either highStage 3: Both high

*Dispenzieri et al J Clin Oncol. 2004 ;22(18):3751-7


0 12 24 36 48

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

porti

on s

urvi

ving

CR (97 patients, 3.6 deaths/100 py) VGPR (233 patients, 9.6 deaths/100 py) PR (140 patients, 23.7 deaths/100 py) NR (179 patients, 47.2 deaths/100 py)

p=0.01

p<0.001

p<0.001

Survival of 649 patients based on hematologic response at 6 months

Validation of the criteria of response to treatment in AL 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. 2012;30(36):4541-4549.

0 12 24 36 48

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

porti

on s

urvi

ving

NT-proBNP progression (at least 300 ng/L and 30% increase), 169 patients NT-proBNP stable, 108 patients NT-proBNP response (at least 300 ng/L and 30% decrease), 100 patients

p<0.001

p<0.001

Survival of 377 patients with baseline NT-proBNP ≥650 ng/L according to NT-proBNP response and progression at 6 months


Pre-HCT Therapy

Added common regimens:• VCD (Bortezomab, cyclophosphamide,

dexamethasone)• RVD/VRD (Bortezomab, lenilidomide,

dexamethasone)• DVD/VDD (Bortezomab, liposomal doxirubicin,

dexamethasone)


Best Response to Therapy

• Near Complete Remission (nCR) added• Serum & urine M-protein detectable by

immunoelectrophoresis (IFE)• Negative SPEP & UPEP• <5% plasma cells in bone marrow.


Plasma Cell Disorder (PCD) Post-HCT DataForm 2116


Disease Specificity Determination

• Q1- Was the recipient transplanted for or do they have a history of amyloidosis?

If yes, go to Q2If no, go to Q3 (best response question)

• Q2- Did the recipient have features of multiple myeloma?

If yes, go to Q3If no, go to Q5 (lab studies at best response)


Laboratory Studies Section

• Lab Studies at Time of Best Response to HCT• Questions 5-33• Completed for both Amyloidosis & Multiple Myeloma


Hematologic & Organ Evaluation Section

• Questions 32-59

• Completed for Amyloid only patients; or

• Multiple Myeloma patients with a history of or concurrent diagnosis of Amyloid


Post-HCT Therapy

• Not using ‘planned’ vs. ‘not planned’ terminology

• Q60- Was therapy given since the date of last report for reasons other than relapse or progressive disease? (include any maintenance and consolidation therapy)


Questions

Documents

Forms Revision: Myeloma Changes