Is this M Spike Important?

The Significance of Monoclonal Gammopathy of

Undetermined Significance

Boca Raton Regional Hospital Internal Medicine Update

March 2019

Joseph Mikhael, MD, MEd, FRCPC

Chief Medical Officer, International Myeloma Foundation

Professor, Translational Genomics Research Institute (TGen)

City of Hope Cancer Center

Objectives

• Review the pathophysiology of monoclonal plasma cells

• Discuss the epidemiology of MGUS and multiple myeloma

• Outline clinical reasons to order a serum protein

electrophoresis

• Present the classification of MGUS and their relative risk of

progression to a malignancy

• Provide a practical approach to managing patients with a

monoclonal protein

2

The Immune System and Cancer

J Clin Invest. 2007 May 1; 117(5): 1137–1146.

NFkB Binding Site

The Myeloma Microenvironment Is Key

to Disease Pathophysiology

Bruno B et al. Lancet Oncol. 2004;5:430-442.

Increase in cytokine production and adhesion molecules Block of

programmed cell death

FAS (CD95)

Pro-caspase B FAS ligand

Collagen fibers

T Cells

NFkB–IkB complex

Protein kinases

LFA1

FADD

cFLIP Cell organelles

Fibronectin

cFLIP/FADD

Natural-Killer Cells

TNFα

Monocytes

Inhibition of Anti-Myeloma Immunity

Dendritic Cells

Angiogenesis Migration Growth

BM Stromal Cells

VEGF

Myeloma Cell

SDF1 IGF1

IL-6 TNFα

VLA4

VCAM1

NFkB

NFkB–IkB complex

JAK–STAT

MAPK

NFkB

AKT

SHP2

MEK

MEK/MAPK

Myeloma Cell

Multiple Myeloma

• 1% of malignancies

• 10% of hematological

cancers

• 30000 Americans

annually

Epidemiology

• Men > Women

• Blacks > Whites

• Median age of diagnosis is 66 – 10% < 50, 2% <40

M-protein Normal

+ - + -

Pathophysiology of plasma cell disease

• Malignant plasma cell dyscrasia

• Accumulation of plasma cells in the bone marrow

• These produce a single immunoglobulin (Ig) – monoclonal protein

• Sequelae relate to presence of plasma cells or interactions they induce via cytokines in microenvironment

The Plasma Cell & Immunoglobulins

Diagnosis of multiple myeloma: The Importance of Light Chains

Serum free light chain immunoassay Exposed

surface

Hidden

surface

Light chain

Heavy chain antibody target

Exposed

surface

Lambda

Kappa

The malignant clone

Bone

Marrow

Lymph node

IgG,A,D,E

plasma cell

IgM

hypermutation

lymphoblast plasmablast

pre-B cell

somatic

Plasma cell

How do plasma cells become “evil”?

Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873

Mechanisms of Disease Progression in the Monoclonal Gammopathies

Different specialists see and diagnose Multiple Myeloma

patients

• Due to the vague

symptoms, patients

commonly present to

PC/IM doctors

• Typical diagnosis by

PC/IM is >6 months

• Hem/Oncs diagnose

much more quickly, <3

months

• Opportunity for quicker

diagnosis by PCPs/IMs

Adapted from Kariyawasan C, et al. Q J Med 2007; 100:635-640

When Should I order a Serum Protein

Electrophoresis??

• Controversial area without absolute consensus:

1. Not routinely in an asymptomatic patient 2. Unexplained anemia in “older” patients 3. Osteopenia/porosis out of keeping with age and gender 4. Unexplained neuropathy 5. Unexplained renal insufficiency 6. Known low levels of immunoglobulins 7. Other clinical suspicion of myeloma, amyloidosis or waldenstroms

macroglobulinemia – anemia, renal insufficiency, bony lesions, very elevated total protein, proteinuria…

Note – NOT routinely because of family history

M spike in gamma region

SPE alone is insensitive at diagnosis

Screening

algorithm Diagnostic sensitivity (%)

SPE MM

AL

87.6

67.2

sIFE + uIFE MM

AL

98.7

94.2

SPE + sFLC MM

AL

100

96.2

Testing with Freelite (sFLC) in addition to SPE improves

detection rates and eliminates the reliance on urine testing

Katzmann Clin Chem 2009;55:1517-22

Dispenzieri Leukemia 2009;23:215-24

“the serum FLC assay

in combination with SPE

and serum IFE yields

high sensitivity, and

negates the need for 24-

hour urine studies for

diagnoses other than

AL amyloidosis.”

Freelite is recommended in IMWG guidelines

sFLCs

SPE,

sIFE +

Query MM

Reprinted by permission from Macmillan Publishers Ltd: Leukemia, © 2009.

Lab tests ordered when initially suspicious of

Myeloma: 6% Guideline Compliance

Genzen et al. Arch Pathol Lab Med 2018; 142:507-515

The Important Details

• Remember Myeloma is a unique cancer – defined by the

presence of organ damage – not just pathology

• Traditionally we wait until CRAB

• For good reason!!! Many will smolder for years…and may

NEVER progress!

• Hence the phrase “Monoclonal Gammopathy of Undetermined

Significance”

What if your friend is walking towards a cliff?

• Will you wait until they are falling to rescue them?

• But what if they are really enjoying the walk and the cliff is miles

away??

Rajkumar SV, Merlini G, San Miguel JF. Nat Rev Clin Oncol 2012

• <10% BMPC AND

• <3gm/dL M protein AND

• No CRAB

• ≥10% BMPC OR

• ≥3 gm/dL M protein AND

• No CRAB

• Clonal PCPD

• CRAB

CRAB = Hypercalcemia, renal failure, anemia, or lytic bone lesions

attributable to a clonal plasma cell disorder

MGUS SMM MM

IMWG. Br J Haematol. 2003;121:749-757.

Previous Disease Definitions

• <10% BMPC AND

• <3gm/dL M protein AND

• No MDE

• ≥10-60% BMPC OR

• ≥3 gm/dL S. M protein OR

• ≥500 mg/24h Ur. M protein AND

• No MDE

• PCPD, AND

• 1 or more MDE

• CRAB

• ≥60% BMPC

• ≥100 FLC ratio

• >1 MRI focal lesion

CRAB= Hypercalcemia, renal failure, anemia, or lytic bone

lesions attributable to a clonal plasma cell disorder

MDE= Myeloma Defining Events

MGUS SMM MM

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Revised IMWG Criteria

Ultra High Risk SMM = Active

Myeloma

Not CRAB but now SLiM CRAB

• S (60% Plasmacytosis)

• Li (Light chains I/U >100)

• M (MRI 1 or more focal lesion)

• C (calcium elevation)

• R (renal insufficiency)

• A (anemia)

• B (bone disease)

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

The Spectrum of Myeloma

MGUS Asymptomatic MM

(smoldering) “True” MM PC Leukemia

Organ damage none none Yes or imminent

(slim crab)

yes

Marrow Disease <10% plasma cells

10-60% plasma cells

≥ 10% plasma cells

Plasma cells in blood

Management Monitor 1-2 times/yr

Close follow up (q 3 mts)

therapy High dose combo chemo

Transformation Rate

1% /yr 10%/yr n/a n/a

Content developed by Dr. Joseph Mikhael

MGUS

Monoclonal Gammopathy of Undetermined Significance

• Presence of a serum monoclonal protein (concentration ≤ 3g/dL)

• Less than 10% plasmacytosis in marrow

• No evidence of End-Organ damage (CRAB)

– Calcium elevation, Renal Insufficiency, Anemia, Bony disease

• Asymptomatic

• No co-existing plasma cell dyscrasia or lymphoproliferative disease

(table)

Diseases associated with a monoclonal

gammopathy

• Plasma cell disorders

• Monoclonal gammopathy of undetermined significance (MGUS)

• Biclonal gammopathy of undetermined significance

• Idiopathic Bence Jones proteinuria

• POEMS syndrome, Osteosclerotic myeloma

• Castleman's disease

• AL (light chain) amyloidosis

• Solitary plasmacytoma

• Multiple myeloma, Smoldering multiple myeloma

• B-cell lymphoproliferative disorders

• Non-Hodgkin's lymphoma

• Chronic lymphocytic leukemia

• Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)

• Post-transplant monoclonal gammopathies

Epidemiology of MGUS

• Prevalence is approximately 1-3% in adults in the USA, Sweden, France

and Japan1

• Higher as we age:

– ≥ 50: 3.2%

– ≥ 70: 5.3%

– ≥ 85: 7.5%2

• 2-3 fold higher incidence in Africans and African American population3

• Annual risk of transformation to MM or related diseases of 1%4

1 Kyle Blood 1972, Axelsson Acta Med Scan 1986, Saleun J Clin Path 1982, Iwanaga Mayo Clin Proc 2007; 2 Kyle NEJM

2006; 3 Singh J Lab Clin Med 1990, Cohen AM J Med 1998, Landgren Blood 2006; 4 Kyle et al NEJM 2002

Kyle R et al. N Engl J Med 2006;354:1362-1369

Estimated MGUS Annual Health Care Costs in USA

Go RS, et al. Leukemia 2016.

• About 540,000 individuals living with a diagnosis of MGUS

• At least $110 million annual cost to health care

Kyle R et al. N Engl J Med 2006;354:1362-1369

Determined the Prevalence of MGUS in USA

• MGUS present in 3% of general population >50 years

• 1.7% in 50-59

• >5% in over 70

• Men > Women

Kyle R et al. N Engl J Med 2007;356:2582-2590

Defined Risk of Progression of MGUS and SMM

MGUS and Non-Malignant Disease

• Clear association with auto-immune disease (esp SLE)

• Actual link not well known

• ? Acute phase reactant

• ? Immune Trigger

• ? Co-incident in age category

• Brown et al Blood 2008 – higher risk of MGUS and MM in pts with

previous autoimmune, infectious, inflammatory and allergic disorders

MGUS…Significant?

• MGUS may be associated with a neuropathy

– Often IgM (with associated antibodies)

– Mechanisms not well understood

– May ultimately be classified separately

– Usually treated as “idiopathic” neuropathy

– Speaks to realm of neuropathy in plasma cell diseases…

• MGUS may progress to a more concerning plasma cell

dyscrasia

– We now understand this better in both physiological and

epidemiological terms…

Kyle R et al. N Engl J Med 2002;346:564-569

Risk of Progression among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance was Diagnosed in 1960 through 1994

MGUS Progression

• Potential Predictive Factors of Progression

– M protein size1

– IG class: IgA>IgM>IgG2

– Bone marrow plasmacytosis3,4

– Presence of urinary Bence Jones proteinuria3

– Free Light Chain Assay5

1 Kyle NEJM 2002, 2 Kyle Blood 2003, 3 Cesana JCO 2002, 4 Perez-Persona Blood 2007 5 Rajkumar BJH 2004

Rajkumar, S. V. et al. Blood 2005;106:812-817

Risk of progression of MGUS to myeloma or related disorder using a risk-stratification model that incorporates the FLC ratio and the size and type of the serum monoclonal

protein

20 year

58%

37%

21%

5%

IgM MGUS

• Only comprises 14-20% of MGUS1

• More likely to progress to lymphoma, Waldenstroms, CLL and

amyloidosis

• Size of IgM most predictive

• Overall risk was 1.5% annually, increased with time

1. Kyle NEJM 2002, McMaster BJH 2007

Subtype of MGUS Diagnostic criteria Risk of

progression Pattern of

progression

IgM MGUS All 3 criteria must be met: 1% per year Waldenström

macroglobulinemia

, AL amyloidosis;

rarely IgM multiple

myeloma

• Serum IgM monoclonal protein <3 gm/dL

• Bone marrow lymphoplasmacytic infiltration <10%*

• No evidence of anemia, constitutional symptoms, hyperviscosity,

lymphadenopathy, or hepatosplenomegaly that can be attributed to the

underlying lymphoproliferative disorder

Non-IgM MGUS All 3 criteria must be met: 0.5% per year Multiple myeloma,

solitary

plasmacytoma, AL

amyloidosis

• Serum monoclonal protein (non-IgM type) <3 gm/dL

• Clonal bone marrow plasma cells <10%*

• Absence of end-organ damage such as hypercalcemia, renal

insufficiency, anemia, and bone lesions (CRAB) that can be attributed to

the plasma cell proliferative disorder

Light-chain MGUS All criteria must be met: 0.3% per year Light-chain

multiple myeloma

and AL

amyloidosis

• Abnormal FLC ratio (<0.26 or >1.65)

• Increased level of involved light chain (increased κ FLC in patients

with FLC ratio >1.65 and increased λ FLC in patients with FLC ratio

<0.26)

• No immunoglobulin heavy-chain expression on immunofixation

• Absence of end-organ damage that can be attributed to the plasma cell

proliferative disorder

• Clonal bone marrow plasma cells <10%*

• Urinary monoclonal protein <500 mg per 24 h

Subtypes of MGUS

Monitoring & Management

• No absolute consensus

• Simplified Algorithm: – Make accurate diagnosis

– Obtain baseline bloodwork (incl total Igs and FLC), 24 hr urine and +/- skeletal survey or other imaging

– Consider bone marrow testing in certain circumstances

– Repeat testing (history, physical, blood work only) at 6 months

– If lower risk, can be seen annually (assuming asymptomatic)

– If higher risk, I prefer every 6 months

Suggested algorithm for bone marrow biopsy and skeletal imaging in patients with monoclonal gammopathy of undetermined significance

#Mayo Clinic Risk Stratification Model. *No unexplained symptoms or laboratory features concerning for serious plasma cell disorder..

Ronald S. Go, and S. Vincent Rajkumar Blood 2018;131:163-173

Suggested algorithm for follow-up of monoclonal gammopathy of undetermined significance. #Mayo Clinic Risk Stratification Model.

Ronald S. Go, and S. Vincent Rajkumar Blood 2018;131:163-173

©2018 by American Society of Hematology

Outcomes & Health Economics*

*For 1,000 Query Multiple Myeloma patients

IMF Global Technology Platform™

45

Iceland

Full sequencing

Early disease

Spain

Immune monitoring

Single cell resistance analyses

Blood monitoring

Mayo

CLIA lab NGF

Cure Trial

Singapore

Asian Trials Network

Centralized NGF/risk

assessment

Australia

Blood DNA mutational

analyses

Clinical trial assessment

Central Platform

Pipeline trials

Imaging

Family Studies

Retrospective studies

Germany

• Most comprehensive screening program for MGUS and MM in

history

• Goal is to screen ALL people over 40 years of age in the country

of Iceland (about 140,000 people)

• 85,000 people have already consented! (as of March 1)

• This can be matched to a massive database of health

information for the country – especially genetic information

• Will provide accurate incidence and risk of progression

• May identify genetic drivers of the disease!

• Includes an intervention study to determine if early intervention

affects the natural history of the disease and improve survival

• Hopefully the start of similar approaches in multiple cancers

46

Improving Survival in MM

*Year ranges represent the year of diagnosis. Note: By linking to the SSA Master Death File, survival was measured as time from diagnosis date to the date of death obtained from the SSA, time from diagnosis date to the date of inpatient death, or time from diagnosis date to September 30, 2015; Survival estimates were presented for multiple myeloma patients diagnosed and treated during 2006-2012 (n=9,521).

Conclusions

• MGUS is a common condition that will likely become more common with advanced testing

• Appropriately ordering serum protein electrophoresis and light chain testing is critical – don’t over or under order!

• The classification of plasma cell disorders and MGUS in particular is important to decide on further investigation and management

• Risk stratification in MGUS affects both management and prognosis

• Continued monitoring of patients with MGUS is needed to detect progression to a more concerning plasma cell disorder

• The iStopMM project in Iceland will likely further enhance our understanding of this disease

Treatment sequence in Myeloma

Induction Consolidation

Front line treatment

Post

consolidation

Maintenance

Rescue

Relapsed

New Carfilzomib Combos

Adding Mono Abs

“more” induction

Lenalidomide 2 mths

? Ixazomib

combinations

Novel MoAbs: Isatuximab…

Selinexor

Venetoclax

PD/PDL-1 Inhibition

CAR T Cell therapy

Multiple small molecules

++++++++

Now

VD

Rev/Dex

CyBorD

VTD

VRD

KRD

SCT

? More induction

Nothing

Thalidomide?

Bortezomib

Lenalidomide

Bortezomib

Lenalidomide

Thalidomide

Carfilzomib

Pomalidomide

Panobinostat

Daratumumab

Ixazomib

Elotuzumab

The Evolution of Myeloma Therapy

THANK YOU!

Joseph Mikhael, MD, MEd, FRCPC

Chief Medical Officer, International Myeloma Foundation

Professor, Translational Genomics Research Institute (TGen)

City of Hope Cancer Center

Director of Myeloma Research and Consultant Hematologist,

HonorHealth Research Institute

jmikhael@myeloma.org