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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