Understanding the �Diagnosis and Treatment �of Plasma cell Disorders

Joselle Cook MD

Assistant Professor of Medicine

Myeloma, Amyloid, Dysproteinemias

Division of Hematology

Mayo Clinic Rochester MN

OpenAI. (2023). ChatGPT (Mar 14 version)

Learning Objectives�

• Understand Plasma Cell Biology and Function
• Recognize the Spectrum of Plasma Cell
• Monoclonal proteins and diagnostic tools
• Approach to MGUS: Diagnosis and Risk Assessment
• When its NOT MGUS…
• Smoldering Multiple Myeloma: Diagnosis and Management
• Newly Diagnosed Multiple Myeloma: Evaluation and Treatment

Plasma cell disorders

Heterogenous group of disorders characterized by Monoclonal protein in serum or urine.

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 Image Credit: extender_01 / Shutterstock

Plasma cells are immunoglobulin factories

• Terminally differentiated B-cell
• Critical part of normal Adaptive Immunity

Image credit: bioRender; Akiko Iwasaki (Creator) Jung-Hee Lee

The Evolution of the Clonal Plasma cell

Furukawa, Y., Kikuchi, J. Molecular basis of clonal evolution in multiple myeloma. Int J Hematol 111, 496–511 (2020).

Early changes

Progression MGUS to MM

Advanced Disease (EMD)

Spectrum of plasma cell disorders

• Amyloidosis�POEMS syndrome
• Other MGCS

Merlini G, Blood 2014, 123(3): 305-7.

Clonal Immunoglobulin/ monoclonal protein: �What is it, How is it measured

Image Credit: periyanayagam/Shutterstock.com

https://www.myeloma.org/monoclonal-protein-tests

Protein Electrophoresis- Quantitative test�Separates serum proteins based on their size and electric charge��

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https://www.myeloma.org/monoclonal-protein-tests

Immunofixation- Qualitative test

What is it?

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Free light chain assessment

Immunoassay techniques

• nephelometry or turbidimetry
• based on light scattering caused by a suspension of solid particles
• Specific antibodies that bind to unbound kappa (κ) and lambda (λ) light chains in the serum

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https://www.bmglabtech.com/en/nephelometry/

Image-https://quizlet.com/246665220/plasma-cell-myeloma-multiple-myeloma-flash-cards/

Mass Spectrometry: Increased sensitivity

Spectral Overlay & Analysis

Identification

Isotype Quantitation

Detects monoclonal proteins by measuring their mass-to-charge ratio�

Differentiates monoclonal vs. polyclonal immunoglobulin light chains

Graphics courtesy Wilson Gonsalves MD

Monoclonal gammopathies: a spectrum�

Graphics courtesy Shaji Kumar MD

MGUS

• No symptoms
• Detected incidentally in workup for another reason
• Prevalence increases with age, rare < 40

≥50 years 3.2%� ≥70 years 5.3% � ≥85 years 7.5% �

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Vachon et al Blood. 2009;114(4):785

El-Koury et al Lancet Haematol. 2022 May;9(5):e340-e349

OpenAI. (2023). ChatGPT (Mar 14 version)

MGUS: Who is at risk

• People of African descent
• at 2 to 3 times higher risk than White individuals
• Develop condition at younger age
• 40-50 age group Black individuals have 6 times risk cf White individuals
• Family members 2 x risk

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PROMISE STUDY�6% -13% in high-risk individuals aged ≥50 (SPEP/IFE vs MS)

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Vachon et al Blood. 2009;114(4):785

El-Koury et al Lancet Haematol. 2022 May;9(5):e340-e349

Whom to SCREEN for MGUS

• Screening is not recommended for monoclonal gammopathies in the general population

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• We do recommend ONE TIME SCREENING for monoclonal gammopathies in HIGH RISK populations

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• Black individuals age ≥40 years, with one or more relatives affected with multiple myeloma or a related disorder

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• People from any other racial/ethnic groups age ≥40 years with two or more relatives affected with myeloma or a related disorder.

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msmart.org

Goal of Screening

MGUS Clinical evaluation

• Rule out Red flag signs and symptoms for MM or other disorders �
• Progressive fatigue
• Persistent Back pain/ Bone pain
• Recurrent infections (e.g. pneumonia)
• Recent onset or unexplained edema
• Exertional dyspnea
• Peripheral neuropathy

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Eythorsson, E et al. Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance: A Cohort Study Nested in a Clinical Trial. Annals of Internal Medicine 2024

MGUS Definition and Work up

• CBC, Creatinine and Calcium
• SPEP/IFE (+/-MS)
• Quantitative immunoglobulins
• +/-Spot urine
• Cross sectional imaging (not XRAY)
• Bone marrow�
• May be deferred in individuals with low risk MGUS (IgG, Mspike <1.5 g/dl, Normal FLC ratio) �
• Frail older adults Limited life expectancy�
• Bone marrow risk calculator https://istopmm.org/riskmodel/

Eythorsson, E et al. Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance: A Cohort Study Nested in a Clinical Trial. Annals of Internal Medicine 2024

Non IgM MGUS�M spike <3g/dl

Bone Marrow <10% Plasmacytosis

No CRAB criteria

C hyperCalcemia >11 mg/dl�R Renal impairment Creatinine >2 or CrCl < 40mL/min�A Anemia Hb<10g/dl or 2g/dl below normal�B Bone lesions

IgM MGUS and Light chain MGUS

• IgM MGUS:
• IgM protein <3 g/dL
• <10% clonal plasma cells
• No lymphadenopathy, hepatosplenomegaly, or hyperviscosity
• Light Chain MGUS:
• Abnormal FLC ratio
• Increased light chains without heavy chain involvement
• <10% clonal plasma cells

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Risk factors predicting for progression of MGUS requiring treatment

S. Vincent Rajkumar et al. Blood, 2005.

Risk Factors

• M-spike > 1.5 g/dL
• Non-IgG Subtype
• Abnormal FLC ratio

High

High Intermediate

Low-Intermediate

Low

When its not MGUS�POLYCLONAL HYPERGAMMAGLOBULINEMIA

A 58-year-old man with alcoholic liver disease presents with mild fatigue.

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Labs show:

• Hb 11.2g/dl, Creatinine 1.1mg.dl, AST 70U/L, ALT 95 U/L, Alk Phos 200U/L �Kappa 4.1 mg/dl (Normal: 0.33–1.94 mg/dL)
• Lambda 3.9 mg/dl (Normal: 0.57–2.63 mg/dL)
• SPEP reports polyclonal hypergammaglobulinemia �IgG 4000mg/dl�No monoclonal protein detected

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Polyclonal hypergammaglobulinemia

Increase in immunoglobulins , without a clonal process due to generalized immune activation

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Liver disease, autoimmune disorders, chronic infections

Image: Riberio et al J Nephropathol 2019 Vol. 8 Issue 2

When its not MGUS�RENAL IMPAIRMENT AND LIGHT CHAIN ABNORMALITIES

A 65-year-old man with chronic kidney disease (eGFR 25mL/min/1.73m²) presents for routine evaluation.

Serum free light chain assay reveals:

• Kappa : 12.5 mg/dL (Normal: 0.33–1.94 mg/dL)
• Lambda : 4.8 mg/dL (Normal: 0.57–2.63 mg/dL)
• Ratio: 2.6 (Normal: 0.26–1.65)
• SPEP and immunofixation are negative for monoclonal proteins.�

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study.  Blood Cancer J. 2022;12(9):133

IMPACT OF RENAL DYSFUNCTION�

In CKD, both kappa and lambda clearance is reduced�

Kappa light chains tend to accumulate more significantly due to their baseline higher production and lower reabsorption efficiency�

Renal Reference Ranges Proposed (2022)

Image: Goyfman et al . International Journal of Nephrology and Renovascular Disease, 10, 129 - 134.

When its not MGUS�MONOCLONAL GAMMOPATHIES OF CLINICAL SIGNIFICANCE

• Umbrella term to describe group of condition caused by small nonmalignant plasma cell/ B cell clone�
• Clone size and clinical constellation does not meet criteria for Multiple myeloma�
• “Dangerous Small Clone”

Clinical approach

Exclude other M-protein associated conditions

Neuropathy

Dermopathy

Ocular

Other

AL amyloid 

POEMS

MGUS associated neuropathies

Anti MAG neuropathy

DADS-M

CANOMAD

SLOMN** (myopathy)

Cryoglobulinemia

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Schnitzler syndrome

Cryoglobulinemia

Scleromyxedema

Necrobiotic xanthogranuloma

TEMPI

Acquired Cutis Laxa

Neutrophilic dermatosis

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Acquired C1 inhibitor deficiency

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Clarkson Disease (capillary leak syndrome) 

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Acquired vWD

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Cold agglutinin disease

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Crystalline keratopathy

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Crystal storing histiocytosis

Image credit : https://www.physio-pedia.com/images/2/20/Damaged_Axon.png, oo H, Oh DH, Chun YS, Kim JC. A case of crystalline keratopathy in monoclonal gammopathy of undetermined significance (MGUS). Korean J Ophthalmol. 2011 Jun;25(3):202-5. PMID: 21655047 Cold agglutinin disease presenting as livedo racemosa Chihiro Shiiya and Mitsuhito Ota CMAJ June 05, 2017 189 (22) E781; DOI: https://doi.org/10.1503/cmaj.161407

Key Takeaway

Presence of small monoclonal protein NOT ALWAYS BENIGN��

Monoclonal protein +Unexplained symptoms= HEME/ Dysproteinemia Referral

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Smoldering Multiple Myeloma (SMM)

�M-Spike > 3 g/dl OR

Urinary protein>500mg/24 hours OR

Bone marrow ≥10-60% �

AND No Myeloma Defining Events

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SLIM-CRAB : HyperCalcemia, Renal Impairment, Anemia and Bone Lesions

OR a biomarker of early progression

S: Sixty Clonal bone marrow plasma cell percentagen≥60%�

Li: Light Chain�Involved:uninvolved serum free light chain ratio ≥100

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M: MRI �>1 focal lesion >5mm on MRI studies

Predicts an 80% or more risk of progression in 2 years

Asymptomatic intermediary condition between MGUS and MM

Smoldering Multiple Myeloma: Statistics�

• Prevalence of SMM was 0.5% >40 years in iSTOPMM
• Rates higher in Men compared to Women (0.7% vs 0.4%)
• Rates increase with each decade of life
• <0.25% under 50 years to >1% older than 80 years

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• Bone marrow biopsy and PET Scan/WBMRI required to confirm the diagnosis

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Prevalence of smoldering multiple myeloma based on nationwide screening. Nat Med. 2023;29(2):467.

Progression to Multiple Myeloma

Mayo Study (2007) 276 patients analyzed between 1970 and 1995

• Overall risk of progression
• 10% per year first 5 years
• 3% per year next 5 years
• 1% per year next 10 years

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• Most patients with SMM will progress with a median time to progression of 4.8 years.

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Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582. 

SMM: How is risk of progression determined?

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Factors

• M Spike >2g/dL
• BMPC >20%
• FLC ratio >20

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Stratification

Low-risk: 0

Intermediate-risk: 1

High-risk: >=2

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2-year risk of Progression

Low risk: 6%

Intermediate risk: 18%

High risk: 44%

Lakshman et al, BCJ, 2018

20/2/20 model

IMWG Risk stratification model for SMM

• IMWG 2020:
• Based on study of 1996 patients from 23 countries

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• Combined score based on combined risk score derived from
• FLC ratio
• M protein
• BMPCs
• Myeloma genetics (FISH)

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• Defines risk more granularly

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 10, 102 (2020). ASH education 2021 Dec 10;2021(1):673-681

SMM patients usually progress on Surveillance Labs or with Bone pain

Abdallah, N.H., Lakshman, A., Kumar, S.K. et al. Mode of progression in smoldering multiple myeloma: a study of 406 patients. Blood Cancer J. 14, 9 (2024).

Early Therapy? with Lenalidomide, Lenalidomide Dex Daratumumab (AQUILA)

Follow up with Annual Imaging and Visit/Labs Q3 to 6 months

ACTIVE Multiple Myeloma

Clonal bone marrow plasma cell >10%

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Or biopsy proven plasmacytoma

Either a myeloma defining event:

C: Hypercalcemia: serum calcium >1 mg/dL higher than the upper limit of normal or >11 mg/dL�

R: Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >2 mg/dL�

A: Anemia: hemoglobin >20 g/L below the lower limit of normal, or a hemoglobin <100 g/L�

B: Bone lesions: osteolytic lesions on x-ray, CT, or PET-CT

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OR a biomarker of early progression

Clonal bone marrow plasma cell percentagen≥60%�

Involved:uninvolved serum free light chain ratio ≥100

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>1 focal lesions on MRI studies

Predicts an 80% or more risk of progression in 2 years

Demonstration of Clone

Survival is improving over time�depends on multiple factors: Staging, Cytogenetic Risk

https://seer.cancer.gov/statfacts/html/mulmy.html

Whole Body Low Dose CT

• 80-90% of MM patient will have bone lesions
• WBLDCT >> X-ray
• Better detection rate
• No bone overlap
• Fast scanning times
• No IV contrast
• 3.5 mSv ( ~1.7mSv for X-rays)

Terpos et al., Haematologia 2015; Hillengras et al., Blood Cancer J 2017

Pre

Post

Pre

Post

Increased internal fat attenuation

Defined sclerotic margins

Reconstitution of cortical bone

PET/CT

• Functional assessment of tumor metabolic activity (PET)
• Morphologic information (CT)
• Excellent for assessing disease activity

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Images from Francis Baffour MD

MRI

• Exquisite tissue contrast
• Superior lesion detection
• Focal lesions
• Diffuse disease
• No ionizing radiation

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Images from Francis Baffour MD

Old risk stratification

High risk was any one of the following:

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• t(4;14)
• t(14;16)
• t(14;20)
• 1q gain or amp
• 17p del/ TP53 mut�

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New risk stratification 2024

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Del 17p^a and/or TP53 mutation�

Bi-allelic del 1p�

t(4;14), (14;16), or t(14;20) + �Gain/Amp 1q or Del 1p�

Gain/Amp 1q plus Del 1p�

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B2M >5.5 with normal renal function High Plasma Cell S-phase�Primary plasma cell leukemia�NDMM with extramedullary disease

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IMS 2024

Approach to upfront treatment

Quad�Induction

Autologous stem cell transplant

Maintenance�+daratumumab

Quad Induction

Or DRd regimen

Maintenance

CART�

Bispecific

Relapse Regimen#

Transplant ineligible or deferred

mSMART Transplant Ineligible

^aDuration is usually until progression, based on tolerance

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Dara-VRd or Isa-VRd for ~9 cycles followed by Len maintenance^a

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For frail patients: DRd^a

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Dara-VRd, Daratumumab, bortezomib, lenalidomide, dexamethasone; Isa-VRd, Isatuximab, bortezomib, lenalidomide, dexamethasone; VRd, Bortezomib, lenalidomide, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone

Dara-VRd or Isa-VRd for ~9 cycles followed by bortezomib plus lenalidomide maintenance^a

Or�For frail patients: DRd or VRd for ~9 cycles followed by doublet DR or VR maintenance^a

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Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v22 //last reviewed Oct 2024

STANDARD RISK MYELOMA

HIGH RISK MYELOMA

mSMART –Transplant Eligible

^a If age >65 or > 4 cycles of induction therapy, consider mobilization with G-CSF plus cytoxan or plerixafor; ^b Duration usually until progression based on tolerance; ^c In patients with grade 2 or higher neuropathy at baseline, and for patients in whom bortezomib needs to be dose reduced or discontinued due to neuropathy, consider carfilzomib instead.

Collect Stem Cells^a

Dara-VRd or Isa-VRd x ~4 cycles

Len until progression; Delayed ASCT^b

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Dara-VRd or Isa-VRd x ~4 cycles

Autologous stem cell transplant (preferred)

Len maintenance^b

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Double or Triple Hit

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Autologous Stem Cell Transplant (ASCT)

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Dara-VRd or Isa-VRd x ~4 cycles

Dar-VRd or Isa-VRd x 4 cycles

Bortezomib plus lenalidomide maintenance till progression^{b, c}

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Bortezomib plus lenalidomide maintenance till progression^{b, c}

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Dara-VRd, Daratumumab, bortezomib, lenalidomide, dexamethasone; Isa-VRd, Isatuximab, bortezomib, lenalidomide, dexamethasone

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v22 //last reviewed Oct 2024

STANDARD RISK MYELOMA

HIGH RISK MYELOMA

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Autologous Stem Cell Transplant (ASCT)

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Summary

• Plasma cell disorders represent a diverse spectrum
• Ranges from benign conditions like MGUS to MGCS and MM
• Monoclonal proteins serving as critical markers for diagnosis, risk stratification, and disease monitoring

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• Early identification and accurate differentiation of the monoclonal gammopathy
• Essential for guiding management
• High-risk populations—particularly individuals of African descent—may benefit from targeted screening approaches

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• Advancements in diagnostics and therapeutics
• Mass spectrometry, Risk-adapted treatment strategies, novel therapies like CAR-T and bispecific antibodies
• Transforming plasma cell disorder management, improving outcomes and survival rates

Thank you! �Questions/ Discussion