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MBBS IV - Junior Clerkship WCS > JC46 (Medicine) - Multiple Myeloma > Flashcards

JC46 (Medicine) - Multiple Myeloma Flashcards

1
Q

Define gammopathy

2 types

A

Gammopathy: over-production of ≥1 classes of immunoglobulin

→ Polyclonal gammopathy: occurs in association with acute or chronic inflammation, eg. infection, sarcoidosis, A/I diseases, some malignancies

→ Monoclonal gammopathy: Ig from a single clone of plasma cells

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2
Q

Markers for clonal plasma cells

A

Kappa or Lambda light chain over-production - Serum free light chain assay

Serum IgG, IgA, IgM level (heavy chain) - Serum M-protein assay

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3
Q

List neoplasms involving clonal expansion of plasma cells

A

Plasmacytoma: solitary lesion of neoplastic proliferation of plasma cells

Multiple myeloma (MM): multiple lesions of neoplastic proliferation of plasma cells

Primary (AL) amyloidosis: clonal plasma cell proliferation leading to organ deposition of amyloid proteins consisting of monoclonal light chains

Light/heavy chain deposition disease: similar light chain production as AL amyloidosis but cannot form amyloid fibrils, non-amyloid organ deposition only

Plasma cell leukaemia (PCL): aggressive MM variant with circulating plasmablast

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4
Q

Malignant causes of monoclonal gammopathies

A

Multiple myeloma (MM)

Waldeström’s macroglobulinemia (WM)

Other lymphoproliferative disease:
Indolent B cell lymphoma
Primary (AL) amyloidosis
Light and heavy chain deposition disease
Plasma cell leukaemia

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5
Q

Benign causes of monoclonal gammpathies

A

MGUS (can be premalignant)
Solitary plasmacytoma
Chronic cold haemagglutinin disease
Rheumatic diseases, eg. RA, PMR
Infections, eg. HIV
Gaucher disease

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6
Q

Compare and contrast: Malignant vs benign causes of monoclonal gammopathies

Bence-Jones proteinuria

Serum paraprotein levels

Serum free light chain ratio

Immunoparesis

Other features

A
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7
Q

Top 3 most common monoclonal gammopathies

A

MGUS (60%)

Multiple myeloma (18%)

Amyloidosis (9%)

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8
Q

Most frequently detected antibody in monoclonal gammopathies

A

IgG (60%)

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9
Q

Describe structure of immunoglobulin

A

Light chain: forms half of variable domain → contributes to specificity
→ Types: only two, i.e. lambda (λ) and kappa (κ)

Heavy chain: apart from half of variable domain, also forms the constant domain → determines type of Ig and therefore its role in immune response (eg. IgA in mucosal immunity)

→ Types: gamma (γ) = IgG, alpha (α) = IgA, delta (δ) = IgD, mu (μ) = IgM, episilon (ε) = IgE

Relevance: an M protein can consist of intact Ig (eg. IgG, IgM, IgA) or free light chain (λ, κ)

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10
Q

Outline the spectrum of monoclonal gammopathies from Normal plasma cells to plasma cell leukaemia

A
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11
Q

Classification of monoclonal gammopathies *

A
  1. Non-IgM producing: Non-IgM MGUS, Smoldering Multiple Myeloma, Multiple Myeloma
  2. IgM producing: IgM MGUS, Smoldering WM, WM, IgM Multiple Myeloma
  3. Light-chain producing: Light chain MGUS, Idiopathic Bence-Jones proteinuria, Light chain Multiple Myeloma
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12
Q

Definition of Non-IgM MGUS, smoldering MM and Multiple myeloma

A

Non-IgM MGUS: ALL of

(1) Serum M protein <3g/dL
(2) Clonal BM plasma cells <10%
(3) No end-organ damage PLUS no myeloma-defining biomarkers

Smoldering MM: ALL of

(1) Serum M protein ≥3g/dL and/or clonal BM plasma cells ≥10%
(2) No end-organ damage PLUS no myeloma-defining biomarkers

Multiple Myeloma: Clonal BM plasma cells ≥10%
PLUS ONE of
(1) End-organ damage, defined as ≥1 of CRAB = Hypercalcemia (corr. Ca ≥2.75 mmol/L), Renal impairment (Cr >176.8, CrCL<40), Anaemia (NcNc >2 below LLN or <10g/dL) and Bone lesion (lytic /osteopenic)
(2) ≥1 of MM-defining biomarkers: ≥60% clonal BM plasma cells, free light chain ratio ≥100, MRI >1 focal bone lesion

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13
Q

Definition of IgM MGUS, Smoldering WM, WM and IgM Multiple myeloma

A
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14
Q

Investigations for monoclonal gammopathies

A
  1. Clinical features (e.g. CRAB in MM)
  2. Serum protein: evident as reversed A:G ratio with high globulin level
  3. Serum + urine protein electrophoresis: identify M protein
  4. Immunofixation: find exact type of M protein
  5. Serum free light chain assay: Kappa and Lambda assay
  6. Investigate underlying cause
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15
Q

Serum + urine protein electrophoresis

Indication

Sample needed

Method

Findings

Limitation

A

Indication: identify M protein

Sample needed: serum (SPEP) or 24h urine (UPEP)

Method: uses electrophoresis to separate serum/urine protein → allow detection and quantification of M protein

Finding:

  • Monoclonal gammopathy: single, narrow peak at γ-globulin area → a/w plasma cell neoplasms
  • Polyclonal gammopathy: broad-based peak or band at γ-globulin area → a/w infectious/inflammatory ds

Note: ~50% light chain MM –ve by SPEP → must do UPEP

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16
Q

Immunofixation for M protein

Indication

Method

Findings

A

Indication: Follow +ve SPEP/UPEP, to differentiate between type of M protein

Method: each sample electrophoresed in 5 lanes → then each lane overlaid with different specific Ab, i.e. anti-γ, anti-μ, anti-α, anti-κ, anti-λ → after precipitation of Ag-Ab complex and washout, the resultant gel is stained

Finding: sharp, well-defined band with similar mobility (i.e. same position on gel) staining +ve for one heavy chain and one light chain (eg. IgG-κ)

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17
Q

Serum free light chain assay

Indication

Findings

A

Role: can detect low concentration of monoclonal free light chains in the serum

Findings: more sensitive than urine immunofixation for monoclonal FLCs

  • Free serum κ light chains = 3.3-19.4mg/L normal
  • Free serum λ light chains = 5.7-26.3mg/L normal
  • κ:λ FLC ratio = 0.26-1.65 normal
18
Q

Investigations for underlying causes of monoclonal gammopathies

A

General: CBC, PBS, Hemolysis markers, SPEP/UPEP with immunofixation, Serum FLC assay

Plasma cell dyscrasias → serum Ca, RFT, whole-body PET/CT ± BM if suspicious
Lymphoproliferative diseases → CBC for WCC and lymphocyte count ± PBS, BM exam MCICM
AL amyloidosis → urinalysis, urine protein:creatinne ratio, LFT and liver USG, cardiac MRI, EMG/NCV for nerve infiltration

19
Q

MGUS

Definition

Clinical presentation

Investigation results

A

MGUS: paraproteinaemia not related with underlying disease, eg. MM/SMM, lymphoma, amyloidosis, WM

Clinical presentation: by definition asymptomatic

Investigations:

□ Incidental finding of M protein
□ Laboratory artifacts: circulating M protein may interfere with other lab tests, eg. spuriously low HDL-C level, high bilirubin level, altered inorganic phosphate level
□ Blood: reversed A:G ratio with ↑globulin, ↑ESR
□ CBC/PBS: normal ± rouleaux formation
□ BM: <10% clonal plasma or lymphoplasmacytic cells

20
Q

Diagnostic criteria of MGUS

A

□ M protein <3g/dL
□ <10% clonal plasma or lymphoplasmacytic cells in BM
□ No end-organ damage, eg. CRAB symptoms

21
Q

MGUS

Progression into which diseases

A

□ Non-IgM MGUS: 0.8%/y risk of progression → MM, plasmacytoma, AL amyloidosis

□ IgM MGUS: 2%/y in first 10y, then 1%/y → WM, AL amyloidosis, NHL, CLL

□ LC MGUS: 0.3%/y risk of progression into idiopathic Bence Jones proteinuria (i.e. LC-SMM)

22
Q

Management of MGUS

A

Risk stratification: determines intensity of F/U
→ Risk factors: serum M protein ≥1.5g/dL, non-IgG MGUS, abnormal FLC ratio

Monitoring for progression: routine F/U with Hx and P/E plus
→ Annual SPEP, serum FLC/UPEP for quantification of M protein
→ CBC, serum Cr, serum Ca for development of myeloma complications

Monitoring for complications:
Fractures: evaluate for osteoporosis with DEXA ± vit D/Ca supplements ± Tx of osteoporosis
Thromboembolism
Second malignancies

23
Q

Multiple Myeloma

Definition

Diagnostic criteria

A

Multiple (plasma cell) myeloma: Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacyoma + one of more of following:

  1. BM clonal plasma cell infiltration: ≥10% of BM cellularity
  2. Serum M protein: ≥3g/dL
  3. ≥1 end-organ damage including hypercalcemia, acute renal failure, anaemia and skeletal destruction with osteolytic lesions, pathological fractures and bone pain

Any one biomarker of malignancy:

  1. Clonal bone marrow plasma cells ≥ 60%
  2. Involved: Uninvolved serum free light chain ratio ≥ 100 with involved free light chain ≥ 1–mg?L
  3. One or more focal lesion on MRI scan ( ≥5mm)
24
Q

Pathogenesis of MGUS

A

Aberrant response to Ag stimulation: unknown Ag stimulus produces abnormal, sustained proliferative signal for plasma cells → ↑proliferative rate → ↑risk of mutation results in cytogenetic abnormalities

Primary cytogenetic changes (eg. IgH translocation, trisomy) → creation of plasma cell clone

25
Q

Pathogenesis of Multiple Myeloma from MGUS

A

SECONDARY cytogenetic change (eg. IgH translocation, Δ17p13 (TP53), RAS mutation, NFκB activating mutation)

>> cell cycle dysregulation (overactive cyclin D), immortalization of plasma cell

Changes in BM microenvironment → favours myeloma cell growth with homing/ migration to BM

  • ↑induction of angiogenesis
  • Paracrine/cytokine loop: MM cells bind to BM stromal cells → interaction and activation of signal transduction pathways stimulate proliferation and develop malignant features
26
Q

Pathogenesis of CRAB end-organ damage in Multiple Myeloma

A

Purely osteolytic bone lesion: osteoblast suppression + osteoclast activation (↑RANKL:OPG ratio)

Hypercalcemia due to osteoclast activation: ↑bone resorption → ↑calcium release into blood

Renal dysfunction:
* Cast nephropathy (most common): precipitation of light chains in tubules → bind with uromodulin, formation of obstructing casts → induce giant cell reaction → interstitial nephritis and fibrosis
- Hypercalcaemia leading to nephrogenic DI, dehydration and pre-renal failure
- AL amyloidosis or light/heavy chain deposition disease → presents with nephrotic syndrome

NcNc anaemia: malignant BM infiltration, disruption of BM microenvironment, renal impairment

27
Q

Further progression of Multiple Myeloma

A

Extramedullary plasmacytoma: myeloma cells undergo further genetic changes → no longer require BM microenvironment to survive

Plasma cell leukaemia: when myeloma transform into leukaemic state with circulating plasmablasts

28
Q

Clinical presentation of Multiple Myeloma

A
  1. NcNc anaemia: fatigue, pallor
  2. Bone: Bone pain, vertebral collapse, cord compression, pathological fracture
  3. Renal disease: Cast nephropathy, Hypercalcaemia, Amyloidosis with nephrotic syndrome
  4. Hypercalcemia
  5. Extramedullar plasmacytoma
  6. Infections (encapsulated or gram-negative organism)
  7. Neurological: Radiculopathy by plasmacytoma, Cord compression, Peripheral neuropathy
29
Q

Causes of neurological signs in Multiple Myeloma

A

→ Radiculopathy: usu T/L/S-spine due to compression by paravertebral plasmacytoma (or rarely by collapsed bone itself)
→ Cord compression due to extramedullary plasmacytoma or vertebral collapse
→ Peripheral neuropathy: uncommon in MM alone, usu a/w amyloidosis

30
Q

Investigations for Multiple Myeloma

A
  1. Basic blood test: CBC (NcNc anaemia), LFT (reversed A:G ratio), RFT (↑Cr), CaPO4 (↑Ca), LDH (prognostic)
    + Pre- Tx tests: glucose, CRP, HBsAg, anti-HBs, anti-HBc, G6PD
  2. PBS: rouleaux (>50%) ± leukopenia (20%), thrombocytopenia (5%), circulating plasma cells
  3. Urine:
    → Dipstick: +ve if nephrotic syndrome
    → Serum + urine electrophoresis for monoclonal gammopathy + immunofixation for type
    → Serum free light chain (FLC): free κ, free λ and κ:λ ratio (90% abnormal)
  4. BM examination:
    → ≥10% plasma cells infiltration: diagnostic
    → Morphology: generally round, eccentric ‘clock-face’ nucleus with marked perinuclear cytoplasmic clearing
    → Immunophenotyping for CD138, κ/λ light chain expression
    → Cytogenetics FISH: ~50% hyperdiploid (HRD), ~50% non-HRD
31
Q

How to detect bony damage by multiple myeloma

A

Common sites: areas of active haematopoesis, incl vertebra bodies, skull, thoracic cage, pelvis, proximal humerus/femur

Skeletal survey: conventional 1st line imaging to detect lesions

  • Includes: PA chest, AP/lateral C/T/L-spine, AP/lateral femur/humerus, AP/lateral skull, AP pelvis
  • Findings: punched out lytic lesions (60%), diffuse osteopenia, pathological fractures (20%)
  • Options: WB low-dose CT, WB MRI (or spine/pelvis), WB PET/CT (usually preferred in QMH)
32
Q

Prognostic markers for Multiple Myeloma

A

Patient: Age, Comorbidities (e.g. renal failure, cord compression)

Tumor factors:

  • ISS staging*****
  • Any extramedullary disease/ plasmacytomas
  • Any plasma cell leukaemia
  • Serum LDH ≥2×ULN
  • Cytogenetic abnormalities on FISH: Hypodiploidy, high risk mutations
  • High proliferation rate: Labelling index (LI) on cytology
  • Gene expression profiling
  • β2-microglobulin

High risk = Add adjunctive radiotherapy and Anti-resoprtives

33
Q

ISS staging for multiple myeloma

A
34
Q

Smoldering MM

Diagnostic criteria

Risk of progression

Management

A

Criteria: Paraprotein IgG/A ≥3g/dL and/or 10-60% BM plasma cell

Urine paraprotein >500mg/24 hours

but no myeloma defining events/ CRAB symptoms

Clinical course: a/w 10%/y risk of progression into symptomatic MM, median time 4.8y

Management:
Observe Q4-6mo as in MGUS if low/intermediate-risk
Consider lenalidomide ± dexamethasone if high-risk → prevent end-organ damage

35
Q

General Management of Multiple Myeloma

A

General: well hydrate + allopurinol 300mg daily (TLS),

correct hyperCa,

dialysis if indicated

± consult ONCO/ORTHO if presenting with skeletal Cx (pathological #, spinal cord compression)

36
Q

Treatment options for Multiple Myeloma

A

Autologous HSCT: (ASCT)

proven to ↑overall survival, ↑progression-free survival, ↑complete remission → considered standard therapy in young, transplant-eligible MM patients

Triple therapy:
Proteasome Inhibitors: bortezomib (V), daratumumab (D), carfilzomib (K)
Immunomodulatory drugs (IMiD): lenalidomide, pomalidomide
Dexamethasone

Novel agents:
Monoclonal antibodies: daratumumab (anti-CD38 Ab), elotuzumab
Nuclear Cytoplasmic Transport Receptor Inhibitor: Selinexor
BCL-2 Inhibitors: Venetoclax (t(11;14) positive)

37
Q

MoA of Triple Therapy for Multiple Myeloma

A

Proteasome inhibitors (PI):
Examples: bortezomib (V), daratumumab (D), carfilzomib (K)
MoA: prevent degradation of pro-apoptotic factors (eg. p53) → activation of intrinsic (mitochondrial) pathway of apoptosis
S/E: ↑risk of infection (require acyclovir ± septrin prophylaxis), peripheral neuropathy

Immunomodulatory drugs (IMiD):
Examples: lenalidomide, pomalidomide
MoA:↓tumour angiogenesis, ↓tumour secreted cytokines, induce caspase-8 → activation of extrinsic (death-receptor) pathway of apoptosis
S/E: ↑risk of thrombosis (require anticoagulant/antiplatelet prophylaxis), myelosuppression

38
Q

Which type of HSCT is used to treat multiple myeloma

A

Autologous HSCT

Allogeneic HSCT is NOT used in MM due to high treatment-related mortality (TRM)

39
Q

Pathogenesis of anaemia due to Multiple Myeloma

A

Marrow infiltration by plasma cells

Rouleaux formation due to high paraproteinemia

Dilution by paraproteins

Renal damage > Low EPO

40
Q

Pathogenesis of Hypercalcemia in Multiple Myeloma

A

Increase Osteoclast activity by lymphokines (cytokines , Macrophage inflammatory factor and tumor necrosis factors)

Positive feedback bone resorption by IL-6 - IL6 released from bone resorption causing more myeloma activity

Renal failure - decrease Ca reabsorption, Vit D3 formation and increase PO4 retention

MBBS IV - Junior Clerkship WCS (131 decks)

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