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Year 5 Path Charis > Haem 4 – Plasma Cell Myeloma & amyloid and Monoclonal gammopathy of uncertain significance > Flashcards

Haem 4 – Plasma Cell Myeloma & amyloid and Monoclonal gammopathy of uncertain significance Flashcards

1
Q

What do multiple myeloma cells produce?

A
  • Produce a serum monoclonal IgG or IgA (paraprotein or M spike)
  • Produce excess of monoclonal (κ or λ) serum free light chains (FLC)
  • Bence Jones protein – urine monoclonal FLC
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2
Q

Myeloma is always preceded by

A

a premalignant condition: Monoclonal Gammopathy of Uncertain Significance (MGUS)

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3
Q

MGUS

IgG
IgA
IgM

MGUS is a premalignant condition resulting in…

A
  • IgA or IgG MGUS  myeloma
  • IgM MGUS  lymphoma

(MGUS - presence of monoclonal immunoglobulin in the blood or urine)

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4
Q

MGUS diagnostic criteria

A
  • Serum M-protein <30g/L
  • BM clonal plasma cells <10%
  • No lytic bone lesions
  • No myeloma-related organ or tissue impairment
  • No evidence of other B-cell proliferative disorder
  • No CRAB criteria
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5
Q

Poor prognostic indicators in MGUS

A
  • Non-IgG M-spike
  • M-spike >15g/L
  • Abnormal serum FLC ratio
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6
Q

Which statement is not correct?
Myeloma incidence peaks at 84 years of age
Most individuals with MGUS will develop myeloma
Myeloma is always preceded by MGUS
IgM myeloma is rare

A

MGUS will develop myeloma (actually only about 1% will develowp myeloma)

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7
Q

Which condition has the highest risk of developing symptomatic disease/progressing to multiple myeloma, MGUS or smouldering myeloma?

A

smouldering myeloma

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8
Q

Diagnosis of smouldering myeloma

A
  • Serum monoclonal protein (IgG or IgA) >=30 g/L or
  • urinary monoclonal protein >500mg/24h and/or
  • BM plasma cells >=10%
  • Absence of myeloma defining events or amyloidosis
  • No CRAB features
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9
Q

Poor prognostic factors in smouldering myeloma and maagement

A
  • Bone marrow myeloma cells >20%
  • M-spike >20g/L
  • Serum FLC ratio >20
Low + intermediate risk – observation
High risk (>2 factors) – treatment
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10
Q

events in MM

A

• Hyperdiploidy (60%) – additional odd number Chr

•	IGH (immunoglobulin heavy chain) rearrangements (Chr 14q32)
o	T(11;14) IGH/CCND1
o	T(4;14) IGH/FGFR3
o	T(14;16) IGH/MAF
  • Primary events present in MGUS, smouldering myeloma and MM but are not enough to drive disease into symptomatic disease
  • Secondary events needed to push disease into symptomatic stage
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11
Q

Common secondary events in MM

A
  • KRAS, NRAS
  • T(8;14) IGH/MYC
  • 1q gain, 1p del
  • Del 17p (TP53)
  • 13-/del 13q
  • Primary events present in MGUS, smouldering myeloma and MM but are not enough to drive disease into symptomatic disease
  • Secondary events needed to push disease into symptomatic stage
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12
Q

Pathogenesis of MM

A
  • Angiogenesis – CD34 staining for new vessel
  • Immunosuppression and infections
  • Anaemia
  • Bone destruction
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13
Q

MM diagnostic criteria

A

• >10% plasma cells in bone marrow or plasmacytoma

and >1 CRAB or MDE

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14
Q

CRAB

A

• Calcium >2.75 mmol/L – thirst, moans, groans, stones, bones

• Renal disease (+ amyloidosis + nephrotic syndrome)
o Cr >177 μmol/L or eGFR <40 ml/min

• Anaemia (+pancytopenia)
o Hb <100g/L or drop by 20g/L

• Bone disease – pain, osteoporosis, osteolytic lesions, fractures e.g. wedge compression, pepper pot skull
o >=1 bone lytic lesions in imaging

• + hyperviscosity syndrome

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15
Q

MDE (myeloma defining events)

A
  • BM plasma cells >60%
  • Involved : uninvolved FLC ratio >100
  • > 1 focal lesion in MRI (>5mm)
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16
Q

MM ix

A

• Immunoglobulin studies
o Serum protein electrophoresis
o Serum FLC levels – more sensitive
o 24h Bence Jones protein in urine

• BM aspirate and biopsy
o IHC for CD138
o Rouleaux on blood film
o >10% plasma cells in BM

• ESR very high

•	Look for CRAB symptoms
o	Bone profile to check calcium
o	U+Es for renal function 
o	FBC for anaemia
o	Low dose CT body/MRI whole body to look for bony lesions

• FISH analysis
o Should include at least high-risk abnormalities

•	Flow cytometry immunophenotyping
o	Diagnosis
o	MRD (minimal residual disease)
17
Q

Hypercalcaemia symptoms + mx

A

o Stones, Bones, moans, groans
 stones - renal effects - polyuria, thirst, nephrocalcinosis, renal coli, AKI, chronic renal failure
 bones - osteitis fibrosa cystica
 CNS effects - fatigue, impaired concentration, altered mentation, confusion, depression, seizures, comma (>3mmol/L)
 GI effects - pancreatitis, anorexia, dyspepsia, nausea, constipation
 Muscle weakness

o Fluids, steroids, zolendronic acid

18
Q

Cord compression in MM mx

A

can be caused by a soft tissue mass or fractured bone

o Dx + tx within 24h

o MRI scan

o Stabilise unstable spine
o Dexamethasone
o Radiotherapy
 (MM very sensitive to dexamethasone + radiotherapy)

o Ig + FLC studies +/- biopsy

19
Q

MM kidney disease definition

A

• Serum creatinine >177μmol/L (>2mg/dL)

or eGFR <40ml/min

20
Q

Cause of myeloma kidney disease + mx

A

• Cast nephropathy
o Main cause of myeloma kidney disease
o High serum FLC
o Bence Jones proteinuria

• Hypercalcaemia, Loop diuretics, infection, dehydration, nephrotoxics
o Nephrotoxic or renal excreted myeloma drugs e.g. zolendronic acid, lenalidomide

  • Myeloma kidney disease should be treated as an emergency – hydration
  • Bortezomib-based therapy
21
Q

Mechanism of FLC acute kidney injury

A

Proximal tubule cell injury & myeloma cast nephropathy

22
Q

What is Monoclonal Gammopathy of renal significance (MGRS) and how is it managed

A

• Applies specifically to any B-cell clonal lymphoproliferation where there are

o >=1 kidney lesions cause by mechanisms related to the produced monoclonal Ig and

o The underlying B cell clone does not cause tumour complications or meet current haematological criteria for immediate specific therapy

• Mx – most patients will require myeloma-type treatment aiming to renal survival (Treat with myeloma type treatments to save the kidneys)

23
Q

What causes AL amyloidosis in MGUS / smouldering myeloma/ MM

A

Misfolded FLC aggregate into amyloid fibrils in target organs
NOT caused by chronic inflammation

•	Lambda light chain is involved in 60%
o	IGLV6-57 in kidney - nephrotic syndrome
	Proteinuria 
	Not BJP
	Peripheral oedema

o IGLV1-44 in cardiac
 Unexplained heart failure – check serum FLC

Other sx - sensory neuropathy, abnormal LFTs, macroglossia, erectile dysfunction, diarrhoea, carpal tunnel syndrome, peripheral neuropathy, HF, RF

Congo red stain –> apple green birefringence

24
Q

surface marker for MM

A

CD138

plasma cell marker

25
Q

How does MM cause immunodeficiency and infections?

A

• MM can cause immunodeficiency as it can damage all parts of the immune system

o Immunoparesis – low serum immunoglobulins

o Myeloid, T cell, NK cell impairment

o Chemotherapy – impairs immune response

o Myeloma immune evasion
• Chest infections (gram +ve, later gram -ve)
• Fungal infections (not that common but happen in later stages (steroids + neutropenia))
• Viral infections are common (herpes zoster reactivation)

26
Q

• Cytogenetic abnormalities defining high risk in MM

A 
o	Del(17p)
o	T(4;14)
o	T(14;16)
o	IGH/FGFR3
o	IGH/MAF
27
Q

First line mx in MM

A
  • Bortezomib (proteosome inhibitor) +/-
  • Dexamethasone
  • Cyclophosphamide
  • Lenalidomide
  • Supportive for CRAB symptoms incl. bisphosphonates
  • When in remission – auto-SCT
28
Q

Relapsed MM mx

A

Dexamethasone
Cyclophosphamide
Thalidomide (inhibits angiogenesis)

or

Daratumumab monotherapy

29
Q

Why are proteosome inhibitors helpful in MM?

A

o Myeloma cells are protein production factories, have a very advanced golgi apparatus system
o Proteosome is crucial in removing misfolded protein
 Proteosome inhibition  Accumulation of misfolded protein  endoplasmic reticulum stress and unfolded protein response  apoptosis of cell

o Alteration of NF-κB pathway

30
Q

Give 3 examples of proteosome inhibitors used in MM

Indications
Route of administration
SE

A

Bortezomib

  • 1st line or relapse
  • IV, SC
  • SE - neuropathy

Carfilzomib

  • Relapse
  • IV
  • SE - cardiotoxicity, thrombocytopena

Ixazomib

  • Relapse
  • PO
  • Favourable toxicity profile
31
Q

Which therapeutic monoclonal antibodies can be used in MM

A

Anti-CD38

Daratumumab
Isatuximab

32
Q

How does daratumumab work

A

 Induction of CDC (complement dependent cytotoxicity)
 Modulation of enzymatic activation
 Apoptosis after cross-linking
 Induction of ADCC an ADCP (antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis)

33
Q

MM treatment in transplant eligible patents

A

Fit and typically <65 y/o
• Induction – (Proteosome inhibitor + Immunomodulatory drugs + Dex) x4-6
+/- Daratumumab

o VTD – Velcade (bortezomib) + Thalidomide + Dexamethasone
o VRD – Velcade (bortezomib) + Revlimid (lenalidomide) + Dexamethasone

+/- daratumumab

• Autologous SCT

• +/- consolidation x2
o VTD
o VRD

• Maintenance for 2 years
o Low dose lenalidomide

34
Q

MM treatment in transplant ineligible patents

A
  • Lenalidomide + Dex or
  • Bortezomib + Cyclophosphamide + Dex or
  • Daratumumab + Bortezomib + Cyclophosphamide + Prednisolone
35
Q

What blood tests should you order If there are raised globulins?

A

request serum protein electrophoresis + serum FLC

36
Q

MGUS vs Smouldering myeloma
vs MM

M spike
BM
CRAB
Organ damage
Significance
A

M spike
MGUS - <30g/l
Smouldering myeloma - >=30 g/l
MM - >30g/l, or serum FLC ratio >100

BM
MGUS - <10% clonal plasma cells
Smouldering myeloma- >=10% clonal plasma cells
MM - any clonal plasma cell population, automatically diagnostic if >=60% plasma cells

CRAB
MGUS - none
Smouldering myeloma - none
MM - yes

Organ damage
MGUS - none
Smouldering myeloma - none
MM - hypogammaglobulinaemia, occult bone disease, hyper viscosity, cytopenia

Significance
MGUS - no tx needed, small transformation rate
Smouldering myeloma - no tx needed, high transformation rate
MM - treatment needed

37
Q

Describe 2 other paraproteinemias

A

• Waldenstrom’s Macroglobulinemia (Lymphoplasmacytoid Lymphoma – LPL)
o Elderly men
o Low-grade NHL
o Lymphoplasmacytoid cells producing monoclonal serum IgM infiltrate the LNs/BM
o Weight loss, fatigue, hyperviscosity syndrome (visual problems, confusion, CCF, muscle weakness)
o Rx
 Plasmapheresis for hyperviscosity
 Rituximab / bendamustine or ibrutinib for active disease

• Systemic amyloidosis
o Different types of amyloidosis
o Presents with
 Macroglossia, carpal tunnel syndrome, peripheral neuropathy, HF, RF
o AL Amyloidosis  build of mis-folded light chains
 This can be in the presence or absence of myeloma
 Misfolded light chains deposit in the tissues & cause problems
 AL Amyloidosis will result in an abnormal kappa:lambda light chain ratio
o Other types of amyloidosis involve different types of misfolded proteins
o Dx
 Biopsy of affected organ using congo-red stain -> apple green birefringence
 SAP scan (new diagnostic test)
o Rx  similar to myeloma

Year 5 Path Charis (44 decks)

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