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YEAR 5: Haematology JK > Plasma Cells and MGUS > Flashcards

Plasma Cells and MGUS Flashcards

1
Q

What is multiple myeloma?

A

Malignancy of bone marrow plasma cells → terminally differentiated and Ig secreting B cells

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2
Q

What is a plasmacytoma?

A

Tumour of plasma cells in bone or soft tissue

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3
Q

What type of antibodies/proteins do plasma cells create in MM?

A

monoclonal IgG/IgA (paraproteins or M Spike)
= excess of monoclonal (kappa or lambda) serum free light chains

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4
Q

What are Bence Jones Proteins?

A

Urine Monoclonal free light chains

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5
Q

What is waldenstrom’s macroglobulinemia?

A

Lymphoplasmacytic lymphoma

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6
Q

Myeloma vs Lymphoma from progenitor cells?

A

Myeloma - long lived plasma cells
Lymphoma - short lived plasma cells

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7
Q

How do B cells develop ?

A
  1. mature into short lived plasma cells and produce IgM
  2. move to germinal centre, undergo somatic hypermutation (to increase antigen affinity) + class switching (heavy chain change) to make either IgG or IgA
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8
Q

Myeloma - epdemiology?

A

2nd most common haem malignancy
median age 67y (old ppl cancer) + incidence increases with age
M>F

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9
Q

MGUS Diagnostic criteria

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

Myeloma Spectrum

A

MGUS : higher than normal proteins but no end organ damage, no tx
smouldering myeloma : intermediate, higher monoclonal proteins
Myeloma : CRAB symptoms, lots of proteins

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11
Q

Which criteria is used to risk stratify mGUS

A

**mayo criteria **

RF : non IgG M-Spike; M-Spike >15g/L or abnormal serum Free light chain ration

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12
Q

Smouldering myeloma

A

intermediate between MGUS and myeloma
1. Serum monoclonal proteins >30g/L/; urine >500mg/d or clonal bone marrow plasma cells 10-60%
2. no myeloma events or amylodosis

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13
Q

Pathogenesis of myeloma

A
  1. Primary : hyperdiploidy during CSH or SHM
  2. Secondary event of genetics e.g. KRAS, del 13 or t(8;14)
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14
Q

Pathogenesis of myeloma in bone?

A
  1. Bone destruction due to osteoclast activation and uncoupling of bone marrow remodelling pathway
  2. Anaemia and immunosuppression due to infiltration
  3. Angiogenesis
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15
Q

Diagnostic criteria for MM

A

CRAB
Calcemia → hypercalcemia due to bone damage

Renal → Creatinine >177, eGFR<40

Anaemia

Bone disease → lytic lesions on imaging

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16
Q

What are myeloma defining events?

A

Bon marrow plasma cells >60%, FLC ratio >100, >1 focal lesion in MRI (>5mm).
Patients may be symptomatic or organ damage but very likely to soon therefore treat as active disease patients.

17
Q

Myeloma Bone disease

A
  • 80% of patients present with
    • Proximal skeleton
    • Back (spine), chest wall and pelvic pain
    • Osteolytic lesions, never osteoblastic
    • Osteopenia
    • Pathological fractures
    • Hypercalcaemia
18
Q

Myeloma emergencies?

A
  1. Cord Compression
  2. Hypercalcemia
19
Q

Myeloma kidney disease

A

Cast nephropathy due to high serum FLC and Bence Jones proteinuria

20
Q

Pathophysiology of MM kidney disease

A
  • Myeloma → PCT cells go into stress = profibrotic and inflammatory response
    • In DCT, react with tamms-horsfal protein which deposits and blocks tubules → light chain casts
21
Q

Why are MM patients at increased risk of infection?

A

more infections (including shingles)

  • Immunoparesis: low serum normal Igs
  • Myeloid, T cells and NK cells impairment
  • Chemotherapy impairs immune response
  • Myeloma immune evasion
22
Q

Myeloma diagnostic work up?

A

Immunoglobulin studies
- serum protein electrophoresis
- serum FLC
-24h bence jones protein

Bone marrow aspirate and biopsy:
- IHC for CD 1388

FISh and flow cytometry

23
Q

International Staging System for MM

A
24
Q

how does myeloma link to AL amyloidosis ?

A

Misfolded free light chains aggregate into amyloid fibrils in target organs

25
Q

Amyloid stain?

A

Congo Red

26
Q

Which light chain is linked to AL amyloidosis in MM?

A

Lambda light chain

27
Q

Clinical presentation of AL amyloidosis in MM

A

Common target organs: kidney, heart, liver, neuropathy

Clinical presentation:

  • Nephrotic syndrome (70%)
    – Proteinuria (not BJP!), peripheral oedema
  • Unexplained heart failure → determinant of prognosis
    – Raised NT-proBNP– Abnormal echocardiography and cardiac MRI
  • Sensory neuropathy
  • Abnormal liver function tests
  • Macroglossia
28
Q

MGRS

A

**monoclonal gammopathy of renal significance **
specifically to any B-cell clonal lymphoproliferation where there are:
1. one or more kidney lesions caused by mechanisms related to the produced
monoclonal immunoglobulin (Ig) and

  1. the underlying B cell clone does not cause tumor complications or meet current
    hematological criteria for immediate specific therapy”
29
Q

Tx for MM

A
  • alkylators and steroids
  • Thalidomide
  • Cereblon E3 ligase modulators
  • proteasome inhibitors
  • immmunotherapy
  • BiTE
  • Anti- BCMA CAR-T cell
30
Q

How are alylators and steroids used in MM Tx?

A

Alkylators and Steroids:

Melphan :

  • Nitrogen mustard derivative
  • Used till late 1990s
  • Highdose still used in Autologous SCT

Cyclophosphamide

  • Widely used in combination therapy → immunomodulation and microenvironment

dexamethasone and Prednisolone

  • Induce Apoptosis in myeloma cells
  • Strong synergy therefore used in most combination regimens
31
Q

How does Thalidomide affect MM>

A
  • inhibits angiogenesis
  • lidomide druges
    Works through CRBN protein → binds and leads to proteosome degradation IKZF1/3 → downregulates IRF 4 → Importantant TF for plasma cell identity = leads to cell death in myeloma
32
Q

Proteosome inhibitors and MM

A
  • proteosomes remove misfolded proteins, and thus cause apoptosis by inhibition as proteins accumulate in cell
  • Bortezomib
  • Carfilzomib
  • isazomib
33
Q

Immunotherapy in MM

A

Anti-CD38
- strongly expressed in normal and malignant plasma cells → not a linage specific marker but no other cell in BM expresses it as much.
-> Daratumumab and Isatuximab

34
Q

Novel immunotherapy in MM : Belantamab?

A

Anti-BCMA (B-cell maturation antigen) toxin conjugate

Antibody uptaken by endosome → distrupts tubulin by releasing toxin - induces cell death

**used in refractory cases **

35
Q

How do Bispecific T cell engages work?

A
  1. Recognises antigen on tumour cells that are specific on plasma cells
  2. CD3 → on T cells
  • Brings T cell effector and tumour cell, activates and kills tumour cells

YEAR 5: Haematology JK (21 decks)

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