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Year 5 Pathology > Plasma Cell Myeloma & amyloid and Monoclonal gammopathy of uncertain significance > Flashcards

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

1
Q

What is Multiple Myeloma?

action of myeloma plasma cells

A

Malignancy of bone marrow plasma cells, the terminally differentiated and immunoglobulin (Ig) secreting B cells

myeloma plasma cells:

  • home and infiltrate bone marrow
  • may form bone expansile/soft tissue tumours: plasmacytomas
  • produce a serum monoclonal IgG or IgA: paraprotein or M-spike
  • produce an excess of (kappa/gamma) serum free light chains
  • Bence Jones proteins: urine monoclonal free light chains
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2
Q

B cell development and myeloma

A

Myeloma is a cancer of terminally differentiated B cells (plasma cells). these cells have undergone all the stages of development to become mature B cells that express IgM or IgD surface immunoglobulins.

B cells leave the bone marrow to migrate to lymphoid organs. Then, they enter the germinal centre.

At the germinal centre:

  • Class-switch recombination
  • Somatic hypermutation

These two events change the subtype of the immunoglobulin that the plasma can produce, from IgM to either IgG or IgA. These processes also refine the specificity of the antibodies. When the cells leave the germinal centre, they either become memory B cells, or plasmablasts. These plasmablasts go back to the bone marrow and differentiate into long-lived plasma cells and produce IgG or IgA immunoglobulins.

NOTE: plasmablasts in the marginal zone differentiate into short-lived plasma cells, which produce IgM (these cannot give rise to myeloma; they give rise to some low-grade lymphomas, including Lymphoplacytic lymphoma and Waldenstrom’s macroglobulinemia).

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3
Q

risk factors of mueloma

what is myeloma preceded by

A

RFs:

  • obesity
  • age
  • genetics (black population, sporadic cases of famialr myeloma)

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

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4
Q

MGUS

A

MGUS: the presence of monoclonal immunoglobulins in blood (asymptomatic, but not innocent)

The most common (known) premalignant condition

Incidence of MGUS increases with age

Up to 1% – 3.5% in elderly population

higher incidence of osteoporosis, thrombosis and bacterial infection compared to general population

Average risk for progression of MGUS to myeloma: 1% annually

Everyone with myeloma has MGUS, not everyone with MGUS will develop myeloma

  • IgG or IgA MGUS -> myeloma
  • IgM MGUS -> lymphoma – IgM myeloma is rare
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5
Q

MGUS diagnostic criteria

A

Serum M-protein < 30g/L (M-protein = monoclonal protein)

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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6
Q

MGUS risk stratification and mx

A

Mayo criteria

RFs:

  • non-IgG M-spike
  • M-spike >15g/L
  • abnormal serum free light chain (FLC) ratio
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7
Q

most common cytogenetic abnormality in myeloma

A

Hyperdiploidy/hyperdiploid karyotype (60%) – the most common primary cytogenic event

Additional copies of chromosomes (affects the odd numbered chromosomes)

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8
Q

What is smoulding myeloma (criteria)

A

smouldering myeloma (also sometimes known as asymptomatic myeloma) is an early form of myeloma which usually progresses to active myeloma, but at a slow rate. In smouldering myeloma abnormal cells can be detected in the bone marrow, and abnormal protein can be detected in the blood and/or urine. Smouldering myeloma is almost an intermediate between MGUS and symptomatic myeloma.

Both criteria must be met:

  • Serum monoclonal protein (IgG or IgA) 30 g/L or urinary monoclonal protein 500 mg per 24 hours and/or clonal bone marrow plasma cells 10-60%
  • Absence of myeloma defining events or amyloidosis (no organ damage or symptoms)
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9
Q

clinical spectrum of myeloma and related plasma cell disorders

A
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10
Q

Pathogenesis of multiple myleoma

A

Bone destruction

Anaemia

Angiogeneiss

Immunosuppression and infection

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11
Q

Diagnostic criteria of multiple myleoma

A

>10% plasma cells in bone mamrrow or plasmacytoma + 1 or more CRAB or MDE

CRAB

  • calcium hypercalcaemia (>2.75 mmol/L)
  • renal disease (creatinine >177 umol/L or eGFR <40ml/min)
  • anaemia (Hb <100g/L or drop by 20g/L)
  • bone disease (one or more bone lytic lesions in imaging)

MDE (myleoma defining events)

  • bone marrow plasma cells >60%
  • involved:uninvolved FLC ration >100
  • >1 focal lesion in MRI (>5mm)
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12
Q

multuple myeloma clinical presentation: bone disease (80%)

A

proximal skeleton = back(spine), chest wall and pelvic pain

osteolytic lesions, never osteoblastic

osteopenia

pathological fractures

hypercalcaemia

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13
Q

myeloma bone disease: imaging

A

whole body CT scan low-dose

CT/FDG-PET scan

whole-body diffusion-weighted MRI

  • bone marrow cellularity
  • active vs treated disease
  • focal vs diffuse pattern of disease
  • residual disease
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14
Q

bone disease and emergencies in myeloma

A

cord compression

  • diagnosis and tx within 24 hrs
  • MRI scan
  • Ig and FLC studies +/- biopsy
  • dexamethasone
  • radiotherapy
  • neurosurgery: rarely reqiored
  • stabilise unstable sign
  • MDT meetin g

hypeprcalcaemia

  • presents with drowsiness, constiaption, fatigue, muscle weakness, AKI
  • fluids, steroids, zolendronic acid
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15
Q

myeloma kidney disease definition, causes, tx

A

Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI) – Acute kidney injury and result of myeloma

  • 20-50% acute kidney injury at diagnosis
  • 2-4% of newly diagnosed patients will require dialysis
  • 25% develop renal insufficiency at relapse
  • Patients with severe kidney disease (eGFR <30ml/min) have a much worse outcome

Causes:

  • Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria
  • Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics
  • Cast nephropathy requires high amounts of serum FLC
  • nephrotoxic/renal excreted myeloma drugs: zolendronic acid, lenalidomide

Treatment: EMERGENCY

  • bortezomib-based therapy
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16
Q

Infections and myeloma

A

Complex humoral and cellularimmunodeficiency

  1. Immunoparesis: low serum normal Igs
  2. Myeloid, T cells and NK cells impairment
  3. Chemotherapy impairs immune response
  4. Myeloma immune evasion
17
Q

Myeloma diagnostic workup

A

Ig studies

  • serum protein eletrophoresis
  • serum FLC levels
  • 24h Bence Jones protein

Bone marrow aspirate and biopsy

  • IHC for CD138

FISH analysis

  • should include at least high risk abnormalities

Flow cytometry immunophenotyping

  • diagnosis
  • MRD
18
Q

Myeloma and AL amyloidosis

A

MGUS or myeloma in the background

Misfolded free light chains aggregate into amyloid fibrils in target organs

The amyloidogenic potential of light chains is more important than their amount

Amyloid fibrils stain with Congo Red, are solid, non- branching and randomly arranged with a diameter of 7 – 12 nm

Lambda light chain is involved in 60%

  • IGLV6-57 in kidney
  • IGLV1-44 in cardiac
19
Q

Al amyloidosis: systemic disiease common target organs and clinical presentations

A

kidney, heart, liver, neuropathy

clinical presentations:

  • 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
20
Q

MGRS Monoclonal Gammopathy of Renal Significance definition and pathology

A

…MGRS applies 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
  2. the underlying B cell clone does not cause tumor complications or meet current hematological criteria for immediate specific therapy”
  • Rare disease, several subtypes
  • Demonstration of the involved monoclonal Ig or light chain is possible in most cases
  • Work up similar to myeloma
  • Many patients will require myeloma-type treatment aiming to renal survival
21
Q

myeloma therapy: alyklators and steroids

A

melphalan

cyloposphamide

dexamathosone and predisolone

22
Q

myeloma therapy: IMiD, Proteasome inhibtors, moAbs

A

IMiD

  • lenalidomide, pomalidomide

Proteasome inhibitors

  • bortesomib
  • carfilzomib
  • ixazomib

moAbs

  • anti-CD38: daratumumab and isatuximab
23
Q

holistic approach for tx decisions in multiple myeloma: 4P

A
24
Q

tx algorithm in new diagnosis myeloma

A
25
Q

Summary 1

A

summary 2

26
Q
A

Year 5 Pathology (27 decks)

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