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Haematology > Multiple Myeloma and related plasma cell disorders > Flashcards

Multiple Myeloma and related plasma cell disorders Flashcards

1
Q

Define Multiple Myeloma

A

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

Myeloma plasma cells:

  • home and infiltrate the bonemarrow
  • may form bone expansile or soft tissue tumours : plasmacytomas

• produce a serum monoclonal IgG or IgA: paraprotein or M-spike

  • produce excess of monoclonal (κ or λ) serum free light chains
  • Bence Jones protein :urine monoclonal free light chains
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2
Q

Describe the epidemiology of myeloma.

A
  • The second most common haematological malignancy, 19th in all cancers
  • Median age 67 years
  • Incidence increases with age
  • Only 1% of patients are younger than 40 years
  • Men > women
  • Black > Caucasian and Asians
  • >17,600 people with myeloma live today in the UK
  • Prevalence of myeloma in the community is increasing
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3
Q

What is the aetiology of myeloma? What are the risk factors?

A

Aetiology is unknown …

Risk factors
• Obesity increases the risk for myeloma (SIGNIFICANT)

  • Age
  • Genetics
  • Incidence in black population
  • Sporadic cases of familiar myelom

… but, myeloma is always preceded by a premalignant condition:

Monoclonal Gammopathy of Uncertain Significance (MGUS)

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4
Q

What is MGUS?

A
  • the most common (known) premalignant condition
  • incidence increases with age
  • up to 1% - 3.5% in elderly population
  • average risk for progression : 1% annually
    • IgG or IgA MGUS→myeloma
    • IgM→lymphoma

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

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5
Q

What is the diagnostic criteria for MGUS?

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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6
Q

How do we calculate the chance of progression from MGUs to myeloma

A
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7
Q

Define smouldering myeloma.

A
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8
Q

What is the progression of myeloma?

A
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9
Q

Describe the primary and secondary genetic events of myeloma?

A
  • Primary events
    • Hyperdiploidy (60%)
    • ❑additional odd number Chr
  • IGH rearrangements (Chr 14q32)
    • ❑t(11;14) IGH/CCND1
    • ❑t(4;14) IGH/FGFR3
    • ❑t(14;16) IGH/MAF

Common secondary events

  • KRAS, NRAS
  • t(8;14) IGH/MYC
  • 1qgain/1pdel
  • del 17p (TP53)
  • 13- / del 13q
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10
Q

Describe the patterns of the driver genetic events in myeloma.

A
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11
Q

How do myeloma cells interact with bone marrow microenvironment?

A
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12
Q

What is the diagnostic criteria of multiple myeloma?

A

MDE - new criteria

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13
Q

How does myeloma present?

A

80% of myeloma patients present with bone disease

  • Proximal skeleton
  • Back (spine), chest wall and pelvic pain
  • Osteolytic lesions, never osteoblastic
  • Osteopenia
  • Pathological fractures
  • Hypercalcaemia
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14
Q

How do we use imaging in myeloma?

A
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15
Q

What is the most COMMON cytogenetic abnormality is myeloma?

A

Hyperdiploid karyotype

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16
Q

Which of the following is NOT a typical clinical myeloma characteristic?

  • Anameia
  • Lytic bone disease
  • Splenomegaly
A

Splenomegaly

17
Q

What are the emergencies in myeloma?

A

Cord compression

  • Diagnosis & treatment within 24hrs
  • MRI scan
  • Ig and FLC studies +/- biopsy
  • Dexamethasone
  • Radiotherapy
  • Neurosurgery: rarely required
  • Stabilise unstable spine
  • MDT meeting

Hypercalcaemia

  • Presents with drowsiness, constipation, fatigue, muscle weakness, AKI
  • Fluids, steroids, zolendronic acid
18
Q

Define myeloma kidney disease

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
19
Q

What causes myeloma kidney disease?

A
  • Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria
  • Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics
20
Q

How does myeloma kidney diases develop?

A
  • Cells in PCT take up light chains
  • This becomes overwhelming
  • Cells go into stress and inflamed
  • Form a gelantinous material –> cast
  • Leads to acute kidney injury
21
Q

Why is kidney disease a determinant of prognosis?

A
  • Patients with severe kidney disease (eGFR <30ml/min) have a much worse outcome
  • Early mortality in severe kidney disease is an area on unmet clinical need
    • 12% early death (<2 months)
    • Prolonged hospital stay, lethal infections
    • Nephrotoxic or renal excreted myeloma drugs: eg zoledronic acid, lenalidomide
22
Q

How do you treat myeloma kidney disease?

A

Myeloma kidney disease should be treated as an emergency

Bortezomib-based therapy is the cornerstone of myeloma kidney disease treatment

23
Q

What is the relation between infections and myeloma?

A

Complex humoral and cellular immunodeficiency

  • Immunoparesis: low serum normal Igs
  • Myeloid, T cells and NK cells impairment
  • Chemotherapy impairs immune response
  • Myeloma immune evasion
24
Q

What are the investigations for myeloma?

A

Immunoglobulin studies

  • Serum protein electrophoresis
  • Serum free light chain levels - screening
  • 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
25
Q

Which of the following is a key histological myeloma marker?

  • CD19
  • CD138
  • Surface Ig
  • CD20
A

CD138

26
Q

What is the international staging system for myeloma?

A
27
Q

What causes Amyloidosis? How do we detect it? What light chains are involved?

A
  • 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
28
Q

What is the clinical presentation of amyloidosis?

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
29
Q

Define Monoclonal Gammopathy of Renal Significance (MGRS)

A

Definition

“…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”
30
Q

Describe MGRS pathology?

A
  • 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
31
Q

How has myeloma been treated in the past? How about now?

A

Melphalan

  • Nitrogenmustardderivate,inusesincethe1960’s
  • Backboneofmyelomatherapyuntillate1990’s
  • High-dosemelphalan200mg/m2stillinuseinAutologousSCT

Cyclophosphamide

  • Widelyusedincombinationwithsteroidsand/orotherdrugs
  • Immunomodulationandmicroenvironment

Dexamethasone and Prednisolone

  • Induceapoptosisinmyelomacells
  • Strongsynergy,partofalmostallcombinationregimens

Thalidomide in combination with cyclophosphamide and dexamethasone was established in the treatment of relapsed myeloma

It was later replaced older therapies as a front line treatment prior to autologous SCT

Thalidomide lead the way for the development of a new class of anti-myeloma drugs

Immunomodulatory drugs (IMiD)

Lenalidomide - 2005: more potent, different toxicity profile, better tolerated

Pomalidomide – 2013 : even more potent than Lenalidomide

Iberdomide–awaits approval

32
Q

How does lenalimdomide work

A

Cereblon Binding Molecules -A new mechanism of action

Selective degradation of IKZF1 and IKZF3

33
Q

Describe the use of proteasome inhibitors in myeloma

A

Myeloma cells are protein production factories

Proteasome is crucial in removing misfolded protein

Accumulation of misfolded protein→endoplasmic reticulum stress and unfolded protein response → apoptosis

34
Q

Describe the use of moABs in multiple myeloma-

A

Daratumumab monotherapy in relapsed/refractory myeloma

36% of patients with multiple previous treatments and refractory disease to standard myeloma therapies responded to daratumumab

35
Q

How do we treat multiple myeloma?

A
36
Q

What is the treatment algorithm in new diagnosis of myeloma?

A
37
Q

What is the objective of myeloma therapy?

A

MRD negativity may be required at least in high-risk disease

38
Q

What are the emerging treatment in myeloma?

A

Monoclonal antibodies

  • Belantamab mafodotin - Anti-BCMA toxin conjugate
  • CAR-BCMA T cell therapy

BCMA: B cell maturing antigen, specific for plasma cells (normal and malignant)

Haematology (16 decks)

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