Haem: Multiple Myeloma Flashcards
Another name for immunoglobulin
M spike
Paraprotein
Epidemiology of Multiple Myeloma
Black
Male
Older (eg. 67)
List some key features of multiple myeloma.
- Cancer of monoclonal plasma cells
- Abundance of monoclonal immunoglobulin
- Osteolytic bone lesions
- Anaemia
- Infections (due to deficient polyclonal response)
- Kidney failure (due to hypercalcaemia)
What is the pre-malignant condition for multiple myeloma?
Monoclonal gammopathy of uncertain significance (MGUS)
What is MGUS
Monoclonal Gammopathy of uncertain significance
Precedes Multiple Myeloma
- Serum M <30g/L
- Bone marrow clonal plasma cells <10%
- No lytic lesions
- No myeloma organ or tissue impairment
- No evidence of B-cell proliferative disorder
Which Ig indicates myeloma? Which indicates lymphoma?
IgA or G = Myeloma
IgM = Lymphoma
How common is multiple myeloma compared to other haematological malignancies?
2nd most common after B cell lymphoma
Risk stratification for MGUS
Mayo criteria
Based on 3 risk factors
- Isotype of immunoglobulin - IgG lower risk
- M-spike >15g/L
- Abnormal serum free light chain ratio
What is smouldering myeloma
Both:
- Serum monoclonal protein (IgG or A) >30g/L
OR urinary ~500mg per 24h
OR bone plasma 10-60% - Absence of myeloma defining events or amyloidosis
(no CRAB)
Spectrum
in between MGUS and Myeloma
What are the 2 main primary mechanisms that drive myeloma development?
- Hyperdiploidy
- IGH rearrangements (heavy chain gene translocations)
What is another term of activated B cells?
Centroblasts
Outline the process by which B cells become plasma cells.
- Centroblasts mature in lymph nodes where they are stimulated by antigens and turn into memory B cells or immature plasmablasts
- Various transcription factors regulate the conversion of plasmablasts into plasma cells
Which components of the cell ultrastructure are particularly developed in plasma cells?
- Endoplasmic reticulum and golgi body
- This is where immunoglobulins are assembled, folded and modified before secretion
NOTE: plasma cells are the most secretory cells in the body (10,000 immunoglobulin per second)
Outline the pathogenesis of multiple myeloma.
- Errors occur in the genome of normal plasma cells (possible due to infection/inflammation)
most common - Hyperdiploid karyotype (extra chromosomes), IGH translocations - This leads to a limited monoclonal accumulation of plasma cells (MGUS)
- This is still harmless (5% of people >75 will have MGUS)
- 1% of people with MGUS per year will acquire more mutations that transform these pre-malignant cells into multiple myeloma cells
- This will trigger a cascade of events in the tumour microenvironment including increased angiogenesis and increased bone resorption
NOTE: it is difficult to develop targeted therapies for multiple myeloma because a lot of different mutations can cause it
What is CRAB?
Hypercalcaemia (>2.75 mmol/L)
Renal failure (creatinine >177μmol/L or eGFR <40ml/min)
Anaemia (Hb <100g/L or drop by 20g/L)
Bone lesions (One or more bone lytic lesions in imaging
What is a myeloma defining event
- Bone marrow plasma cells ≥60%
- Involved : uninvolved FLC ratio >100
- > 1 focal lesion in MRI (>5mm)
What is the diagnostic criteria for multiple myeloma?
≥10% plasma cells in bone marrow + ≥1 CRAB or myeloma defining event
What is the median survival for patients with multiple myeloma?
3-4 years
Describe the histological appearance of mature plasmacytic cells.
- Nucleus is pushed to one side of the cell
- Clumped chromatin
- Large cytoplasm (low nuclear-to-cytoplasmic ratio)
Describe the histological appearance of immature plasmablastic cells.
- Prominent nucleoli
- Reticular chromatin
- Less abundant cytoplasm
What is the presence of immature plasmablastic cells associated with?
The presence of these cells is associated with a poor prognosis
Which antigens do myeloma cells test positive for on immunohistochemistry?
CD138 - commonly used diagnostic marker
CD38 - can be targeted by monoclonal antibodies
Which antigens do myeloma cells test negative for on immunohistochemistry?
- CD19
- CD20 (unlike B cell lymphomas and CLL)
- Surface immunoglobulin
How does multiple myeloma lead to lytic bone disease?
The myeloma cells release osteoclast activating factors and osteoblast inhibiting factors
How is bone imaging utilised in myeloma
- X-ray now obselete
- Whole body CT
- CT/PDG-PET
-
Whole body diffusion weighted MRI
- Bone marrow cellularity
- Active vs treated disease
How can multiple myeloma lead to paralysis?
Pathological fracture of a vertebra can lead to spinal cord compression.
Which imaging techniques are used to investigate multiple myeloma and what are their benefits?
- MRI - sensitive for bone marrow infiltration, expensive
- CT - sensitive for very small lytic lesions, high radiation dose
- PET scans - detects active disease, usually used with CT/MRI
Outline the mechanisms by which multiple myeloma causes kidney injury.
20-50% AKI at diagnosis
- Cast nephropathy - caused by high serum FLC, which is filtered and precipitates in tubules
- Hypercalcaemia - nephrocalcinosis
Normal amount of light chains in blood
20mg/dL
Multiple Myeloma diagnostic workup
Immunoglobulin studies
- Serum protein electrophoresis (M-spike)
- Involved:Uninvolved FLC ratio serum assay
- 24h urine Bence Jones protein
Bone Marrow aspirate/biopsy
- IHC for CD138
FISH
- For high risk mutations
Flow Cytometry
- Diagnostic
- Monitioring
Staging of Multiple Myeloma
How can myeloma cause AL amyloidosis
Light chains have the potential to misfold and deposit = Amyloid
(because of variable regions in immunoglobulin, can occur in MGUS or Smouldering)
Target organs:
Kidneys, Heart
others - GI, Skin, Liver, Spleen, Lymph
Stain for amyloid
Congo Red
Solid, non-branching and randomly arranged with diameter of 7-12nm
Common presentations of amyloidosis
- Nephrotic (70%)
- Proteinuria, Oedema
- Unexplained HF - (10%)
- Raised NT-pro-BNP
- Abnormal Echo and cardiac MRI
- Sensory Neuropathy
- Abnormal LFTs (9%)
- Macroglossia
- Malabsorption plus GI symptoms
What is MGRS
Monoclonal Gammopathy of Renal significance
Any B cell lymphoproliferation where there are:
- 1+ kidney lesions caused by mechanisms related to Ig produced and..
- Underlying B cell clone does not cause tumour complications or meet criteria for immediate specific therapy
What is the ideal treatment for MM
Autologous stem cell transplant
What are the four main types of drug treatment of multiple myeloma?
- Classical alkylator chemotherapy drugs (e.g. melphalan, cyclophosphamide)
- Steroids (very cytotoxic to lymphocytes)
- Immunomodulators (IMIDs e.g. thalidomide)
- Proteasome inhibitors e.g. bortezomib
Describe the physiological role of proteasomes.
- All proteins produced by a cell are folded in the endoplasmic reticulum
- If this process goes wrong, misfolded proteins would accumulate in the ER
- These misfolded proteins are insoluble and non-functional and lead to fatal ER stress and cell death
- So, we have proteasomes in the cytoplasm which targets misfolded proteins and degrades the into amino acids (a process called ER-associated degradation (ERAD))
- Inhibition of proteasomes leads to an accumultation of misolded proteins in myeloma cells leading to cell death
NOTE: proteasome inhibitors only work in multiple myeloma and not other cancers
List some examples of proteasome inhibitors.
- Bortezomib
- Carflizomib
Which old drug is used in the treatment of multiple myeloma?
Thalidomide - downregultes pro-survival cytokines and induces apoptosis
Give an example of a monoclonal antibody used to treat multiple myeloma.
Daratumumab - anti-CD38 antibody, binds to cell surface of plasma cells causing complement activation and cell lysis/death
Outline the 2 main treatment algorithms for MM
Emerging medications for multiple myeloma
Belantamab mafodotin
- Anti-BCMA (B cell maturation antigen) - highly specific for malignant plasma cells
- Conjugated to toxic drug - will kill cell antibody binds to
- 60% response rate in refractory MM
Anti-BCMA CAR T cells
Side effects
- Cytokine release syndrome
- Neurotoxicity
- Infection and cytopenias
