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
Preceding Multiple Myeloma
Serum M <30g/L
Bone marrow cells <10%
Asymptomatic
No lytic lesions
No myeloma organ or tissue impairment
No evidence of B-cell proliferative disorder
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 Multiple myeloma
Mayo criteria
Based on 3 factors
- Isotype of immunoglobulin - IgG lower risk,
- M-spike >15g/L,
- Abnormal serum free light chain
What is smouldering syndrome
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 main mechanisms that drive plasma cell development?
- Class switch recombination
- Transcriptional control
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)
- 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 are the main clinical features of multiple myeloma?
- Calcium (high)
- Renal failure
- Anaemia
- Bone lesions (pain, pathological fractures)
- Monoclonal paraprotein
NOTE: patients with MGUS have no clinical features - there are some arbitary cut-offs for MGUS/multiple myeloma based on monoclonal serum protein, bone marrow plasma cells and annual risk of progression to multiple myeloma
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
NOTE: the presence of these cells is associated with a poor prognosis
Which antigens do myeloma cells test positive for on immunohistochemistry?
- CD138
- CD38
- CD56/CD58
- Monotypic cytoplasmic immunoglobulin
- Light chain restriction
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
Dont use Xrays so much - now more Cross secitonal - CT or PET
or diffuse weighted MRI - showing effect of treatment; bone marrow cellularity
(as lytic lesions will be there after therapy)
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
- Immunoglobulin light chains activate inflammatory mediators in the proximal tubule epithelium
- Proximal tubule necrosis
- Fanconi syndrome (renal tubule acidosis with failure of reabsorption in the proximal tubule) with light chain crystal deposition
- Cast nephropathy (light chains + uromodulin) - blocking renal tubules
Normal amount of light chains in blood
20mg/dL
Multiple Myeloma diagnostic workup
Immunoglobulin studies
Serum free light chains - usually all needed (Serum electrophoresis)
24h Bence Jones usually not necessary
Bone Marow aspirate
CD138
Flow Cytometry
Diagnosis
Staging of Multiple Myeloma
International Staging System ISS
Based on B2 Serum microglobulin, & Albumin
and Revised ISS
How can myeloma relate to 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 Neuopathy
Abnormal LFTs (9%)
Macroglossia
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 cone does not cause tumour complications or meet criteria for immediate specific therapy
What are the four main domains of treatment of multiple myeloma?
- Classical cytostatic drugs (e.g. melphalan)
- Steroids (very cytotoxic to lymphocytes)
- Immunomodulators (IMIDs e.g. thalidomide)
- Proteasome inhibitors
What is melphalan?
- An alkylating agent that acts as a cytostatic drug
- Very effective when given as part of high-dose chemotherapy with an autologous stem cell transplant
- Related compounds include cyclophosphamide
Outline the process of autologous stem cell transplantation.
- Patients receive induction treatment for 6 months to reduce the burden of myeloma
- Stem cells from the bone marrow are harvested
- Patients receive a single shot of high-dose melphalan to kill myeloma cells (also toxic to bone marrow)
- Patient is reinfused with own stem cells to rescue blood cell formation
- Within 24 hours, stem cells find their way to the bone marrow
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 - targets the turnover of transcription factors which are essential for myeloma cell survival
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
Emerging medications for multiple myeloma
Belantamab mafodotin
antibody targeting marker (BCMA) for plasma cells (normal and malignant) – v. specific (not as prevalent of CD38)
Carries a toxin with it – will kill the cell it binds to
60% response rate as. Monotherapy
Car T cells
Isloating patient T cells and making them attack cancer
side effects - cytokine release syndrome
