W7 - plasma cell myeloma & amyloid & MGUS Flashcards
Name 2 haematological cancers causing massive hepatosplenomegaly with no lymphadenopathy
CML, myelofibrosis
Hb 140/L, WWC 120 x 10^9/L, platelets 300 x 10^9/L (PB neutrophils basophils and myelocytes) – BM 3% blasts
A) Accelerated phase CML
B) Blast crisis CML
C) chronic phase CML
D) CLL
Chronic phase CML – CML and not CLL b/c peripheral blood shows myeloid cells
Hb is up, platelets are preserved, and blast is only 3% = this is still in the chronic phase of CML
Ph translocation BCR-ABL1 rearrangement is oncogenic via novel __________ _______
fusion oncoprotein
What is MM? What is it a malignancy of?
multiple myeloma - malignancy of BM plasma cells
Myeloma plasma cells:
- home and infiltrate the ______ ______
- may form bone expansile or soft tissue tumours called _________
- produce serum monoclonal ____ or _____, called _________
- produce excess o monoclonal kappa or lambda ____ ___ ____
- urine monoclonal free light chains are called ____ ____ _____
- BM
- plasmacytomas
- IgG, IgA, paraprotein (M spike)
- serum free light chains
- Bence Jones protein
What is the 2nd most common haematological cancers?
Multiple myeloma
What is the median age of diagnosis of MM?
What is the distribution between sex/ethnicity?
67 years of age
men > women
Black (x2) > Caucasians and Asians
What is the aetiology of MM? What are the risk factors
aetiology = unknown
risk factors:
- obesity
- age
- genetics (Black)
- genetics (sporadic familial cases)
MM is always preceded by a premalignant condition called
Monoclonal Gammopathy of Uncertain Significant (MGUS)
What is MGUS?
presence of a monoclonal antibody in the serum
What are the diagnostic criteria for MGUS?
- Serum M-protein <30g/L
- BM clonal plasma cells <10%
- No lytic bone lesions
- No myeloma-related organ or tissue impairment
- No evidence of other B-cell proliferative disorder
What is the average risk of progression of MGUS to MM?
1% annually
Other than MM, what other things (3) is MGUS associated with?
- osteoporosis
- thrombosis
- bacterial infection
What are the 3 risk factors used in MGUS risk stratification for progression to MM?
Non-IgG M-spike
M spike >15g/L
abnormal serum free light chain (FLC) ratio
What is smouldering myeloma? Describe the criteria
another premalignant condition prior to MM, similar to MGUS
Diagnostic criteria:
- serum monoclonal protein (IgG or IgA) >30g/L
- absence of myeloma defining events
What are the 3 risk factors used in smouldering myeloma risk stratification for progression to MM?
- BM myeloma cells >20%
M spike >20 g/L
Serum FLC ratio >20
Which premalignant condition most commonly leads to MM?
smouldering myeloma
What is the most common primary genetic pathogenesis in MM? What is the other?
Do they cause MM by themselves?
- Hyperdiploidy (60%)
- Rearrangement in chromosome 14q32 which codes for Ig
No => other 2ndary events will happen which will lead to MM
The myeloma cells interact with BM microenvironment, causing… (4)
- inhibit osteoblasts = bone destruction
- angiogenesis
- anaemia
- Immunosuppression => hence infections
What is the diagnostic criteria for MM?
>10% plasma cells in BM or plasmacytoma + 1 CRAB or MDE
CRAB:
C = hypercalcaemia
R = renal disease (high creatinine, low eGFR)
A = anaemia
B = bone disease
Myeloma defining events (MDE):
- BM plasma cells >60%
- involved/uninvolved FLC ratio >100
- >1 focal lesion in MRI
How does MM present usually?
80% present with bone disease
- proximal skeleton (spine, chest wall, pelvic pain)
- osteolytic lesions
- osteopenia
- pathological fractures
- hypercalcaemia
- renal impairment
What imaging modalities is better than XR Films for MM?
- CT scans
- FDG-PET scan
- whole body diffusion-weighted MRI
What is one bone emergency caused in MM?
Cord compression => soft tissue compression onto cord OR spinal fracture
Management of cord compression (complication of MM)
DIAGNOSE AND TREAT within 24 hours
- Imaging => MRI scan
- Dexamethasone, radiotherapy, neurosurgery sometimes, stabilise unstable spine
What is a serum abnormality seen in MM complication?
Treatment?
Hypercalcaemia
Fluids, steroids, bisphosphonates
What are some complications (4) of MM?
- Hypercalcaemia
- Pathological fractures
- Cord compression
- Myeloma kidney disease
What causes a higher chance of patient developing myeloma kidney disease?
cast nephropathy is caused by HIGH serum free light chain (FLC) levels and hence, Bence Jones proteins in the urine
so higher FLC = higher chance of myeloma kidney sdisease
What is the emchanism of FLC kidney injury?
They go from the glomerulus to the filtrate. This happens in normal individuals too but we have small amounts of FLC.
The proximal tubule will reabsorb FLCs and will help break them down.
When these cells are overwhelmed, they go into stress and there are inflammatory changes. some FLCs not reabsorbed will travel further down the nephron, and interact with uromodulin, and will lead to inflammatory and eventually fibrotic changes, causing AKI/kidney disease.
What is the prognosis and outcome in MM patient with kidney disease?
Severe kidney disease => much worse outcome (12% early death), prolonged hospital stays, lethal infections, nephrotoxicity
The main cause of myeloma kidney disease is
High levels of serum FLCs and Bence Jones proteinuria
MM leads to both deficiency in ______ & _______ immunity
humoral (Igs)
AND
cellular (meyloid, T cell, NK cell impairment)
What tests (5) do you order o diagnose MM?
- Serum protein electrophoresis
- Serum FLC levels
- 24hr Bence Jones proteins (more for disease monitoring)
2 better than 3 for diagnosis
- BM biopsy
=> IHC for CD138
=> IHC for lamba or kappa light chains (one or the other would be high) - FISH analysis (genetics)
What system is used in MM staging and risk stratification? What is measured?
International staging system (3 stages)
=> measures serum B2-microglobulin and serum albumin
What is AL amyloidosis?
A systemic disease in which FLCs, due to their physical properties, misfold and form amyloid fibrils which deposit in different organs
What IHC can be used to stain amyloid fibrils?
Congo Red
The amount of amyloid fibrils is important in determining amyloidogenic potential - T or F?
False - the potential of the fibrils to form is more important than the []
Which light chain is more involved in AL amyloidosis?
Lambda (60%)
Which organs are common targets in AL amyloidosis?
kidney
heart
liver
nervous system
What is the clinical presentation of AL amyloidosis?
nephrotic syndrome (70%) => proteinuria, peripheral oedema
unexplained HF
sensory neuropathy
abnormal LFTs
macroglossia
erectile dysfunction
diarrhoea
and many more.
What is Monoclonal gammopathy of renal significance (MGRS)?
How is it investigated? Treated?
MGRS is a rare disease with several subtypes, involving monoclonal Ig r light chain in most cases
Work up and treatment similar to myeloma => aim for renal survival
What is Monoclonal Gammopathy of Renal Significance? How do you investigate and treat?
MGRS is a rare disease involving monoclonal IG or light chains, leading to kidney disease
workup similar to MM => treatment is myeloma-type aiming for renal survival
Name 4 therapies used for multiple myeloma (MM)
1. IMiD/immunomodulatory therapy = Lenalidomide (Thalidomide analogue)
2. Proteosome inhibitors (Bortezomib)
3. Anti-CD38 abs
4. Steroids (Dexa)
