Multiple Myeloma Flashcards
What is multiple myeloma?
A haematological cancer characterised by clonal proliferation of plasma cells in the BM, typically associated with a monoclonal component in the serum and/or urine (paraprotein, usually IgG or IgA)
→ osteolytic bone disease, anaemia, and renal failure
What is the CRAB of multiple myeloma?
- HyperCalcaemia - >2.75mmol/L
- Renal Impairment - Cr >177 or eGFR <40
- Anaemia - <100g/L drop of 20g/L; normochromic, normocytic
- Bone lesions - Lytic
What is the epidemiology of multiple myeloma?
- 2nd most common haematological cancer
- 67yrs median age
- M>F
- Black > caucasian
What is the aetiology of multiple myeloma?
Unknown
- ?Genetic inheritance
- ?Association to ionising radiation and petroleum products
What are the risk factors for multiple myeloma?
- MGUS
- abnormal free light-chain ratio (kappa/lambda ratio <0.26 or >1.65 is a powerful indicator for progression to MM)
- FH
- radiation
- petroleum
How does myeloma evolve?
Almost in all cases they evovle from an asymptomatic pre-malignant stage (MGUS - monoclonal gammopathy of undetermined significance0) at a rate of 1% per year.
In others there is an intermediate asymptomatic pre-malignant stage called “smouldering” myeloma. This progresses to myeloma at 10%/yr.
What is the protein which builds up in kidneys in multiple myeloma?
Bence Jones’ proteins
What are the symptoms of multiple myeloma?
- Bone pain - osteolytic lesions in back, ribs; fractures
- Anaemia- tiredness
- Hyperviscosity - bleeding, headaches, visual disturbance, bruisiing
- Infections
- Kidney failure - (due to Bence Jones’ protein precipitating in the renal tubules)
- Hypercalcaemia- thirst, nausea, constipation, mental change
- Dehydration (due to proximal tubule dysfunction from light-chain precipitation)
What are the diagnostic features of multiple myeloma?
Clonal BM plasma cells ≥10%, or biopsy-proven plasmacytoma + 1 or more of:
- Evidence of end-organ damage that can be attributed to:
- Hypercalcaemia: serum Ca >0.25 mmol/L (>1 mg/dL) higher than upper limit of normal or >2.75 mmol/L (>11 mg/dL)
- Renal insufficiency: Cr clearance <40 mL per minute or serum Cr >177 micromol/L (>2 mg/dL)
- Anaemia: Hb >20 g/L below lower limit of normal, or a Hb value <100 g/L
- Bone lesions on imaging
- Any one or more of the following biomarkers of malignancy:
- BM plasma cell percentage ≥60%
- Involved:uninvolved serum free light-chain ratio ≥100
- >1 focal lesion (each ≥5 mm) on MRI
What are the diagnostic features of smouldering myeloma?
- M protein (IgA or IgG) >30g/L in serum +/- BM plasma cells 10-60% +/- urinary paraprotein >500mg/24hrs AND
- No myeloma-defining events or amyloidosis
+ No CRAB features.
What are the diagnostic features of MGUS?
- M proteins <30g/L AND
- <10% plasma cells in BM
- Absence of CRAB (endo organ damage features)
(MGUS = monoclonal gammopathy of undetermined significance)
+No CRAB features.
What investigations would you do and what would you find?
- Immunoglobulin studies e.g. SPE, serum FLC levels, 24hr Bence Jones protein
- BM aspirate and biopsy - IHC for CD138
- FISH analysis - for high risk abnormalities
- Flow cytometry for immunophenotyping - diagnosis, minimal residual disease detection
Other:
- Urinalysis - Bence Jones proteins
- FBC - anaemia normocytic normochromic, thrombocytopenia, leukopenia
- U&E, creatinine - impaired renal function; Cr >176
- ESR - elevated
- Serum calcium - high
- Blood film - rouleaux formation with a bluish background
- CT/PET of symptomatic areas - ?lytic lesions
What do these show?
- Hb 93
- WCC 3.14
- Plt 87
- MCV 101
- Neut 1.6
- ESR12
No abnormal white cells on differential.
- Pancytopenia - all blood counts reduced
- MCV is elevated
- Normal/high ESR - partly due to reduced haemoglobin; but mostly due to increased protein in plasma (e.g.paraprotein in myeloma)
AML is unlikely as there are no abnormal white cells on differential.
When might you do a plasma exchange in myeloma?
Not commonly required but may have a role in patients with significantly impaired renal function at presentation.
Why might you get spinal compression in myeloma? What investigations would you do?
Vertebral damage due to myeloma–> plasmacytoma or vertebral collapse–> spinal cord compression
Investigations:
- skeletal survey - looks for othr areas of skeletal damage which might be osteoporotic or lytic in nature
- bone marrow aspiration - required to confirm myeloma diagnosis (excess of plasma cells)
- MRI scan of spine - degree of bone marrow infiltration
What are paraproteins?
IgA/IgG secreted by plasma cells which do not work as intended
What are the causes of myeloma kidney disease?
- Cast nephropathy - Light chains and Tamm Horsfall glycoproteins accumulate in proximal tubule forming casts. AL amyloidosis forms by misfolded lambda chains.
- Bence Jones proteins
- Hypercal
- Dehydration
Other: infection, drugs (loop diuretics, nephrotoxics)
What are the expansile tumours of MM called?
Plasmacytomas
What are the two types of abundant proteins in myeloma?
Bence jones = free light chains
Monoclonal IgA/G a.k.a. paraprotein/M spike
Compare MM and Waldenstrom’s macroglobulinaemia.
W = IgM producing cells MM = IgG/IgA producing cells
- If the patient has IgG/IgA MGUS what will they progress to?
- If the patient has IgM MGUS what will they progress to?
- MM
- Lymphoma
What is the WHO diagnostic criteria for MGUS?
- Serum M-protein <30g/L
- BM clonal plasma cells <10%
AND
- No lytic bone lesions
- No myeloma-related organ or tissue impairment
- No evidence of other B-cell proliferative disorder
What criteria stratifies risk to MM progression in MGUS?
Mayo criteria - looks at non-IgG spike, if M-spike >15g/L and at SFLC ratio
What are the two main criteria which define smouldering MM?
a). M protein >30g/L (or urinary 0.5g/day)
+/- BM plasma cells 10-60%
b) No amyloidosis and no MM defining events
List the stages of progression of myeloma.
- MGUS - PC <10%, M <30g/L
- Smouldering - PC>10%, M >30g/L
- Symptomatic MM*
- Remitting relapsing MM
- Refractory
- Plasma cell leukaemia
* >10% or plasmacytoma + urine/serum paraprotein + symptoms after this stage
What are the myeloma defining events i.e. numbers/%?
a) PC >60%
b) SFLC ratio >100 (invovled:uninvolved)
c) >1 focal bone lesion on MRI (>5mm)
What are the two main emergencies in MM?
Cord compression and hypercalcaemia
Which biologic may be used in MM kidney disease?
Bortezomib
Name two alkylators used for MM.
Melphalan
Cyclophosphamide
Name 2 steroids for MM.
Dexamethasone
Prednisolone
Name 2 immunomodulatory drugs for MM.
-omides e.g. lenalidomide (less toxic, more potent), thalidomide
Name 2 proteosome inhibitors for MM. Why are they useful?
Bortezomib
Carfilzomib
Ixazomib
Plasma cells proteosomes are crucial for removing misfolded proteins so if you remove this fucntion apoptosis of plasma cells will occur due to stress
What is the main treatment of MM for transplant eligible and ineligible patients?
Transplant-eligible:
- Induction: PI + IMiD + Dex (x4-6) (VRD, VTD) +/- daratumumab
- Autologous stem cell transplant
- +/- consolidation (x2)(VTD, VRD)
- Maintenance for 2 years with low dose lenalidomide
Transplant-ineligible:
- Lenalidomide + dex OR
- Bortezomib-cyclophosphamide-dex
Is MM curable?
No
How common is MGUS?
most common premalignant condition
1-3% of elderly affected
increases with age
Where are bone lesions usually found in MM? What type of imaging is used to detect these?
80% in PROXIMAL skeleton, spine, chest wall and pelvis
CT or FDG-PET or MRI (not XR)
What are the features of AL amyloidosis?
- nephrotic syndrome (70%) - proteinuria (not BJP), peripheral oedema
- unexplained heart failure - biggest prognostic factor
- sensory neuropathy
- abnormal liver function tests
- macroglossia
What are the complications of AL amyloid renal disease?
NephrOtic syndrome → proteinuria (but not BJP)
