Multiple Myeloma and related plasma cell disorders Flashcards
Define multiple myeloma
Malignancy of bone marrow plasma cells, the terminally differentiated and immunoglobulin (Ig) secreting B cells
What is seen in myeloma causing plasma cells?
Home and infiltrate the bone marrow
May form bone expansile or soft tissue tumours: plasmacytomas
Produce a serum monoclonal IgG or IgA: paraprotein or M-spike
Produce excess of monoclonal serum free light chains
Bence Jones protein: urine monoclonal free light chains
What are the risk factors for multiple myeloma?
Obesity Age Men Black > caucasian and asian Genetics
What always precedes myeloma?
A premalignant condition: Monoclonal Gammopathy of Uncertain Significance (MGUS)
What is monoclonal gammopathy of uncertain significance?
Presence of monoclonal antibody paraprotein / M-protein in the blood or urine
What are the diagnostic criteria for MGUS?
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
What does IgG or IgA MGUS progress to?
Myeloma
What does IgM MGUS progress to?
Lymphoma
What other conditions are those with MGUS at risk of?
Osteoporosis
Thrombosis
Bacterial infection
Shorter life expectancy
What is the average risk of progression for MGUS?
1% annually
What is the risk stratification used for MGUS?
Mayo criteria - risk factors
Non-IgG M-spike
M-spike >15g/L
Abnormal serum free light chain (FLC) ratio
What is smouldering myeloma?
Pre-malignant disease for multiple myeloma
What criteria must be met for smouldering myeloma?
Serum monoclonal protein (IgG or IgA) >= 30g/L or urinary monoclonal protein >= 500mg per 24 hr and/or clonal bone marrow plasma cells 10-60
How does bone destruction occur in multiple myeloma?
Myeloma cells interact with bone marrow microenvironment
What is the result of bone destruction in multiple myeloma?
Destruction of bone leads to calcium in the blood and lytic lesions
What are the other results of the myeloma cells interacting with bone marrow microenvironment?
Angiogenesis
Anaemia
Immunosuppression and infections
What is the diagnostic criteria for multiple myeloma?
> 10% plasma cells in bone marrow or plasmacytoma >1 CRAB or MDE
What are the features of CRAB as a diagnostic indicator for multiple myeloma?
C: Hypercalcaemia - calcium >2.75mmol/L
R: Renal disease - creatinine >177umol/L or eGFR <40ml/min
A: Anaemia - Hb <100g/L or drop by 20g/L
B: bone disease - one or more bone lytic lesions in imaging
What are the 2014 Myeloma Defining Events (MDE)?
Bone marrow plasma cells >60%
Involved: uninvolved FLC ratio >100
>1 focal lesion in MRI (>5mm)
What is the clinical presentation of multiple myeloma bone disease?
Proximal skeleton Back (spine), chest wall and pelvic pain Osteolytic lesions, never osteoblastic Osteopenia Pathological fractures Hypercalcaemia
Why are plain XR films (skeletal surveys) obsolete in imaging myeloma bone disease?
Low sensitivity, require >30% bone mass loss
What imaging is used in myeloma bone disease?
Whole body CT scan low-dose
CT / FDG-PET scan
Whole-body diffusion- weighted MRI
What are the advantages of whole-body diffusion-weighted MRI?
Bone marrow cellularity
Active vs treated disease
Focal vs diffuse pattern of disease
Residual disease
What two emergenices are liked to myeloma?
Cord compression
Hypercalcaemia
What will happen if someone has suspected cord compression?
Diagnosis & treatment within 24 hours MRI scan Ig and FLC studies +/- biopsy Dexamethasone Radiotherapy Neurosurgery: rarely required Stabilise unstable spine MDT meeting
How does hypercalcaemia present?
Drowsiness Constipation Fatigue Muscle weakness AKI
How is hypercalcaemia managed?
Fluids
Bisphosphonates (zolendronic acid)
Steroids
What is the definition of myeloma kidney disease?
Serum creatinine >177umol/L (>2mg/dL) or eGFR <40ml/min (CDK-EPI)
What is the cause of myeloma kidney disease?
Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria
Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics
What is key in the management of myeloma kidney disease?
Should be treated as an emergency
Rehydration
Bortezomib-based therapy
Why are infections common in myeloma?
Complex humoural and cellular immunodeficiency Immunoparesis: low serum normal Igs Myeloid, T cells and NK cells impairment Chemotherapy impairs immune response Myeloma immune evasion
What are the areas needed in myeloma diagnostic workup?
Immunoglobulin studies
Bone marrow aspirate
FISH analysis
Flow cytometry immunophenotyping
What immunoglobulin studies are required as part of myeloma diagnostic workup?
Serum protein electrophoresis
Serum free light chain level
24h Bence Jones protein
What is looked for on bone marrow aspirate and biopsy in myeloma diagnostic workup?
IHC for CD138
What is International Staging System (ISS) stage I for myeloma?
serum β2-microglobulin <3.5mg/L, serum albumin ≥3.5g/dL
What is International Staging System (ISS) stage III for myeloma?
serum β2-microglobulin ≥5.5 mg/L
What are some features of AL Amyloidosis?
MGUS or myeloma in the background
Misfolded free light chains aggregate into amyloid fibrils in target organs
The amyloidogenic potential of light chains is more important that their amount
Amyloid fibrils stain with Congo Red, are solid, non-branching and randomly arranged with a diameter of 7-12nm
What light chain is involved in 60% of AL Amyloidosis?
Lambda
IGLV6-57 in kidney
IGLV1-44 in cardiac
What are the common targets of AL Amyloidosis?
Kidney
Heart
Liver
Neuropathy
What is the clinical presentation of AL Amyloidosis?
Nephrotic syndrome (proteinuria, peripheral oedema)
Unexplained heart failure –> determinant of prognosis
Sensory neuropathy
Abnormal LFTs
Macroglossia
What is monoclonal gammopathy of renal significance (MGRS)?
MGRS applies specifically to any B-cell clonal lymphoproliferation where there are:
One or more kidney lesions caused by mechanisms related to the produced monoclonal immunoglobulin (Ig) and
The underlying B cell clone does not cause tumour complications or meet current haematological criteria for immediate specific therapy
What is the pathology of MGRS?
Rare disease with several subtypes
Demonstration of 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
What classes of drugs are used in myeloma?
Immunomodulatory drugs
Proteasome inhibitors
What are the features of Bortezomib in myeloma therapy?
Currently approved for first line or relapse
IV or SC
Neuropathy is main toxicity
What are the features of Carflizomib in myeloma therapy?
More potent than Bortezomib
Approved in relapse
IV only
Thrombocytopenia, cardiotoxicity
What are the feature of Ixazomib in myeloma therapy?
Approved in relapse, in combination
Oral drug
Favourable toxicity profile
What is the first therapeutic moAb approved for multiple myeloma?
Daratumumab
What is the treatment algorithm in new diagnosis myeloma for transplant-eligible patients?
Induction: PI + IMid + Dex +/- Daratumumab (x4-6)
Autologous Stem Cell transplantation
+/- Consolidation x2
Maintenance for 2 years - low dose Lenalidomide
What is the treatment algorithm in new diagnosis myeloma in transplant-ineligible patients?
Lenalidomide + Dex OR Bortezomib - Cyclophosphamide = Dex OR Daratumumab - Bortezomib - Cyclophosphamide - Prednisolone
