Multiple Myeloma, MGUS, Plasma Cell Flashcards
What Symptoms does Multiple Myeloma generally present with?
CRAB
- Calcium (high),
- Renal failure
- Anaemia,
- Bone lesions (osteoporosis, osteolytic lesions)
What cells are malignant in Multiple Myeloma?
Where are they usually located?
Long-lived Monoclonal plasma cells proliferating in Bone Marrow,
producing monoclonal antibodies (IgG, IgA) or Serum Free Light Chains
What is the epidemiology of Multiple Myeloma?
What is the prognosis?
- Old (67) (Middle-aged to elderly)
- incidence increases with age (3% prevalence in patients >50)
- Men>women
- Black>Caucasian and asian
- 30% 10 year survival (Average 5-7 years)
What is the aetiology of Multiple Myeloma?
Unknown, Risk Factors
- Obesity
- age
- genetics (black, familiar myeloma sporadic cases)
What is the abbreviation MGUS?
Monoclonal Gammopathy of Uncertatin significant
What are the diagnostic criteria for MGUS?
Premalignant condition, where
- Paraproteins: monoclonal immunoglobulins (IgG or IgA) detectable in serum < 3 g/dL
- AND <10% of the BM is monoclonal plasma cells
- AND NO no CRAB symtpoms
( or no evidence of other B-cell proliferative disorders)
What is the progression risk for MGUS to Mutliple Myeloma per year?
1-2%
What are risk factors that increase the risk of progression from MGUS to Multiple Myeloma?
Cumulative Risk for the following:
- Non-IgG M-spike
- M-spike >15g/L
- Abnormal Serum free light chain ratio
(M-spike = monoclonal spike on electrophoresis)
What is smouldering myeloma?
What are the diagnostic criteria?
Premalignant condition (between MGUS and MM) with NO CRAB symptoms and
- Monoclonal serum protein ≥ 30g/L
- BM plasma cells ≥ 10%
- Annual risk of progression to MM 10%
What is the progression rate of SMmouldering myeloma to Multiple Myeola within 2 years?
Up to 46% (if 2+ risk factors present)
What are the defyining Biomarkers of Multiple Myeloma?
Aka biomarkers as diagnostic criteria
- ≥ 60% clonal bone marrow plasma cells (or any if CRAB symprotms present)
- SFLC level ≥ 100 mg/L with an involved:uninvolved SFLC ratio ≥ 100
- > 1 focal skeletal lesion on MRI (≥ 5 mm in size)
What are the defyning clinical features of Multiple Myeloma?
- Any signs of organ damage (CRAB symtpoms)
- Calcium > 11 mg/dL or > 1 mg/dL above the ULN
- Renal insufficiency: GFR < 40 mL/min or serum creatinine > 2 mg/dL
- Anemia: Hb < 10 g/dL or more than 2 g/dL below the LLN
- Bone lesions: ≥ 1 osteolytic lesions on imaging
What are primary and secondary genetic events in the disease development of MM?
Usually
Primary Either
- Hyperdiploidy (60% of cases) (additional odd number chromosomes)
- IGH rearrangements (immunoglobulin heavy chains) (with chromosome 14)
Secondary:
Number of specifc mutations in TSG (e.g. p53) / pro-oncogenes
How does MM lead to Bone lesions?
Interaction of Plasma Cell-Osteoclast interaction
- production of osteoclastogenic factors (e.g. TNF alpha, IL-1, RANK-L) –> osteolytic lesions
How does MM cause Anaemia?
Due to bone Marrow infliltration by malignant cells and replacement of normal marrow
What criteria have to be met, to be diagnosed with Myeloma without any CRAB symtpoms?
People would develop MM within next 2 months
- > 60% Plasmacytes in BM or plasmaocytes
- Involved:uninvolved FLC ratio >100
- > 1 focal lesion of MRI >5mm
What are typicla features of Myeloma Bone disease?
Generally 80% of patients present with bone
- proximal skeleton (common spine, chest, pelvic pain)
- osteolytic (not osteoblastic lesions)
- continue
How is Myeloma Bone disease diagnosed?
- Whole body CT low dose (Xray now obsolete)
- FDG PET scan
- whole body diffusion weighted MRI (sensitive to residual treated disease)
What are the characteristics of Myeloma Kidney disease?
Due to overproduction and renal deposition of monoclonal immunoglobulins / light chains
- Serum creatinine >177 umol/l or eGFR <40
- AKI as reslt of myeloma
How does MM cause Renal disease?
- High serum free light chains and Bence Jones Protien (causing cast nephropathy)
- Also:hypercalcaemia contributing
What is the renal effects of high levels of Serum Free light chains?
Serum Free light chains can’t be abrobed –> high in Tubule –> SFLC bind to THP? protein presentt in kidney –> form blop
What is the management of Myeloma Kidney disease
Treat MM to reduce Serum free light chains:
Bortezombid (Proteasome inhibitor) based therapy
+ Acutely: reyhdration (but don’t fluid overload)
What investigations are done for the Diagnosis of Multiple Myeloma?
What results would you expect?
Immunoglobulin studies
- Serum proein elecrophoresis (dense, narrow band in “gamma” region)
- serum FLC levels
- 24h bence jones protein (urine)
Blood film
- rouleaux formation
BM aspirate + Biopsy
* IHC for CD138
FISH analysis (to exclude high risk variants)
Flow cytometroy
How is MM staged?
Revised 2-International Stageing system (ISS/ Durie-Salmon staging)
- Microglobulin levels and genetic high risk groups taken into consideration
What is the Relationship of Amyloidosis and MM?
MGUS and Myeloma can both cause Amyloisis (with production of musfolded free light chains)
What are the main target organs of Amyloidosis?
Can be any organ but most commonly
- Cardiac (Unexplained heart failure)
- Renal (Neprhotic syndrome (70%)
- Anything else (Sensory neuropathy, abnormal LFT, macroglossia etc.)
What is MGRS
Rare
Monclonal Gammopathy of renal signsificance
Pre-malignionant condittion where the SFLC produced cause some form of renal disease (treated like Myeloma with aim of renal survival)
WHat is a key cell surface marker for myeloma?
CD138
What is the diffference of AL and AA Amyloidosis?
AL: due to deposition and increased production of light chains (Myeloma)
AA: reactive due to chronic disease (inflammation, infection, malignancy)
What is the role of steroids in MM treatment?
Induces apoptosis in Myeloma Cells
Strong synergy (part of almost all other regimes)
Who is eligible for Stem cell transplantation in MM
Generally Fit patients <65
(auto-SCT when in remission of disease)
What is the aim of treatment of MM?
Generally disease free, however treatment is not curative usually (not minimal redisual disease) for best outcome
What is the first line treatment for Multiple Myeloma?
First line – Bortezomib (Protease inhibitor) + / - dexamethasone,
cyclophosphamide (alkylating agent)
lenalidomide (in conjunction with one other treatments and dexamethasone)
What additional proteins are most commonly produced in Multiple Myeloma?
Usually IgG
Other common:
IgA and Serum Free light chains
How would Amyloidosis be diagnosed?
AL: amyloidosis: serum free light chains will show abnormal kappa:lambda light chain ratio
Definitively diagnosed by biopsy (with congo-red stain showing apple-green birefringence)
