Myeloma and Lymphoma Flashcards
Where does the process of B cell differentiation occur and what are the steps?
First stage in bone marrow (Ag independent stage)
Pro-B > Pre B > Immature B > Naïve B (outside of bone marrow)
Second stage is in the secondary lymphoid organs (antigen dependent) - mature naïve develop into proliferating blast cells
What is significant about B cell differentiation in terms of diagnosing myeloma?
The plasma cells acquire different antigens at different points of differentiation, these antigens can be detected - each antigen CD? acts as a marker for the different intermediate cells in B cell differentiation
How are immunoglobulins classified?
According to amino acid sequence in the constant region of the heavy chains - IgG, IgM, IgA, IgD, IgE
and the light chains - kappa or lambda
What 5 major are normally identified in protein electrophoresis of serum, which is of interest in terms of myeloma?
1) Serum albumin
2) Alpha-1 globulin
3) Alpha-2 globulin
4) Beta globulins
5) Gamma globulins - called the M spike, this is of interest in myeloma, a normal M spike of polyclonal immunoglobulin which is shallow with no obvious peaks
In myeloma, how would the gamma globulin peak appear on protein electrophoresis and why?
Rather than the shallow increase you would have one large peak reflecting the large scale production of monoclonal immunoglobulins - compared to the polyclonal production in a normal M spike
If an M spike is identified on protein electrophoresis, what is the next step?
Immunofixation - enables the detection and identification of type of monoclonal Ig
How is immunofixation carried out?
- Serum or urine is placed on a gel and electric current is applied to separate out the proteins
- Anti immunoglobulin antisera is added to each migration lane
- If the immunoglobulin is present, a complex is precipitated
What is myeloma?
An incurable malignant disorder of clonal plasma cells
What is annual incidence of myeloma?
60-70 per million in the Uk
What is the median age of presentation of myeloma?
70
What ethnicity is at greater risk of developing myeloma?
Afro-carribean higher risk compared with Caucasians
Myeloma is seen to be one of a spectrum of plasma cell dyscrasias - which 2 conditions lie before myeloma and which lies after in terms of severity?
1) MGUS - monoclonal gammopathy of undetermined significance
2) Asymptomatic/smouldering/indolent myeloma
3) Myeloma
4) Plasma cell leukaemia
What is significant about MGUS?
Its is now thought that most cases of myeloma are preceded by MGUS
Name 7 other plasma cell dyscrasias?
1) MGRS - monoclonal gammopathy of real significance
2) High-risk MGUS
3) Amyloidosis
4) Solitary plasmacytoma (with/without bone involvement)
5) Systemic AL amyloidosis
6) POEMS syndrome
7) Myeloma with adverse cellular features
What is solitary plasmacytoma?
Get a discrete mass of abnormal plasma cells which can be deposited in bones such as femur or humerus but on further investigation no myeloma can be found in the marrow
What is the IMWG diagnostic criteria for myeloma? 3
1) Clonal BM plasma cells >10% or biopsy proven bony or extramedullary plasmacytoma AND any one or more of
2) CRAB features
3) MDEs
What are CRAB features?
Symptoms because of myeloma C - hypercalcaemia R - renal insufficiency A - anaemia (plasma cell taking up too much room in the bone marrow) B - bone lesions
What are ‘myeloma defining events’?
Having a myeloma defining event is implication for asymptomatic/ smouldering myeloma cases - so more inclined to treat
Name the 3 ‘myeloma defining events’ as defined by the IMWG diagnostic criteria?
1) >60% of plasma cells on BM biopsy
2) SFLC ratio (serum free light chain measurement) >100g/L provided the absolute levels of the involvement of LC is >100mg/L
3) >1 focal lesion on MRI measuring >5mm
What percentage of myeloma patients have renal insufficiency at diagnosis?
20-25%
What percentage of myeloma patients have renal insufficiency at some point during their disease course?
50%
What percentage of myeloma patients will have persistent renal impairment despite therapy?
50%
What percentage of myeloma patients will require RRT (renal replacement therapy)?
2-12%
What is meant by external factors affecting the kidney in myeloma?
Factors separate to the myeloma which are making the kidneys worse which we can do something about
Name the 9 external factors affecting the kidney in myeloma?
1) Renal venous thrombosis
2) Bisphosphonates (used to treat hypercalcaemia which is usually due to myeloma)
3) ACE inhibitors
4) Type 1 cryoglobulinaemia
5) Dehydration
6) NSAIDs
7) CT contrast
8) Hyper viscosity - extra proteins produced by neoplastic cells make blood very viscous
9) Hypercalcaemia
What is the immediate management for AKI with suspected myeloma, why should it be treated immediately?
It is a medical emergency - ‘time = nephrons’
Immediate treatment = steroids
Following the administration of steroids what are the next 4 steps in the management of AKI with suspected myeloma?
1) Blood film
2) Electrophoresis
3) Immunofixation
4) Bone marrow biopsy with flow cytometry
What is intensive therapy used to manage myeloma?
4 cycles of chemo with VCD
Patient given GCSF to stimulate production of stem cells and increase levels in the peripheral blood
Patients stem cells are harvested from peripheral blood and frozen
Patients are given another large dose of chemotherapy
Patients serum then auto-replaced to help the patient get back to normal
In which patients is intensive therapy for myeloma used?
Those who are younger and fitter
What is the average number of months before remission after intensive therapy?
18 months
What is the treatment between intensive therapy and remission?
Cycles of RD chemo
Can bone marrow transplantation be used in managing myeloma?
Sometimes - but is associated with high mortality and remission still occurs
Name 3 newer agents to treat myeloma?
1) Daratumumab (antiCD138)
2) Carfilzomib (proteasome inhibitor)
3) Ixazomib (proteasome inhibitor)
Monoclonal Ab
What is non-intensive therapy used to treat myeloma, which patients is this used in?
Used in a lot of patients in their 60s/70s who have lots of other comorbidities to keep the myeloma under control and keep them out of hospital
5 rounds of chemo - CDTa
4 more rounds of chemo - VCD
RD chemo until disease progresses
What is the immediate therapy given in suspected myeloma?
Steroids
What are the 3 simple measures its important to follow in the treatment of myeloma?
1) Hydration
2) Avoid nephrotoxics
3) Chemotherapy (attenuated dosing)
What are the 3 IMWG diagnostic criteria for MGUS?
1) Serum M protein
Which sex is MGUS greater in?
Males
How is MGUS likely to present on bloods?
Hb, and Ca2+ normal
Creatinine maybe slightly raised
One type of IgG raised eg. IgG kappa
What is the prevalence of MGUS?
- 2% people more than 50
- 3% people more than 70
- 9% people more than 80
What is the risk of progression from MGUS to myeloma?
Majority progress to myeloma
What 3 other conditions do people with MGUS also progress to?
1) Waldenstrom’s macroglobulinaemia
2) Primary AL amyloidosis
3) Lymphoproliferative disorders
What 3 things increase the risk of progression from MGUS?
1) High vs low M protein (15g/L)
2) IgA/IgM vs IgG PP
3) Abnormal SFLC ratio vs normal
What is AL amyloidosis?
Amyloid light chain amyloidosis
Have a population of neoplastic plasma cells which secrete abnormal protein, these light chain fragments misfold and self aggregate to form beta-pleated fibrils which get deposited in different organs eg. kidneys, liver and heart
What is the incidence of AL amyloidosis?
600 new cases per year
What is a common presentation of AL amyloidosis?
Nephrotic range proteinuria - mainly albumin, small monoclonal light chain involvement
In addition to nephrotic range proteinuria, what are the 3 other possible clinical features of AL amyloidosis?
1) Cardiac and liver involvement - 30%
2) Peripheral neuropathy - 10%
3) ESRF (end stage renal failure) - 40%
When a patient presents with a neck mass, what are the 3 possible malignant causes and the 5 possible non-malignant causes?
Malignant: 1) Lymphoma 2) Chronic lymphocytic leukaemia 3) Metastatic cancer of the lung, breast and cervix Non malignant: 1) Infective (bacterial , viral, mycobacterial) 2) Inflammatory (sarcoidosis) 3) Lipoma 4) Fibroma 5) Haemangioma
What are the important further investigations when a patient presents with a neck mass (7 bloods, 3 imaging)?
Bloods: U&Es, FBC, LFT, Ca2+, LDL (if raised more suspicious of high grade lymphoma), Igs and protein electrophoresis
Imaging: CXR, US of neck lump, fine needle aspirate and/or core needle biopsy
What blood result would make you more suspicious of a high grade lymphoma in a patient presenting with a neck mass?
Raised LDL
What are the broad categories of lymphoma?
Hodgkin and non Hodgkin
What is follicular lymphoma?
Neoplastic disorder of lymphoid tissue
Type of non Hodgkin lymphoma characterised by slowly enlarging lymph nodes
Follicular lymphoma accounts for what percentage of all non Hodgkin lymphomas?
15%
How is the incidence of follicular lymphoma affected by age and sex?
No difference between sexes
Incidence in creases with age
What is the characteristic chromosomal change in follicular lymphoma, what effect does this have?
Translocation - t(14:18)
Brings the bcl2 protooncogene under the influence of the Ig heavy chain gene leading to overexpression of the bcl-2 protein, this confers a survival advantage to the neoplastic lymphoid cells be inhibiting apoptosis
What is the median survival and overall 5 year survival in follicular lymphoma?
Median survival = 8-10 years
Five year overall survival = 72-77%
Which index can be used in assessing prognosis in follicular lymphoma, what 5 parameters does it use?
Follicular International Prognostic Index (FLIPI)
1) Age >60 years
2) Ann harbor stage III or IV
3) LDL above the limit of normal at diagnosis
4) Hb
Using the FLIPI (follicular internation prognostic index) how does score affect prognosis?
If a patient has 4 or more prognostic factors than the 10 year survival rate it 36% compared with 71% for those with one or none
What characterises Hodgkins lymphoma?
The presence of Hodgkin-Reed Sternberg (HRS) cells within a cellular infiltrate of non malignant inflammatory cells
How are HRS (Hodgkin Reed Sternberg) cells neoplastic?
Fail to express Ig and evade apoptosis through a variety of methods eg. Activation of NKkB, incorporation of EBV and latent membrane proteins (LMP1 and LMP2)
What are the 4 classical classifications of lymphoma, what is it based on?
Based on appearance of biopsy Nodular lymphocyte is predominant Classifications: 1) Nodular sclerosis 2) Mixed cellularity 3) Mixed lymphocyte-rich 4) Lymphocyte depleted
How is lymphoma managed?
Chemo and radiotherapy with doses/number of courses depending on stage
Is lymphoma curable?
Yes a lot of people are cured
What is the percentage 5 year survival for lymphoma?
85%
The long term effects of lymphoma therapy are significant, name 4 significant long term effects?
1) Increased mortality still seen at >20 years post therapy
2) Pulmonary toxicity
3) CV disease
4) Secondary malignancies
