MM Flashcards
Give a general overview of multiple myeloma
It is an expansion of the plasma cells - terminally differentiated B cells that secrete Ig and are effector cells of specific humoral immune response
It is the second most common haematopoietic malignancy and affects 4000 people every year in the UK it has a very poor median survival
There is increased incidence with age and the median age of diagnisis is 65-70
It is doubly common in black people and the second most common haem malignancy after lymphoma
What is the aetiology of multiple myeloma?
It is not know
Linked to some occupational exposures
There is a 3-4x increased risk in farmers, laxative users, radiologists
Asbestos, petroleum products, pesticides and rubber or wood products are thought to be a risk but really not much is know
What are the clinical featues of Multiple myeloma?
Bone pain - usually in the back from vertebral fractures Fatigue Pneumonia Paralysising cord compression CRAB Hypercalcaemia Renal Failure Anaemia Bone pain
What is the pre malignant condition for MM?
MGUS
Monoclonal gammopathy of undetermined significant
Smouldering myeloma
What is a plasma cell?
Terminally differentiated effector cell of the humoral immune response. It is a very mature fully differenitated b cell which makes antibodies
Describe b cell development
Antigens are recognised by the b cell receptor, this then activates and travels to the lymph node where it becomes somatically hypermutated. They develop similar but different antibodies before further maturing and becoming plasma blasts. The plasma cells then make the antibody
Describe how b cell activation can become dysregulated in MM
Activation of the b cell requires multiple differentiation proteins, these can become mutated and constitutively switche on which can lead to active cellular processes resulting in the features of myeloma
What are the key transcription factors that underly the coordinated differentiation process shown?
BCL-6 BLIMP1 CIITA ID3 PAX 4 xbp1
Briefly explain how Igs are able to have such heterogeneity
VDJ
Random bringing of D segments with J segments and middle DNA removed and deleted
V then added forming VDJ
This is the heavy chain
For the light chain the kappa region is attempted first, if this fails then they try the lamda chain, hence why more kappa than lamda in the blood
Class switching - switching elements in the DNA allow for class switching which can change the class
What are the main features of multiple myeloma?
Bone lesions - osteolytic bone lesions are visible on x ray
Kidney failure occurs as the light chains which are secreted are filtered by the kidney. The precipitate and clog up the kidneys this occures in the kidney tubules
Describe the morphology of a myeloma film
Clumped chromatin
Nucleus pushed to one side byt the golgi - this is because the golgi takes a bigger role in manufacturing Igs so is bigger - this is characterised by the light bit in the dark cytoplasm
Nucleus appears dense
What is the immunophenotype of myeloma?
Positive for: CD38 CD138 CD56/58 monotypic cytoplasmic Ig LC restricted
Negative for: CD19 CD20 and surface Ig
What are the cytogenetic analysis of MM?
The IgH chain is found on the telomeric region of chromosome 14, the mutations leading to MM therefore can be found to disturb this area t(4;14)(p16.3;q32): IGH-FGFR3-MMSET1 t(11;14)(q13;q32): IGH-Cyclin D1 t(6;14)(p21;q32): IGH-cyclin D3 t(14;16)(q32;q32): IGH-c-MAF
Del(13q) adverse prognosis
Describe what happens with the MMSET gene
MMSET interacts with proteins to activate oncogenic signalling pathways, this establishes causal roles for MMSET in driving cancer initiation development and survival
Which are the mutations with the worst prognosis?
Monosomy 13q (50% of MM)- worst prognosis t(4;14)(p16.3;q32) - FGFR3-MMSET1
