Week 16 - Multiple Myeloma Flashcards
What are antibodies?
Immunoglobulins / gammaglobulins that are produced to respond to foreign structures (antigens)
What part of the antigen is recognised by the antibody?
Epitope
Broad role of T lymphocytes and B lymphocytes
T - cellular immunity B - humoral (serum) immunity
What is the main function of antibodies?
to neutralise and eliminate the Ags they recognise
What are the two forms of antibodies?
membrane bound on B cell surface Secreted (circulation, tissues, mucosa)
Describe activity of membrane bound Igs
On B cell surface, generally IgD and IgM I don’t think membrane bound antibodies have significant effector functions
Describe activity of secreted Igs
Circulate in blood, can access sites of pathogens Binding abilities AND effector functions May float around as monomer (IgG, IgA, IgE) dimer (IgA) or pentamer (IgM)
Structure of antibodies
two identical heavy chains + two identical light chains 5 types of heavy chains , 2 types of light chains
Main components of serum antibody concentrantion
IgG (5-16g/L); IgA (0.8-4g/L); IgM (0.5-2g/L)
What might you find in urine?
Light chain small enough to get into urine, useful diagnostic feature for some cancers if found in urine
Which immunoglobulin has 4 regions in its heavy chain? How many do the others have?
IgM 3
Types of epitopes (2)
Linear - adjacent amino acid residues COnformational epitopes - non-sequential
What are the effector functions of antibodies?
Neutralisation of microbes, toxins Opsonisation of microbes (marking them for phagocytosis) Activation of complement Antibody-dependent cell-mediated cytotoxicity (marking tumour cells for NK cells to find)
Describe hypervariable regions
Portion of antibody that will directly bind with antigen, this bit changes the most to make sure as many antigens as possible can be caught
Generally describe principles of generation of antibody diversity
During development - antibody genes are rearranged to make various alternatives (recombine using VDJ regions)
What is allelic exclusion?
One (heavy chain or light chain segment) is made first - if okay, the other one is made for the set
What is clonal selection?
Antibodies are waiting in the lymph tissues/organs - when an antigen shows up, the correct clone is multiplied to deal with it
Which classes of antibodies work best at different sites and against certain pathogen (blood, mucosa, parasites)
Blood - IgG, IgM Mucosa - IgA Parasites - IgE
Describe the principles of antibody isotype switching
xxx SLIDE 46 Variable region does NOT change Why would it switch? To preform different effector functions
What prompts B cells to start isotype switching?
T helper cells
Describe purpose / role of polymeric (pentameric IgM
Stronger and can bind to more antigens (10 sites)
What is the only antibody that can cross the plcenta to provide neonatal protection?
IgG
What is the main type of antibody in mucosal secretions? And where?
AgA - survives longer as dimer GI , resp, breast milk
Roles of IgE
Fighting parasites, allergic reactions (type 1 hypersensitivity such as asthma)
If you detect IgM what does it mean?
Early infection (first one to be produced)
What is myeloma?
Malignant tumour arising in bone marrow Monoclonal plasma cells
What is a plasma cell?
B-lymphocytes that release antibodies in response to antigens
How is myeloma diagnosed by pathologists?
Infiltration of bone marrow by abnormal number of plasma cells (more than 30%) Alongside other clinical evidence
How can you identify plasma cells (histopathology)?
‘Eccentric’ nucleus, with pale blob next to it
Describe kappa vs lambda staining
Identifying the light chains Using light stain restriction If the ratio is much different, you know if it is neoplastic condition rather than inflammation
Diagnostic criteria for plasma cell myeloma
Marrow plasmacytosis >30% Plasmacytoma on biopsy M-component - serum (IgG>3.5; IgA>A>2) and urine (1g/24hr of Bence Jones Protein) + minor criteria Lytic bone lesions Reduced normal immunoglobulins Major criteria but to lesser extent
How does plasma cell myeloma affect the body? (4)
Tumour eroding bone Replacement of the bone marrow (which results in anaemia, other issues) Kidney - build up of light chain which damages tubules Tissues - amyloid build up
Role of osteoblasts vs osteoclasts
Osteoblasts - make bone Osteoclasts - break bone down Cytokines disrupt the relationship between these components
What does the breakdown of bone result in?
Calcium released into the blood
Components of renal failure in myeloma
Free light chain form solid casts in nephron The free light chain can also form amyloid which can cause proteinuria and nephrotic syndrome Effects of hypercalcaemia (causes dehydration) Effects of NSAIDs taken for bony pain
What is amyloid? Why do they appear and what do they cause?
Amyloid is a collection of any protein which has assembled abnormally into B-pleated sheets. They become insoluble and build up in extracellular spaces leading to cell strangulation and death
What are the types of amyloid?
AL - Immunoglobulin light chain AA - Serum amyloid A (caused by chronic inflammation) AB - Amyloid prescursor protein (Alzheimer’s)
What is the diagnostic histopathological feature of amyloid?
Polarised light makes amyloid glow apple green Congo red stain will also turn it red but this is not diagnostic
Histopathological investigations for myeloma (2)
Bone marrow biopsy Serum electrophoresis
Describe major complications of myeloma (4)
Calcium high Renal dysfunction Anaemia Bone lesions (lytic)
What is MGUS?
Premalignant issue xxxxxxxxx
What is the progression through different stages of myeloma?
Premalignant MGUS Smouldering (asymptomatic) myeloma Symptomatic myeloma Relapsed and refractory myeloma Plasma cell leukaemia
What is a plasma cell?
Terminally differentiated B lymphoid cell
Most common types of antibody in myeloma (3)
IgG (60%) IgA (20-25%) Light chains only (15-20%) BUT 5% are non-secretory (can’t pick up anything in blood tests)
What tests are required to diagnose myeloma?
Hint there is something wrong - anaemia (so Hb), raised ESR Test - FBC, blood chemistry, electrophoresis, BM aspirate, Imaging (e-ray, CT, MRI, PET), genetic profiling
Diagnostic differences between MGUS, smoldering, and multiple myeloma
More or less than 10% plasma cells - between MGUS and myeloma end organ damage - between smoldering and multiple
Defining high risk smoldering and management
High risk smouldering myeloma with 70-80% chance of disease progression in 2 years 3 criteria S- BM >60% clonal plasma cells Li- SFLC ratio >100 M- 2 or more lesions on MRI
Outline the pain associated with myeloma (2)
Pain as a complication of disease - bone and nerve Pain as a complication of treatment
Outline imaging recommendations for patients with myeloma
Whole-body MRI scanning is first-line (BUT not often and option) Whole body low dose CT is next best Next option is skeletal survey (but plain x-rays not very sensitive)
What % of patients with myeloma have bone pain?
75%
Components of good history for bone pain
Quality of the pain Site of the pain Associated symptoms
Why do patients with multiple myeloma get pain?
Tumour volume Lytic lesions Pathological fractures Nerve root or spinal cord compression
Outline role of cytokines in myeloma pain
Cancer cells release cytokines sensitizing neurones. This can lead to up regulation of pain receptors, central sensitization in spinal cord and long-term potentiation
Outline the role of RANKL
Rank ligand inhibitors work directly to regulate osteoclasts - but not more effective than bisphosphonates so far and much more expensive
Treatment goals with multiple myeloma (5)
Induce remission, if possible Prevent immune suppression Prevent hematologic abnormalities (anemia, low platelets) Prevent end-organ damage Prevent fractures Maintain function, quality of life, control symptoms
Potential treatments for pain
Gabapentin, opiates / fentanyl, benzodiazepines
Treatment options for myeloma
PICTURE
Potential surgical interventions in myeloma (5)
Stabilising fractures Decompression of spinal cord Vertebroplasty Balloon kyphoplasty Radiotherapy
Role of bisphosphonates and how they work? What is a significant risk?
Role in treatment of malignant hypercalcaemia and bone pain Inhibitors of osteoclastic bone resorption Reduction in vertebral and non vertebral fractures in MRC myeloma VI trial Can contain nitrogen or not, they have high affinity to bone and then are ingested by osteoclsts BUT RISK OF significant jaw damage
Describe the relationship between myeloma and peripheral neuropathy - what factors make it more likely?
Can be disease related (amyloid, nerve root compression, etc.) or co-morbidities (diabetes / weight loss) or drug related (thalidomide / preosome inhibitors etc) Can cause sensory, motor or autonomic symptoms
What scale of patients with myeloma have peripheral neuropathy?
11-20% of newly diagnosed patients 83% in relapsed / refractory patients
