Multiple Myeloma Flashcards
What are the 6 key features of myeloma?
- Monoclonal PCs
- Paraprotein
- Osteolytic lesions
- Anaemia
- Infections
- Kidney failure
- What is multiple myeloma?
- What is transformation?
- Multiple myeloma is a cancer of the transformed plasma cells, terminally differentiated B cells that secrete Ig and are the effector cells of the specific humoral immune response
- Transformation results from a range of numeric and structural genetic aberrations that accumulate from a pre-malignant condition (MGUS) to terminal progression
What is the median survival of myeloma?
Median survival 4-7 years
Multiple myeloma is a plasma cell cancer. What is a plasma cell?
Plasma cells are the terminally differentiated effector cells of the specific humoral immune response
Describe plasma cell development
Encountering antigen drives a virgin B cell to generate a low-affinity plasma cell or stimulates its migration to a germinal centre. In the germinal centre, affinity maturation occurs and is mediated through two processes: somatic hypermutation and antigen selection. Subsequently, class switch recombination occurs, leading to the development of immunoglobulin (Ig) isotypes. Once this process is complete, the plasmablast leaves the germinal centre and migrates to the bone marrow where it becomes a long-lived plasma cell that produces antibody. The machinery that is necessary to generate these physiological DNA rearrangements can malfunction, leading to mutations in crucial oncogenes and tumour suppressor genes, and malignant change. Key challenges for a plasma cell include switching off cellular characteristics that are no longer required, such as cell cycling, activating programmes that are essential for antibody production, and undergoing apoptosis if they do not find a receptive niche in the bone marrow. Failure to complete these programmes correctly could potentially leave active cellular processes, which may result in the features of myeloma. The key transcription factors underlying this coordinated differentiation process are also shown. BCL-6, B cell lymphoma 6; BLIMP1, B lymphocyte-induced maturation protein 1; CIITA, MHC class II transactivator; ID3, DNA-binding protein inhibitor ID3; PAX5, paired box gene 5; XBP1, X box-binding protein 1.
What is the pathogenesis of multiple myeloma?
Pre-malignant MGUS
- Genetic instability occurs ot a normal cell
- Translocations at 14q32 (50%)
- Deletion of chromosome 13 (50%)
- Leads to monoclonal gammopathy of undetermined significance
- 1% per year there is an increase in damaged cells, and microenvironmental changes in bone marrow –> increased angiogenesis and increased bone resorption
Multiple myeloma
- A further mutation e.g.
- N-RAS (30%)
- K-RAS (40%)
- Potential secondary translocation
- These lead to the development of myeloma
Describe the common malignant transformations of plasma cells that lead to myeloma
- Multiple myeloma has complex heterogeneous cytogenetic abnormalities.
- Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB).
- 55–60% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease.
Describe the cellular wiring of a typical myeloma cell
P.S its awful so don’t worry
a | As malignant plasma cells accumulate in the bone marrow, positive cytokine- and cell adhesion-mediated feedback loops are established between the plasma cell and stromal cells that facilitate the growth of the myeloma clone. These feedback loops not only support the survival of the myeloma clone but also mediate drug resistance and constitute therapeutic targets.
b | Myeloma plasma cells produce copious amounts of immunoglobulin and, therefore, are heavily reliant on protein handling pathways including the unfolded protein response (UPR), proteasome, aggresome and autophagy pathways.
c | Cell surface antigens that could be targeted by therapeutic antibodies.
d | Translocations involving the immunoglobulin heavy chain locus (IGH@) result in partner gene overexpression, which affects epigenetic modifications and cell proliferation.
e | Numerous signalling pathways are constitutively activated and/or deregulated in myeloma, including PI3K, nuclear factor-κB (NF-κB), RAS–RAF–MAPK and Janus kinase (JAK)–signal transducer and activator of transcription (STAT). In addition, overexpression of MAF and MYC are important. The end results are the hallmarks of myeloma, which include abnormal plasma cell differentiation, deregulation of the cell cycle, decreased apoptosis and increased myeloma cell growth and survival. APRIL, a proliferation-inducing ligand (also known as TNFSF13); BAFF, B cell-activating factor (also known as TNFSF13B); BCL-6, B cell lymphoma 6; BCR, B cell receptor; BLIMP1, B lymphocyte-induced maturation protein 1; CAMDR, cell-adhesion-mediated drug resistance; CCND, cyclin D; CCR3, C-C chemokine receptor type 3; CDK, cyclin-dependent kinase; CDKi, CDK inhibitor; CS1, cleavage signal-1 protein; FGFR, fibroblast growth factor receptor; FKHR, forkhead in rhabdomyosarcoma (also known as FOXO1); GSK3, glycogen synthase kinase 3; HGF, hepatocyte growth factor; HM1.24, HM1.24 antigen (also known as BST2); HOXA9, homeobox A9; ICAM, intercellular adhesion molecule; IGF, insulin-like growth factor; IL-6, interleukin 6; IRE1α, inositol-requiring enzyme 1α; IRF4, interferon regulatory factor 4; ITGB, integrin-β; KDM, lysine demethylase; MLL, mixed-lineage leukaemia; MMSET, multiple myeloma SET domain; MUC1, mucin 1; PAX5, paired box gene 5; SDF1, stromal cell-derived factor 1; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; XBP1, X box-binding protein 1.
Describe the acronym CRAB for multiple myeloma
Calcium elevated
Renal impairment
Anaemia
Bone lesions
+ Monoclonal protein
Key findings in MM diagnosis
What are some signs and symptoms of Multiple myeloma?
- Back pain
- Abnormality on routine lad test
- Fatigue
- Acute renal failure
- Pneumonia
- Paralysis - spinal cord compression
What is MGUS?
MGUS = Monoclonal gammopathy of underdetermined significance
- No CRAB symptoms
- Monoclonal serum protein <30g/L
- BM plasma cells <10%
- Annual risk of progression to MM 1-2%
- Rare in young, increasing incidence with age (5% >70 years)
What are the demographics of myeloma?
- 4,500 new cases per year in the UK
- 15-20,000 people are living with myeloma in the UK
- 15% of blood cancers and 1% of cancers
- median age at diagnosis 65-70y
- median survival 3-4y (6-10y in patients fit for intensive tx)
What is the potential aetiology of myeloma?
- increased risk in farmers, laxative takers, cosmetologists, radiologists
- asbestos, petroleum products, pesticides, rubber/wood products
- High-dose radiation (>100cGy, 4-5x risk in Hiroshima/Nagasaki survivors)
- Chronic infection/inflammation (rheumatoid arthritis; viral – HHV8/HIV?)
How can monoclonal gammopathy be detected?
Serum protein electrophoresis
What do the images show?
A&B and C&D
A &B - Mature plasmcytic myeloma cells, with clumped chomatin, low-nuclear-tocytoplasmic ratio, abundant cytoplasm, rare nuclei
C and D - Immature plasmablastic myeloma cells with prominent nuceloli, reticular chromatin, less abundant cytoplasm
Describe cellular interactions in Myeloma bone disease
MM plasma cells activate osteoclast - increasing bone resorption and helps activate osteoclast activating factors - increasing the amount of osteoclasts and precursors
MM plasma cells inhibit osteoblasts and increase osteoblast inhibitory factors
Describe kidney injury in myeloma
- FLCs (free light chains) activate inflammatory mediators in the proximal tubule epithelium
- Proximal tubule necrosis
- Fanconi syndrome (renal tubule acidosis) with FLC crystal deposition.
- Cast nephropathy
Describe the action of Immune modulators (IMIDs) such as thalidomide and myeloma
