4. Plasma cell myeloma and amyloid, and monoclonal gammopathy of uncertain significance

Question 1

What is the definition of multiple myeloma?

Answer 1

A cancer of transformed plasma cells, terminally differentiated B cells, that secrete immunoglobulins and are effector cells of the specific humoral immune response.

Question 2

What are key features of myeloma?

Answer 2

• Cancer of monoclonal plasma cells
• Monoclonal plasma cells produce monoclonal immunoglobulin (paraprotein)
• Osteolytic bone lesions
• Anaemia
• Infections (due to deficient polyclonal response)
• Kidney failure

Question 3

What do the transformation of plasma cells in multiple myeloma result from?

Answer 3

The transformation results from a range of numeric and structural genetic aberrations that accumulate from a pre-malignant condition (monoclonal gammopathy of uncertain significance) to terminal progression

Question 4

What do the characteristic complications of multiple myeloma arise from?

Answer 4

Has characteristic complications arising from complex interactions with the tumour microenvironment (bone disease) and large-scale Ig secretion (renal failure)

Question 5

What is the 2nd most common haematopoietic malignancy?

Answer 5

Mutliple myeloma (after B cell lymphomas)

Question 6

What is the prognosis and median survival for multiple myeloma?

Answer 6

Myeloma is debilitating and incurable (median survival: 4-7 years). Novel treatments are improving survival rates.

Question 7

What cells are terminally differentiated effector cells of the specific humoral immune response?

Answer 7

Plasma cells

Question 8

What two things does the development of plasma cells involve?

Answer 8

Class switch recombination and transcriptional control

Question 9

Where do centroblasts (activated B cells) mature and what do they mature into?

Answer 9

Centroblasts (activated B cells) mature in lymph nodes where they are then stimulated by antigens and turn into memory B cells or into immature plasmablasts

Question 10

What regulates the conversion of the plasmablasts into plasma cells?

Answer 10

Various transcription factors

Question 11

What intracellular structure is very well expanded in mature plasma cells? And why?

Answer 11

Mature plasma cells have a very well expanded endoplasmic reticulum and golgi because that is where immunoglobulins are assembled, folded and modified before their secretion.

Question 12

Why are plasma cells the MOST secretory cells within the body?

Answer 12

Produce up to around 10,000 Ig per second

Question 13

What is the pathogenesis of multiple myeloma?

Answer 13

• Early on in a normal plasma cell (possible through infection/inflammation) errors will occur in the genome
• Genomic instability leads to translocations mostly at the immunoglobulin gene loci
• These initial changes will lead to a limited monoclonal accumulation of plasma cells
• At this point, it is harmless (about 5% of people > 75 years will have this)
• It is referred to as monoclonal gammopathy of uncertain significance (MGUS)
• 1% of people per year who have MGUS will acquire additional mutations (e.g. RAS mutations) which transforms these pre-malignant cells into fully malignant multiple myeloma cells

Question 14

What is monoclonal gammopathy?

Answer 14

Monoclonal = forming a clone which is derived asexually from a single individual or cell. Gammopathy = A gammopathy is an abnormal increase in immunoglobulin synthesis.

Question 15

The pre-malignant cells that have transformed into fully malignant multiple myeloma cells. This will then trigger a cascade of events in the tumour microenvironment such as:

Answer 15

Increased angiogenesis and increased bone resorption

Question 16

Why is it difficult to develop targeted therapies for multiple myeloma?

Answer 16

Because there are loads of different mutations that can cause it

Question 17

What clinical features suggest a diagnosis of multiple myeloma?

Answer 17

CRAB: Calcium elevated, renal impairment, anaemia, bone lesions - with monoclonal paraprotein.
NOTE: the clinical features are very important because a patient with MGUS will have a high monoclonal protein but without any clinical manifestations.

Question 18

Why are clinical features important in myeloma?

Answer 18

The clinical features are very important because a patient with MGUS will have a high monoclonal protein but without any clinical manifestations

Question 19

What are arbitrary cut-offs used to distinguish MGUS from myeloma based on?

Answer 19

Monoclonal serum protein, BM plasma cells and annual risk of progression to multiple myeloma

Question 20

How many cases of MM are diagnosed every year?

Answer 20

4500 cases diagnosed in the UK every year

Question 21

What is the median age of diagnosis for MM?

Answer 21

65-70 years

Question 22

What is the median survival of MM?

Answer 22

3-4 years

Question 23

What type of gammopathy is a normal response to infection?

Answer 23

Polyclonal gammopathy

Question 24

What is the difference between mature plasmacytic cells and immature plasmablastic cells on histology?

Answer 24

Mature Plasmacytic Cells: the nucleus is pushed to one side, there is clumped chromatin with a low nuclear-to-cytoplasmic ratio, large cytoplasm.

Immature Plasmablastic Cells (C and D): Myeloma cells have prominent nucleoli, reticular chromatin, and less abundant cytoplasm.

IMPORTANT: plasmablastic myelomas have a POOR prognosis.

Question 25

In immunohistochemistry, what are myeloma cells positive for?

Answer 25

Myeloma cells are POSITIVE for: CD138, CD38, CD56/58, monotypic cytoplasmic immunoglobulin, light chain restriction (either kappa or lambda positive)

Question 26

In immunohistochemistry, what are myeloma cells negative for?

Answer 26

CD19, CD20 (lymphomas and CLL are all CD20 positive), surface Ig

Question 27

What percentage of patients have lytic lesions in myeloma bone disease?

Answer 27

80-90% of patients have lytic lesions (or low bone density)

Question 28

What percentage have a pathological fracture at the time of diagnosis of multiple myeloma and what percentage have a pathological fracture at some point?

Answer 28

20% have a pathological fracture at the time of diagnosis, up to 60% have a pathological fracture at some point

Question 29

What are the impacts of myeloma bone disease?*

Answer 29

Pathological fractures, spinal cord compression can lead to paralysis, hypercalcaemia can lead to renal failure and bone pain (impacts on mobility, independence and quality of life)

Question 30

What imaging is used MM?

Answer 30

MRI, CT scans, PET scans

Question 31

Why is MRI used in MM? And what is an issue with MRI?

Answer 31

High sensitivity for bone marrow infiltration. Response monitoring is possible. EXPENSIVE.

Question 32

Why are CT scans used in MM?

Answer 32

Better at detecting very small lytic lesions, good for radiotherapy planning and higher radiation dose

Question 33

Why are PET scans used in MM?

Answer 33

Detects active disease, often combined with MRI

Question 34

What are the mechanisms of kidney injury in myeloma?

Answer 34

Immunoglobulin light chains activate inflammatory mediators in the proximal tubule epithelium. This leads to proximal tubule necrosis. Fanconi syndrome (renal tubule acidosis) occurs with light chain crystal deposition. Cast nephropathy.

Question 35

What is the treatment for multiple myeloma?

Answer 35

FOUR main domains of treatment: 1. classical cytostatic drugs (e.g. melphalan); 2. steroids (steroids are very toxic towards lymphocytes); 3. IMIDs (immunomodulators) e.g. thalidomide, lenalidomide, pomalidomide; 4. proteasome inhibitors.

Question 36

What is melphalan and when is it effective?

Answer 36

It is a cytostatic drug. This is an old-fashioned drug. Nitrogen-mustard type alkylating agent. Very effective when given as part of high-dose chemotherapy with an autologous stem cell transplant.

Question 37

What are some related compounds to melphalan?

Answer 37

Cyclophosphamide, chlorambucil and ifosphamide

Question 38

How does an autologous stem cell transplant work? Who is it suitable for?

Answer 38

- Only suitable for patients who are fit enough to undergo quite an intensive treatment. - Patients will receive about 6 months of induction treatment to reduce the burden of myeloma. - Then, stem cells are collected from the bone marrow, purified and frozen. - Patients will then receive a single shot of high-dose melphalan to kill myeloma cells (this is also toxic to the bone marrow) - Once the melphalan has been metabolised, the patient is re-infused with their own stem cells to rescue blood formation - Within 24 hours, these stem cells will find their way into the bone marrow and start to make new blood.

Question 39

What are more modern treatments for multiple myeloma and what are examples of them?

Answer 39

Protease inhibitors e.g. bortezomib and carfilzomib. They only tend to work in MM and not in other cancers

Question 40

How do proteosome inhibitors work?

Answer 40

TLDR: Proteasome inhibitors are a type of drug that prevents proteasomes, the garbage disposal system of the cell, from chewing up excess proteins. The proteins build up and kill the myeloma cells. - REMEMBER: plasma cells and myeloma cells are protein secretion factories with highly developed secretory apparatus - All proteins made by the cell which are either secreted or membrane-bound will be folded in the endoplasmic reticulum (ER). - If this process goes wrong, misfolded proteins will accumulate in the ER - These misfolded proteins are insoluble and non-functional and can cause fatal ER stress leading, ultimately, to cell death - So, in all of our cells, we have a proteasome - The proteasome regulates many cellular functions, but with regards to myeloma, its main function is that it fishes out the misfolded proteins and degrades them into amino acids. This is called ER-associated degradation (ERAD). - If you INHIBIT the proteasome, you will get an accumulation of misfolded proteins in the myeloma cells leading to myeloma cell death

Question 41

What was thalidomide previously used for?

Answer 41

Previously used as an anti-morning sickness drug which was found to be teratogenic

Question 42

What could thalidomide be used for?

Answer 42

However, thalidomide is very effective against myeloma cells. It targets the turnover of transcription factors that are particularly important for myeloma cell survival.