Haematology 11 - Plasma cell myeloma and Monoclonal Gammopathy of Uncertain Significance

Question 1

What immunoglobin is produced by myeloma cells?

Answer 1

One single type (eith IgG or IgA) which is known as paraprotein or M spike

Question 2

What are Bence Jones proteins?

Answer 2

Urine monoclonal free light chains

Question 3

What are the two most significant risk factors for myeloma?

Answer 3

Obesity
Black > causasians/ asians

Question 4

What % of plasma cells is there in symptomatic multiple myeloma?

Answer 4

>10%

Question 5

What is the most notable interaction of myeloma cells with the bone marrow micro-environment?

Answer 5

Produce RANK ligand which stimulates osteoclasts to cause bone resorptions

Question 6

What is the incidence of IgM myeloma?

Answer 6

Very rare (<1% of myelomas)

Question 7

What does CRAB stand for in MM?

Answer 7

Calcium (hypercalcaemia, >2.75)

Renal (creatinine >177/ eGFR <40)

Anaemia (<100/drop>20)

Bone disease (≥ lytic lesions)

Question 8

What is the most common and 2nd most common cytogenetic abnormality in myeloma?

Answer 8

1. Hyperdiploid karyotype
2. IgH gene rearrangement (14q23)

Question 9

What are the 3 2014 Myeloma Defining Events

Answer 9

BM plasma cells >60%
involved:uninvolved FLC ratio >100
>1 focal lesion on MRI

Question 10

Which part of the skeleton is affected by myeloma?

Answer 10

Proximal skeleton (spine, skull, knees)

Question 11

Where are myeloma patients most likely to feel pain?

Answer 11

Back, chest wall, pelvis

Question 12

What % of myeloma patients present with bone disease?

Answer 12

80%

Question 13

What scan is necessary to detect bone lesions in myeloma?

Answer 13

Whole body CT is first line (X ray obsolete for this use)
PET scan can also be used
Gold-standard = whole body diffusion-weighted MRI as this shows active vs treated disease

Ig and FLC studies +/- biopsy

Question 14

What are the 2 most likely emergency presentations of myeloma?

Answer 14

Cord compression

Hypercalcaemia

Question 15

How would you treat hypercalcaemia in MM?

Answer 15

Fluids, steroids, zolendronic acid

Question 16

What tests should be done to diagnose myeloma?

Answer 16

First:
Serum protein electrophoresis = monoclonal gammopathy
Serum free light chains (screening)
24h Bence Jones protein - monitoring

Next:
Bone marrow aspirate and biopsy for immunohistochemistry
FISH (for prognostic)

Question 17

What is the best way to treat cord compression in myeloma?

Answer 17

Dexamethosone
Radiotherapy

Question 18

What risk does myeloma present to the kidney?

Answer 18

Cast nephropathy - FLCs and Bence Jones proteinuria cause proximal tubule cell injury

overload of light chains → proximal tubule cells stress -> inflammatory response triggered -> light chains not reabsorbed → interact with uromodulin → casts formation

Question 19

How should myeloma kidney disease be treated in an emergency?

Answer 19

Bortezomib-based therapy

Question 20

How does myeloma affect immunity?

Answer 20

↓ serum normal Ig

BM micro-environment interference also impairs myeloid, T and NK cells

Chemo also impairs immune response

→ pneumonia, HZV, fungal

Question 21

Diagnostic criteria in MM

Answer 21

≥10% plasma cells in bone marrow or plasmacytoma + ≥1 CRAB or MDE

Automatically diagnostic if ≥60% plasma cells

Question 22

What is tested for in BM biopsy in suspected myeloma?

Answer 22

Immunohistochemistry for CD138 - specific for myeloma cells in BM

Question 23

What test can detect cytogenetic abnormalities of prognostic significance in myeloma?

Answer 23

FISH

Question 24

What are the 3 parameters in the international staging system for myeloma?

Answer 24

Serum beta microglobulin

Cytogenetic risk

LDH

Question 25

Recall 6 options for myeloma therapy

Answer 25

1. Alkylators (eg cyclophosphamide) 2. Steroids (eg dex + pred) 3. Thalidomide 4. Cereblon-binding drugs 5. Proteosome inhibitors 6. Therapeutic monocloncal Abs

Question 26

How do alkylators work?

Answer 26

immunomodulation and microenvironment

Question 27

How do steroids work in MM?

Answer 27

dex + pred ## Footnote Induce apoptosis in myeloma cells Strong synergy, part of almost all combination regimens

Question 28

How do proteasome inhibitors work in multiple myeloma

Answer 28

Proteosome remove misfolded proteins Accumulation of misfolded protein → endoplasmic reticulum stress and unfolded protein response → apoptosis

Question 29

How does thalidomide work in MM?

Answer 29

inhibits angiogenesis → established in combo w/ cyclophosphamide and dexamethasone

Question 30

How do cereblon-binding drugs work?

Answer 30

immunomodulatory drugs - decrease levels of IRF4 --\> decreased myc --\> myeloma cell death

Question 31

What do therapeutic monoclonal Abs target in MM?

Answer 31

Anti-CD38 (daratumumab)

Question 32

Treatment algorithm in MM

Answer 32

Question 33

What is the name of the premalignant condition that always precedes myeloma?

Answer 33

Monoclonal gammaopathy of uncertain significance (MGUS)

Question 34

What are the diagnostic criteria for MGUS?

Answer 34

Serum M-protein \<30g/L BM clonal plasma cells \<10% Asymptomatic

Question 35

What are the 3 risk factors for MGUS progression?

Answer 35

1. Non-IgG M spike 2. M spike \>15g/L 3. Abnormal serum free light chain ratio

Question 36

What is the difference between a pre-myeloma MGUS and pre-lymphoma MGUS?

Answer 36

Pre-myeloma: IgG/A-producing B cells Pre-lymphoma: IgM-producing B cells

Question 37

What is Waldenstrom’s-Lymphoplacytic lymphoma?

Answer 37

A lymphoplasmocytic lymphoma with IgM paraprotein - hyperviscosity symptoms

Question 38

What is smouldering myeloma?

Answer 38

Serum M-protein \>30g/L BM clonal plasma cells \>10% Asymptomatic Higher transformation rate than MGUS

Question 39

How does AL amyloidosis link to myeloma?

Answer 39

Misfolded FLCs aggregate into amyloid in target organs amyloidogenic potential of light chains \> amount

Question 40

Give 5 features of the clinical presentation of AL amyloidodis?

Answer 40

Nephrotic syndrome Unexplained heart failure Sensory neuropathy Abnormal liver function tests Macroglossia

Question 41

How does amyloidosis affect the kidney?

Answer 41

Nephrotic syndrome Proteinuria (NOT BJP), peripheral oedema

Question 42

How does amyloidosis affect the heart?

Answer 42

Raised NT-proBNP Abnormal echocardiography and cardiac MRI

Question 43

which lights chains are most commonly involved in AL amyloidosis?

Answer 43

Lambda light chain is involved in 60%

Question 44

How to diagnose amyloidosis?

Answer 44

Congo red stain + apple green birefringence under polarised light

Question 45

What is MGRS?

Answer 45

Monoclonal gammaopathy of Renal significance

Question 46

How is MGRS defined?

Answer 46

1. One or more kidney lesions caused by monoclonal immunoglobulin (Ig) 2. underlying B cell clone does not cause tumor complications or meet current hematological criteria for immediate specific therapy

Question 47

Which monoclonal antibody is used in myeloma treatment?

Answer 47

Anti-CD38 (daratumumab)

Question 48

What are the clinical effects of myeloma due to?

Answer 48

1. BM microenvironment interaction 2. Circulating paraprotein

Question 49

What is the cause of dinovoangiogenesis in myeloma?

Answer 49

CD34 expression on myeloma cells promotes angiogenesis

Question 50

What type of nephropathy does myeloma cause?

Answer 50

Cast nephropathy

Question 51

What are the first investigations to be done in suspected myeloma?

Answer 51

Serum protein electrophoresis Serum free light chains

Question 52

What condition can produce MGUS/ myelomas part of its progression?

Answer 52

AL amyloidosis

Question 53

What is multiple myelome a malignancy of?

Answer 53

plasma cells