Multiple Myeloma and related plasma cell disorders

Question 1

Define multiple myeloma

Answer 1

Malignancy of bone marrow plasma cells, the terminally differentiated and immunoglobulin (Ig) secreting B cells

Question 2

What is seen in myeloma causing plasma cells?

Answer 2

Home and infiltrate the bone marrow
May form bone expansile or soft tissue tumours: plasmacytomas
Produce a serum monoclonal IgG or IgA: paraprotein or M-spike
Produce excess of monoclonal serum free light chains
Bence Jones protein: urine monoclonal free light chains

Question 3

What are the risk factors for multiple myeloma?

Answer 3

Obesity
Age
Men
Black > caucasian and asian 
Genetics

Question 4

What always precedes myeloma?

Answer 4

A premalignant condition: Monoclonal Gammopathy of Uncertain Significance (MGUS)

Question 5

What is monoclonal gammopathy of uncertain significance?

Answer 5

Presence of monoclonal antibody paraprotein / M-protein in the blood or urine

Question 6

What are the diagnostic criteria for MGUS?

Answer 6

Serum M-protein <30g/L
Bone marrow clonal plasma cells <10%
No lytic bone lesions
No myeloma-related organ or tissue impairment
No evidence of other B-cell proliferative disorder

Question 7

What does IgG or IgA MGUS progress to?

Answer 7

Myeloma

Question 8

What does IgM MGUS progress to?

Answer 8

Lymphoma

Question 9

What other conditions are those with MGUS at risk of?

Answer 9

Osteoporosis
Thrombosis
Bacterial infection
Shorter life expectancy

Question 10

What is the average risk of progression for MGUS?

Answer 10

1% annually

Question 11

What is the risk stratification used for MGUS?

Answer 11

Mayo criteria - risk factors
Non-IgG M-spike
M-spike >15g/L
Abnormal serum free light chain (FLC) ratio

Question 12

What is smouldering myeloma?

Answer 12

Pre-malignant disease for multiple myeloma

Question 13

What criteria must be met for smouldering myeloma?

Answer 13

Serum monoclonal protein (IgG or IgA) >= 30g/L or urinary monoclonal protein >= 500mg per 24 hr and/or clonal bone marrow plasma cells 10-60

Question 14

How does bone destruction occur in multiple myeloma?

Answer 14

Myeloma cells interact with bone marrow microenvironment

Question 15

What is the result of bone destruction in multiple myeloma?

Answer 15

Destruction of bone leads to calcium in the blood and lytic lesions

Question 16

What are the other results of the myeloma cells interacting with bone marrow microenvironment?

Answer 16

Angiogenesis
Anaemia
Immunosuppression and infections

Question 17

What is the diagnostic criteria for multiple myeloma?

Answer 17

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

Question 18

What are the features of CRAB as a diagnostic indicator for multiple myeloma?

Answer 18

C: Hypercalcaemia - calcium >2.75mmol/L
R: Renal disease - creatinine >177umol/L or eGFR <40ml/min
A: Anaemia - Hb <100g/L or drop by 20g/L
B: bone disease - one or more bone lytic lesions in imaging

Question 19

What are the 2014 Myeloma Defining Events (MDE)?

Answer 19

Bone marrow plasma cells >60%
Involved: uninvolved FLC ratio >100
>1 focal lesion in MRI (>5mm)

Question 20

What is the clinical presentation of multiple myeloma bone disease?

Answer 20

Proximal skeleton
Back (spine), chest wall and pelvic pain
Osteolytic lesions, never osteoblastic
Osteopenia
Pathological fractures
Hypercalcaemia

Question 21

Why are plain XR films (skeletal surveys) obsolete in imaging myeloma bone disease?

Answer 21

Low sensitivity, require >30% bone mass loss

Question 22

What imaging is used in myeloma bone disease?

Answer 22

Whole body CT scan low-dose
CT / FDG-PET scan
Whole-body diffusion- weighted MRI

Question 23

What are the advantages of whole-body diffusion-weighted MRI?

Answer 23

Bone marrow cellularity
Active vs treated disease
Focal vs diffuse pattern of disease
Residual disease

Question 24

What two emergenices are liked to myeloma?

Answer 24

Cord compression

Hypercalcaemia

Question 25

What will happen if someone has suspected cord compression?

Answer 25

``` Diagnosis & treatment within 24 hours MRI scan Ig and FLC studies +/- biopsy Dexamethasone Radiotherapy Neurosurgery: rarely required Stabilise unstable spine MDT meeting ```

Question 26

How does hypercalcaemia present?

Answer 26

``` Drowsiness Constipation Fatigue Muscle weakness AKI ```

Question 27

How is hypercalcaemia managed?

Answer 27

Fluids Bisphosphonates (zolendronic acid) Steroids

Question 28

What is the definition of myeloma kidney disease?

Answer 28

Serum creatinine >177umol/L (>2mg/dL) or eGFR <40ml/min (CDK-EPI)

Question 29

What is the cause of myeloma kidney disease?

Answer 29

Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics

Question 30

What is key in the management of myeloma kidney disease?

Answer 30

Should be treated as an emergency Rehydration Bortezomib-based therapy

Question 31

Why are infections common in myeloma?

Answer 31

``` Complex humoural and cellular immunodeficiency Immunoparesis: low serum normal Igs Myeloid, T cells and NK cells impairment Chemotherapy impairs immune response Myeloma immune evasion ```

Question 32

What are the areas needed in myeloma diagnostic workup?

Answer 32

Immunoglobulin studies Bone marrow aspirate FISH analysis Flow cytometry immunophenotyping

Question 33

What immunoglobulin studies are required as part of myeloma diagnostic workup?

Answer 33

Serum protein electrophoresis Serum free light chain level 24h Bence Jones protein

Question 34

What is looked for on bone marrow aspirate and biopsy in myeloma diagnostic workup?

Answer 34

IHC for CD138

Question 35

What is International Staging System (ISS) stage I for myeloma?

Answer 35

serum β2-microglobulin <3.5mg/L, serum albumin ≥3.5g/dL

Question 36

What is International Staging System (ISS) stage III for myeloma?

Answer 36

serum β2-microglobulin ≥5.5 mg/L

Question 37

What are some features of AL Amyloidosis?

Answer 37

MGUS or myeloma in the background Misfolded free light chains aggregate into amyloid fibrils in target organs The amyloidogenic potential of light chains is more important that their amount Amyloid fibrils stain with Congo Red, are solid, non-branching and randomly arranged with a diameter of 7-12nm

Question 38

What light chain is involved in 60% of AL Amyloidosis?

Answer 38

Lambda IGLV6-57 in kidney IGLV1-44 in cardiac

Question 39

What are the common targets of AL Amyloidosis?

Answer 39

Kidney Heart Liver Neuropathy

Question 40

What is the clinical presentation of AL Amyloidosis?

Answer 40

Nephrotic syndrome (proteinuria, peripheral oedema) Unexplained heart failure --> determinant of prognosis Sensory neuropathy Abnormal LFTs Macroglossia

Question 41

What is monoclonal gammopathy of renal significance (MGRS)?

Answer 41

MGRS applies specifically to any B-cell clonal lymphoproliferation where there are: One or more kidney lesions caused by mechanisms related to the produced monoclonal immunoglobulin (Ig) and The underlying B cell clone does not cause tumour complications or meet current haematological criteria for immediate specific therapy

Question 42

What is the pathology of MGRS?

Answer 42

Rare disease with several subtypes Demonstration of involved monoclonal Ig or light chain is possible in most cases Work up similar to myeloma Many patients will require myeloma-type treatment aiming to renal survival

Question 43

What classes of drugs are used in myeloma?

Answer 43

Immunomodulatory drugs | Proteasome inhibitors

Question 44

What are the features of Bortezomib in myeloma therapy?

Answer 44

Currently approved for first line or relapse IV or SC Neuropathy is main toxicity

Question 45

What are the features of Carflizomib in myeloma therapy?

Answer 45

More potent than Bortezomib Approved in relapse IV only Thrombocytopenia, cardiotoxicity

Question 46

What are the feature of Ixazomib in myeloma therapy?

Answer 46

Approved in relapse, in combination Oral drug Favourable toxicity profile

Question 47

What is the first therapeutic moAb approved for multiple myeloma?

Answer 47

Daratumumab

Question 48

What is the treatment algorithm in new diagnosis myeloma for transplant-eligible patients?

Answer 48

Induction: PI + IMid + Dex +/- Daratumumab (x4-6) Autologous Stem Cell transplantation +/- Consolidation x2 Maintenance for 2 years - low dose Lenalidomide

Question 49

What is the treatment algorithm in new diagnosis myeloma in transplant-ineligible patients?

Answer 49

``` Lenalidomide + Dex OR Bortezomib - Cyclophosphamide = Dex OR Daratumumab - Bortezomib - Cyclophosphamide - Prednisolone ```