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

Summarise the function of myeloma 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 (κ or λ) serum free light chains

Bence-Jones protein: Urine monoclonal free light chains

Question 3

Summarise the epidemiology of multiple myeloma.

Answer 3

The second most common haematological malignancy, 19th in all cancers.

Median age 67 years.

Incidence increases with age.

Only 1% of patients are younger than 40 years.

Men > women • Black > Caucasian and Asians.

>17,600 people with myeloma live today in the UK.

Prevalence of myeloma in the community is increasing

Question 4

Explain the aetiology/risk factors of multiple myeloma.

Answer 4

Aetiology is unknown.

Risk factors:

• Obesity increases the risk for myeloma
• Age
• Genetics
• Incidence in black population
• Sporadic cases of familiar myeloma

Question 5

What is multiple myeloma always preceeded by?

Answer 5

A premalignant condition:

Monoclonal Gammopathy of Uncertain Significance (MGUS)

Question 6

Summarise the epidemiology of MGUS.

Answer 6

The most common (known) premalignant condition

Incidence increases with age

Up to 1% - 3.5% in elderly population

Average risk for progression: 1% annually​

Question 7

Which Ig antibodies predispose for myeloma?

Answer 7

IgG or IgA MGUS

Question 8

What does IgM MGUS progress to?

Answer 8

Lymphoma

Question 9

What is MGUS associated with?

Answer 9

Higher incidence of osteoporosis, thrombosis and bacterial infection compared to general population

Question 10

What is the WHO diagnostic criteria for MGUS?

Answer 10

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 11

What are risk factors for MGUS?

Answer 11

Non-IgG M-spike

M-spike >15g/L

Abnormal serum free light chain (FLC) ratio

Question 12

Define smouldering multiple myeloma.

Answer 12

Both criteria must be met:

• Serum monoclonal protein (IgG or IgA) >=30g/L or urinary monoclonal protein >=500mg per 24 hours and/or clonal bone marrow plasma cells 10-60%.
• Absence of myeloma defining events or amyloidosis.

Question 13

What are risk factors for smouldering multiple myeloma?

Answer 13

Bone marrow myeloma cells ≥20%

M-spike ≥20g/L

Serum FLC ratio ≥20

>=2 risk factors is high risk

Question 14

What is the general timecourse for multiple myelome and related plasma cell disorders?

Answer 14

MGUS > Smouldering myeloma > Symptomatic myeloma > Remitting-relapsing > Refractory > Plasma cell leukaemia

Question 15

How does multiple myeloma affect the bone marrow microenvironment?

Answer 15

Bone destruction

Anaemia

Angiogenesis

Immunosuppressants > infections

Question 16

How is multiple myeloma diagnosed?

Answer 16

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

Question 17

What is CRAB?

Answer 17

C: Hypercalcaemia: Calcium >2.75mmol/L

R: Renal disease: Creatinine >177μmol/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 18

What is MDE?

Answer 18

2014 Myeloma Defining Events (MDE)

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

Question 19

What is the association between myeloma and bone disease?

Answer 19

80% of myeloma patients present with bone disease

Question 20

What is the clinical presentation of multiple myeloma patients?

Answer 20

Proximal skeleton

Back (spine), chest wall and pelvic pain

Osteolytic lesions, never osteoblastic

Osteopenia

Pathological fractures

Hypercalcaemia

Question 21

What are emergencies associated with bone disease in multiple myeloma patients?

Answer 21

Cord compression:

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

Hypercalcaemia:

• Presents with drowsiness, constipation, fatigue, muscle weakness, AKI
• Fluids, steroids, zolendronic acid

Question 22

Define myeloma kidney disease.

Answer 22

Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI) – Acute kidney injury and result of myeloma.

Question 23

What are causes of myeloma kidney disease?

Answer 23

Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria.

Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics.

20-50% acute kidney injury at diagnosis.

2-4% of newly diagnosed patients will require dialysis.

25% develop renal insufficiency at relapse.

Question 24

What is the association with myeloma kidney disease and prognosis of multiple myeloma?

Answer 24

Patients with severe kidney disease (eGFR <30ml/min) have a much worse outcome.

Question 25

Why is multiple myeloma associated with immunodeficiency?

Answer 25

Immunoparesis: Low serum normal Igs

Myeloid, T cells and NK cells impairment

Chemotherapy impairs immune response

Myeloma immune evasion

Question 26

What is the diagnostic workup for multiple myeloma?

Answer 26

Immunoglobulin studies:

• Serum protein electrophoresis
• Serum free light chain levels
• 24h Bence Jones protein

Bone marrow aspirate and biopsy: IHC for CD138

FISH analysis: Should include at least high risk abnormalities

Flow cytometry immunophenotyping: Diagnosis

Question 27

What are common target organs of AL amyloidosis?

Answer 27

Kidney

Heart

Liver

Neuropathy

Question 28

What are signs and symptoms of AL amyloidosis?

Answer 28

Nephrotic syndrome (70%) – Proteinuria (not BJP!), peripheral oedema

Unexplained heart failure → determinant of prognosis – Raised NT-proBNP – Abnormal echocardiography and cardiac MRI

Sensory neuropathy

Abnormal liver function tests

Macroglossia

Question 29

What is Monoclonal Gammopathy of Renal Significance (MGRS)?

Answer 29

MGRS applies specifically to any B-cell clonal lymphoproliferation where there are:

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

Question 30

What is the pathophysiology of MGRS?

Answer 30

Rare disease, several subtypes

Demonstration of the 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 31

What can be used in myeloma therapy?

Answer 31

Melphalan

• Nitrogen mustard derivate, in use since the 1960’s
• Backbone of myeloma therapy until late 1990’s
• High-dose melphalan 200mg/m2 still in use in Autologous SCT

Cyclophosphamide

• Widely used in combination with steroids and/or other drugs
• Immunomodulation and microenvironment

Dexamethasone and Prednisolone

• Induce apoptosis in myeloma cells
• Strong synergy, part of almost all combination regimens

Question 32

Why are proteasome inhibitors useful in multiple myeloma?

Answer 32

Myeloma cells are protein production factories.

Proteasome is crucial in removing misfolded protein

Question 33

What are some proteasome inhibitors used in the treatment of myeloma?

Answer 33

Bortezomib – 2003

• Currently approved for first line or relapse
• IV or S/C use
• Neuropathy is main toxicity

Carfilzomib - 2012

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

Ixazomib - 2015

• Approved in relapse, in combination
• Oral drug
• Favourable toxicity profile