Multiple Myeloma and Related Plasma Cell Disorders Flashcards by Kat Qiao

Define multiple myeloma.

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

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Summarise the function of myeloma plasma cells.

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

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Summarise the epidemiology of multiple myeloma.

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

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Explain the aetiology/risk factors of multiple myeloma.

Aetiology is unknown.

Risk factors:

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

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What is multiple myeloma always preceeded by?

A premalignant condition:

Monoclonal Gammopathy of Uncertain Significance (MGUS)

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Summarise the epidemiology of MGUS.

The most common (known) premalignant condition

Incidence increases with age

Up to 1% - 3.5% in elderly population

Average risk for progression: 1% annually

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Which Ig antibodies predispose for myeloma?

IgG or IgA MGUS

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What does IgM MGUS progress to?

Lymphoma

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What is MGUS associated with?

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

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What is the WHO diagnostic criteria for MGUS?

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

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What are risk factors for MGUS?

Non-IgG M-spike

M-spike >15g/L

Abnormal serum free light chain (FLC) ratio

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Define smouldering multiple myeloma.

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.

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What are risk factors for smouldering multiple myeloma?

Bone marrow myeloma cells ≥20%

M-spike ≥20g/L

Serum FLC ratio ≥20

>=2 risk factors is high risk

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

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

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How does multiple myeloma affect the bone marrow microenvironment?

Bone destruction

Anaemia

Angiogenesis

Immunosuppressants > infections

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How is multiple myeloma diagnosed?

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

What is CRAB?

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

What is MDE?

2014 Myeloma Defining Events (MDE)

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

What is the association between myeloma and bone disease?

80% of myeloma patients present with bone disease

What is the clinical presentation of multiple myeloma patients?

Proximal skeleton

Back (spine), chest wall and pelvic pain

Osteolytic lesions, never osteoblastic

Osteopenia

Pathological fractures

Hypercalcaemia

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

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

Define myeloma kidney disease.

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

What are causes of myeloma kidney disease?

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.

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

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

Why is multiple myeloma associated with immunodeficiency?

**Immunoparesis:** Low serum normal Igs Myeloid, T cells and NK cells impairment Chemotherapy impairs immune response Myeloma immune evasion

What is the diagnostic workup for multiple myeloma?

**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

What are common target organs of AL amyloidosis?

Kidney Heart Liver Neuropathy

What are signs and symptoms of AL amyloidosis?

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

What is Monoclonal Gammopathy of Renal Significance (MGRS)?

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.

What is the pathophysiology of MGRS?

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

What can be used in myeloma therapy?

**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

Why are proteasome inhibitors useful in multiple myeloma?

Myeloma cells are protein production factories. Proteasome is crucial in removing misfolded protein

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

**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