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YR5 Haematology > Multiple Myeloma and Related Plasma Cell Disorders > Flashcards

Multiple Myeloma and Related Plasma Cell Disorders Flashcards

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1
Q

Define multiple myeloma.

A

Malignancy of BM plasma cells, the terminally differentiated + immunoglobulin (Ig) secreting B cells.

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2
Q

List 4 actions of myeloma plasma cells.

A

Home + infiltrate BM

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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3
Q

7 epidemiological facts of multiple myeloma.

A

2nd most common haematological malignancy, 19th in all cancers.

Median age 67y.

Incidence increases with age.

1% <40y

M > F

Black > Caucasian + Asians.

Prevalence of myeloma increasing

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4
Q

Explain the aetiology/ risk factors of multiple myeloma.

A

Aetiology is unknown.

Risk factors:

Obesity

Age

Genetics: Incidence in black population + sporadic cases of familiar myeloma

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5
Q

What is multiple myeloma always preceeded by?

A

A premalignant condition:

Monoclonal Gammopathy of Uncertain Significance (MGUS)

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6
Q

Summarise the epidemiology of MGUS.

A

Incidence increases with age

Up to 1% - 3.5% in elderly

Average risk for progression: 1% annually​ (most don’t)

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7
Q

In MGUS, which Ig antibodies predispose for myeloma?

A

IgG

IgA

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8
Q

What does IgM MGUS progress to?

A

Lymphoma

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9
Q

What is MGUS associated with?

A

Osteoporosis

Thrombosis

Bacterial infection

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10
Q

What is the WHO diagnostic criteria for MGUS?

A

Serum M-protein <30g/L

BM 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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11
Q

What are risk factors for MGUS?

A

Non-IgG M-spike

M-spike >15g/L

Abnormal serum free light chain (FLC) ratio

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12
Q

Which 2 criteria define smouldering multiple myeloma?

A

Serum monoclonal protein (IgG or IgA) >30g/L or urinary monoclonal protein >500mg per 24h +/- clonal BM plasma cells 10-60%.

Absence of myeloma defining events or amyloidosis.

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13
Q

What are risk factors for smouldering multiple myeloma?

A

BM myeloma cells ≥20%

M-spike ≥20g/L

Serum FLC ratio ≥20

>2 RFs = high risk

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14
Q

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

A
  1. MGUS
  2. Smouldering myeloma
  3. Symptomatic myeloma
  4. Remitting-relapsing
  5. Refractory
  6. Plasma cell leukaemia
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15
Q

How does multiple myeloma affect the bone marrow microenvironment?

A

Bone destruction

Anaemia

Angiogenesis

Immunosuppressants + infections

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16
Q

How is multiple myeloma diagnosed?

A

≥10% plasma cells in BM

or

Plasmacytoma + ≥1 CRAB or MDE

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17
Q

What is CRAB?

A

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: >,1 bone lytic lesion on imaging

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18
Q

What is MDE?

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A

Myeloma Defining Events (MDE)

BM plasma cell pop. high ≥60%

Involved: Uninvolved FLC ratio >100

> 1 focal lesion in MRI (>5mm)

19
Q

What is the association between myeloma and bone disease?

Study These Flashcards
A

80% myeloma patients present with bone disease

20
Q

6 features of clinical presentation in multiple myeloma patients?

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A

Proximal skeleton

Back (spine), chest wall + pelvic pain

Osteolytic lesions, never osteoblastic

Osteopenia

Pathological fractures

Hypercalcaemia

21
Q

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

Study These Flashcards
A

Cord compression:

Dx + Tx within 24h

MRI scan

Ig + 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

22
Q

Define myeloma kidney disease.

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A

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

AKI resulting from myeloma.

23
Q

What are causes of myeloma kidney disease?

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A

Cast nephropathy is caused by high SFLC levels + Bence Jone proteinuria.

Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics.

20-50% AKI at dx.

2-4% of newly diagnosed require dialysis.

24
Q

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

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A

12% early death

Prolonged hospital stay + lethal infections

25
Why is multiple myeloma associated with immunodeficiency?
Immunoparesis: Low serum normal Igs Myeloid, T cells + NK cells impairment Chemotherapy impairs immune response Myeloma immune evasion
26
What is the diagnostic workup for multiple myeloma?
**Immunoglobulin studies:** Serum protein electrophoresis Serum FLC levels 24h Bence Jones protein **BM aspirate + biopsy:** IHC for CD138 **FISH analysis:** Should include at least high risk abnormalities **Flow cytometry immunophenotyping**
27
What are common target organs of AL amyloidosis?
Kidney Heart Liver Neuropathy
28
What are 5 signs and symptoms of AL amyloidosis?
Nephrotic syndrome 70%: Proteinuria (not BJP!), peripheral oedema Unexplained HF → determinant of prognosis: Raised NT-proBNP, Abnormal echocardiography + cardiac MRI Sensory neuropathy Abnormal LFTs Macroglossia
29
What is Monoclonal Gammopathy of Renal Significance (MGRS)?
Applies specifically to any B-cell clonal lymphoproliferation where there are: 1. \>,1 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.
30
What is the pathophysiology of MGRS?
Rare disease, several subtypes Demonstration of the involved monoclonal Ig or light chain possible in most cases Work up similar to myeloma Many require myeloma-type tx aiming to improve renal survival Many lose kidney function
31
Which drugs have been used for a long time in myeloma therapy?
**Cytostatic drugs: Melphalan, Cyclophosphamide** **Immunomodulatory drugs: Thalidomide, Lenalidomide** **Steroids: Dexamethasone + Prednisolone**
32
Why are proteasome inhibitors useful in multiple myeloma?
Myeloma cells are protein production factories- all proteins made folded in ER. Proteasome degrades misfolded protein Causes accumulation of misfolded protein, ER stress + apoptosis ER associated degradation (ERAD)
33
What are some proteasome inhibitors used in the treatment of myeloma?
**Bortezomib** Approved for first line or relapse IV or S/C Neuropathy is main toxicity **Carfilzomib** More potent than Bortezomib Approved in relapse IV only Thrombocytopenia, cardiotoxicity **Ixazomib** Approved in relapse, in combination Oral Favourable toxicity profile
34
Describe the pathogenesis of multiple myeloma
Primary event: Hyperdiploidy (60%) / IgH rearrangements Secondary event: KRAS, NRAS, MYC
35
Which is the most common cytogenetic abnormality in myeloma?
Hyperdiploid karyotype
36
How does AL amyloidosis arise?
MGUS or myeloma in background Misfolded SFLCs aggregate into amyloid fibrils in target organs Amyloidogenic potential of FLC more important than amount
37
How may Amyloid fibrils be recognised?
Stain with Congo Red Solid, non-branching + randomly arranged
38
Name a key histopathological myeloma marker
CD138
39
Name 2 anti-CD38 moAbs and state their MOA
Daratumumab Isatuximab Binds CD38 on MM cells Initiates complement cascade → cell death Binds CTL + Macrohages → cell death Crosslinking → Apoptosis
40
What type of response has the best prognosis, and thus is what treatment aims for?
Complete response, minimal residual disease negative (MDR -ve) Complete response alone is not enough, as MDR +ve patients have worse outcome
41
Name 3 emerging therapeutic agents entering myeloma standard of care
CAR T-cell therapy BiTE Immunoconjugates: brings together tumour cell + effector T cell, stimulates T cell to kill tumour cell
42
Why are steroids used in multiple myeloma?
Induce apoptosis in myeloma cells Strong synergy, part of almost all combination regimens
43
Describe the use of Melphalan in multiple myeloma
Autologous Haematopoietic Stem Cell Transplant 1. Stem cells harvested from blood + stored 2. High dose Melphalan used to kill myeloma cells (alkylating agent→X-links) 3. Re-infusion of stem cells to rescue blood formation
44
Describe the use of Thalidomide in multiple myeloma
Targets the turnover of transcription factors that are key to myeloma cell survival

YR5 Haematology (20 decks)

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