Haem 4 – Plasma Cell Myeloma & amyloid and Monoclonal gammopathy of uncertain significance

Question 1

What do multiple myeloma cells produce?

Answer 1

• Produce a serum monoclonal IgG or IgA (paraprotein or M spike)
• Produce excess of monoclonal (κ or λ) serum free light chains (FLC)
• Bence Jones protein – urine monoclonal FLC

Question 2

Myeloma is always preceded by

Answer 2

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

Question 3

MGUS

IgG
IgA
IgM

MGUS is a premalignant condition resulting in…

Answer 3

• IgA or IgG MGUS  myeloma
• IgM MGUS  lymphoma

(MGUS - presence of monoclonal immunoglobulin in the blood or urine)

Question 4

MGUS diagnostic criteria

Answer 4

• 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
• No CRAB criteria

Question 5

Poor prognostic indicators in MGUS

Answer 5

• Non-IgG M-spike
• M-spike >15g/L
• Abnormal serum FLC ratio

Question 6

Which statement is not correct?
Myeloma incidence peaks at 84 years of age
Most individuals with MGUS will develop myeloma
Myeloma is always preceded by MGUS
IgM myeloma is rare

Answer 6

MGUS will develop myeloma (actually only about 1% will develowp myeloma)

Question 7

Which condition has the highest risk of developing symptomatic disease/progressing to multiple myeloma, MGUS or smouldering myeloma?

Answer 7

smouldering myeloma

Question 8

Diagnosis of smouldering myeloma

Answer 8

• Serum monoclonal protein (IgG or IgA) >=30 g/L or
• urinary monoclonal protein >500mg/24h and/or
• BM plasma cells >=10%
• Absence of myeloma defining events or amyloidosis
• No CRAB features

Question 9

Poor prognostic factors in smouldering myeloma and maagement

Answer 9

• Bone marrow myeloma cells >20%
• M-spike >20g/L
• Serum FLC ratio >20

Low + intermediate risk – observation
High risk (>2 factors) – treatment

Question 10

events in MM

Answer 10

• Hyperdiploidy (60%) – additional odd number Chr

•	IGH (immunoglobulin heavy chain) rearrangements (Chr 14q32)
o	T(11;14) IGH/CCND1
o	T(4;14) IGH/FGFR3
o	T(14;16) IGH/MAF

• Primary events present in MGUS, smouldering myeloma and MM but are not enough to drive disease into symptomatic disease
• Secondary events needed to push disease into symptomatic stage

Question 11

Common secondary events in MM

Answer 11

• KRAS, NRAS
• T(8;14) IGH/MYC
• 1q gain, 1p del
• Del 17p (TP53)
• 13-/del 13q
• Primary events present in MGUS, smouldering myeloma and MM but are not enough to drive disease into symptomatic disease
• Secondary events needed to push disease into symptomatic stage

Question 12

Pathogenesis of MM

Answer 12

• Angiogenesis – CD34 staining for new vessel
• Immunosuppression and infections
• Anaemia
• Bone destruction

Question 13

MM diagnostic criteria

Answer 13

• >10% plasma cells in bone marrow or plasmacytoma

and >1 CRAB or MDE

Question 14

CRAB

Answer 14

• Calcium >2.75 mmol/L – thirst, moans, groans, stones, bones

• Renal disease (+ amyloidosis + nephrotic syndrome)
o Cr >177 μmol/L or eGFR <40 ml/min

• Anaemia (+pancytopenia)
o Hb <100g/L or drop by 20g/L

• Bone disease – pain, osteoporosis, osteolytic lesions, fractures e.g. wedge compression, pepper pot skull
o >=1 bone lytic lesions in imaging

• + hyperviscosity syndrome

Question 15

MDE (myeloma defining events)

Answer 15

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

Question 16

MM ix

Answer 16

• Immunoglobulin studies
o Serum protein electrophoresis
o Serum FLC levels – more sensitive
o 24h Bence Jones protein in urine

• BM aspirate and biopsy
o IHC for CD138
o Rouleaux on blood film
o >10% plasma cells in BM

• ESR very high

•	Look for CRAB symptoms
o	Bone profile to check calcium
o	U+Es for renal function 
o	FBC for anaemia
o	Low dose CT body/MRI whole body to look for bony lesions 

• FISH analysis
o Should include at least high-risk abnormalities

•	Flow cytometry immunophenotyping
o	Diagnosis
o	MRD (minimal residual disease)

Question 17

Hypercalcaemia symptoms + mx

Answer 17

o Stones, Bones, moans, groans
 stones - renal effects - polyuria, thirst, nephrocalcinosis, renal coli, AKI, chronic renal failure
 bones - osteitis fibrosa cystica
 CNS effects - fatigue, impaired concentration, altered mentation, confusion, depression, seizures, comma (>3mmol/L)
 GI effects - pancreatitis, anorexia, dyspepsia, nausea, constipation
 Muscle weakness

o Fluids, steroids, zolendronic acid

Question 18

Cord compression in MM mx

Answer 18

can be caused by a soft tissue mass or fractured bone

o Dx + tx within 24h

o MRI scan

o Stabilise unstable spine
o Dexamethasone
o Radiotherapy
 (MM very sensitive to dexamethasone + radiotherapy)

o Ig + FLC studies +/- biopsy

Question 19

MM kidney disease definition

Answer 19

• Serum creatinine >177μmol/L (>2mg/dL)

or eGFR <40ml/min

Question 20

Cause of myeloma kidney disease + mx

Answer 20

• Cast nephropathy
o Main cause of myeloma kidney disease
o High serum FLC
o Bence Jones proteinuria

• Hypercalcaemia, Loop diuretics, infection, dehydration, nephrotoxics
o Nephrotoxic or renal excreted myeloma drugs e.g. zolendronic acid, lenalidomide

• Myeloma kidney disease should be treated as an emergency – hydration
• Bortezomib-based therapy

Question 21

Mechanism of FLC acute kidney injury

Answer 21

Proximal tubule cell injury & myeloma cast nephropathy

Question 22

What is Monoclonal Gammopathy of renal significance (MGRS) and how is it managed

Answer 22

• Applies specifically to any B-cell clonal lymphoproliferation where there are

o >=1 kidney lesions cause by mechanisms related to the produced monoclonal Ig and

o The underlying B cell clone does not cause tumour complications or meet current haematological criteria for immediate specific therapy

• Mx – most patients will require myeloma-type treatment aiming to renal survival (Treat with myeloma type treatments to save the kidneys)

Question 23

What causes AL amyloidosis in MGUS / smouldering myeloma/ MM

Answer 23

Misfolded FLC aggregate into amyloid fibrils in target organs
NOT caused by chronic inflammation

•	Lambda light chain is involved in 60%
o	IGLV6-57 in kidney - nephrotic syndrome
	Proteinuria 
	Not BJP
	Peripheral oedema

o IGLV1-44 in cardiac
 Unexplained heart failure – check serum FLC

Other sx - sensory neuropathy, abnormal LFTs, macroglossia, erectile dysfunction, diarrhoea, carpal tunnel syndrome, peripheral neuropathy, HF, RF

Congo red stain –> apple green birefringence

Question 24

surface marker for MM

Answer 24

CD138

plasma cell marker

Question 25

How does MM cause immunodeficiency and infections?

Answer 25

• MM can cause immunodeficiency as it can damage all parts of the immune system o Immunoparesis – low serum immunoglobulins o Myeloid, T cell, NK cell impairment o Chemotherapy – impairs immune response o Myeloma immune evasion • Chest infections (gram +ve, later gram -ve) • Fungal infections (not that common but happen in later stages (steroids + neutropenia)) • Viral infections are common (herpes zoster reactivation)

Question 26

• Cytogenetic abnormalities defining high risk in MM

Answer 26

``` o Del(17p) o T(4;14) o T(14;16) o IGH/FGFR3 o IGH/MAF ```

Question 27

First line mx in MM

Answer 27

- Bortezomib (proteosome inhibitor) +/- - Dexamethasone - Cyclophosphamide - Lenalidomide * Supportive for CRAB symptoms incl. bisphosphonates * When in remission – auto-SCT

Question 28

Relapsed MM mx

Answer 28

Dexamethasone Cyclophosphamide Thalidomide (inhibits angiogenesis) or Daratumumab monotherapy

Question 29

Why are proteosome inhibitors helpful in MM?

Answer 29

o Myeloma cells are protein production factories, have a very advanced golgi apparatus system o Proteosome is crucial in removing misfolded protein  Proteosome inhibition  Accumulation of misfolded protein  endoplasmic reticulum stress and unfolded protein response  apoptosis of cell o Alteration of NF-κB pathway

Question 30

Give 3 examples of proteosome inhibitors used in MM Indications Route of administration SE

Answer 30

Bortezomib - 1st line or relapse - IV, SC - SE - neuropathy Carfilzomib - Relapse - IV - SE - cardiotoxicity, thrombocytopena Ixazomib - Relapse - PO - Favourable toxicity profile

Question 31

Which therapeutic monoclonal antibodies can be used in MM

Answer 31

Anti-CD38 Daratumumab Isatuximab

Question 32

How does daratumumab work

Answer 32

 Induction of CDC (complement dependent cytotoxicity)  Modulation of enzymatic activation  Apoptosis after cross-linking  Induction of ADCC an ADCP (antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis)

Question 33

MM treatment in transplant eligible patents

Answer 33

Fit and typically <65 y/o • Induction – (Proteosome inhibitor + Immunomodulatory drugs + Dex) x4-6 +/- Daratumumab o VTD – Velcade (bortezomib) + Thalidomide + Dexamethasone o VRD – Velcade (bortezomib) + Revlimid (lenalidomide) + Dexamethasone +/- daratumumab • Autologous SCT • +/- consolidation x2 o VTD o VRD • Maintenance for 2 years o Low dose lenalidomide

Question 34

MM treatment in transplant ineligible patents

Answer 34

* Lenalidomide + Dex or * Bortezomib + Cyclophosphamide + Dex or * Daratumumab + Bortezomib + Cyclophosphamide + Prednisolone

Question 35

What blood tests should you order If there are raised globulins?

Answer 35

request serum protein electrophoresis + serum FLC

Question 36

MGUS vs Smouldering myeloma vs MM ``` M spike BM CRAB Organ damage Significance ```

Answer 36

M spike MGUS - <30g/l Smouldering myeloma - >=30 g/l MM - >30g/l, or serum FLC ratio >100 BM MGUS - <10% clonal plasma cells Smouldering myeloma- >=10% clonal plasma cells MM - any clonal plasma cell population, automatically diagnostic if >=60% plasma cells CRAB MGUS - none Smouldering myeloma - none MM - yes Organ damage MGUS - none Smouldering myeloma - none MM - hypogammaglobulinaemia, occult bone disease, hyper viscosity, cytopenia Significance MGUS - no tx needed, small transformation rate Smouldering myeloma - no tx needed, high transformation rate MM - treatment needed

Question 37

Describe 2 other paraproteinemias

Answer 37

• Waldenstrom’s Macroglobulinemia (Lymphoplasmacytoid Lymphoma – LPL) o Elderly men o Low-grade NHL o Lymphoplasmacytoid cells producing monoclonal serum IgM infiltrate the LNs/BM o Weight loss, fatigue, hyperviscosity syndrome (visual problems, confusion, CCF, muscle weakness) o Rx  Plasmapheresis for hyperviscosity  Rituximab / bendamustine or ibrutinib for active disease • Systemic amyloidosis o Different types of amyloidosis o Presents with  Macroglossia, carpal tunnel syndrome, peripheral neuropathy, HF, RF o AL Amyloidosis  build of mis-folded light chains  This can be in the presence or absence of myeloma  Misfolded light chains deposit in the tissues & cause problems  AL Amyloidosis will result in an abnormal kappa:lambda light chain ratio o Other types of amyloidosis involve different types of misfolded proteins o Dx  Biopsy of affected organ using congo-red stain -> apple green birefringence  SAP scan (new diagnostic test) o Rx  similar to myeloma