Haem 4 – Plasma Cell Myeloma & amyloid and Monoclonal gammopathy of uncertain significance Flashcards
What do multiple myeloma cells produce?
- 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
Myeloma is always preceded by
a premalignant condition: Monoclonal Gammopathy of Uncertain Significance (MGUS)
MGUS
IgG
IgA
IgM
MGUS is a premalignant condition resulting in…
- IgA or IgG MGUS myeloma
- IgM MGUS lymphoma
(MGUS - presence of monoclonal immunoglobulin in the blood or urine)
MGUS diagnostic criteria
- 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
Poor prognostic indicators in MGUS
- Non-IgG M-spike
- M-spike >15g/L
- Abnormal serum FLC ratio
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
MGUS will develop myeloma (actually only about 1% will develowp myeloma)
Which condition has the highest risk of developing symptomatic disease/progressing to multiple myeloma, MGUS or smouldering myeloma?
smouldering myeloma
Diagnosis of smouldering myeloma
- 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
Poor prognostic factors in smouldering myeloma and maagement
- Bone marrow myeloma cells >20%
- M-spike >20g/L
- Serum FLC ratio >20
Low + intermediate risk – observation High risk (>2 factors) – treatment
events in MM
• 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
Common secondary events in MM
- 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
Pathogenesis of MM
- Angiogenesis – CD34 staining for new vessel
- Immunosuppression and infections
- Anaemia
- Bone destruction
MM diagnostic criteria
• >10% plasma cells in bone marrow or plasmacytoma
and >1 CRAB or MDE
CRAB
• 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
MDE (myeloma defining events)
- BM plasma cells >60%
- Involved : uninvolved FLC ratio >100
- > 1 focal lesion in MRI (>5mm)
MM ix
• 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)
Hypercalcaemia symptoms + mx
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
Cord compression in MM mx
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
MM kidney disease definition
• Serum creatinine >177μmol/L (>2mg/dL)
or eGFR <40ml/min
Cause of myeloma kidney disease + mx
• 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
Mechanism of FLC acute kidney injury
Proximal tubule cell injury & myeloma cast nephropathy
What is Monoclonal Gammopathy of renal significance (MGRS) and how is it managed
• 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)
What causes AL amyloidosis in MGUS / smouldering myeloma/ MM
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
surface marker for MM
CD138
plasma cell marker
How does MM cause immunodeficiency and infections?
• 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)
• Cytogenetic abnormalities defining high risk in MM
o Del(17p) o T(4;14) o T(14;16) o IGH/FGFR3 o IGH/MAF
First line mx in MM
- Bortezomib (proteosome inhibitor) +/-
- Dexamethasone
- Cyclophosphamide
- Lenalidomide
- Supportive for CRAB symptoms incl. bisphosphonates
- When in remission – auto-SCT
Relapsed MM mx
Dexamethasone
Cyclophosphamide
Thalidomide (inhibits angiogenesis)
or
Daratumumab monotherapy
Why are proteosome inhibitors helpful in MM?
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
Give 3 examples of proteosome inhibitors used in MM
Indications
Route of administration
SE
Bortezomib
- 1st line or relapse
- IV, SC
- SE - neuropathy
Carfilzomib
- Relapse
- IV
- SE - cardiotoxicity, thrombocytopena
Ixazomib
- Relapse
- PO
- Favourable toxicity profile
Which therapeutic monoclonal antibodies can be used in MM
Anti-CD38
Daratumumab
Isatuximab
How does daratumumab work
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)
MM treatment in transplant eligible patents
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
MM treatment in transplant ineligible patents
- Lenalidomide + Dex or
- Bortezomib + Cyclophosphamide + Dex or
- Daratumumab + Bortezomib + Cyclophosphamide + Prednisolone
What blood tests should you order If there are raised globulins?
request serum protein electrophoresis + serum FLC
MGUS vs Smouldering myeloma
vs MM
M spike BM CRAB Organ damage Significance
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
Describe 2 other paraproteinemias
• 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
