HAEM: Multiple myeloma, amyloid and MGUS Flashcards
Define multiple myeloma.
Malignancy of bone marrow plasma cells, the terminally differentiated and immunoglobulin (Ig) secreting B cells
Features of myeloma plasma cells:
- Where do they home?
- What tumours do they form?
- What happens to Ig and free light chains?
- What is found in urine?
- Home and infiltrate the bone marrow
- Plasmacytomas - expansile bone or soft tissue tumours
- Excess monoclonal IgG and IgA (paraprotein or M-spike) AND excess monoclonal kappa or lambda serum free light chains
- Urine shows monoclonal free light chains called Bence Jones protein
Which types of B cells are implicated in myeloma? What about Waldenstrom’s lymphoplasmacytic lymphoma?
Myeloma = IgG or IgA producing long-lived plasma cells
Waldenstrom’s = IgM producing short-lived plama cells
How common is myeloma in terms of other haematological cancers? What is the median age of diagnosis? Which ethnicities/sex?
- Second most common haematological malignancy, prevalence increasing
- 67years median age
- males > females
- black > caucasian
What are the risk factors for myeloma?
Aetiology unknown but RF include:
- obesity
- age
- genetics - black ethnicity, sporadic cases of familial myeloma
- MGUS (this premalignant condition ALWAYS precedes myeloma)
What does MGUS stand for?
Monoclonal gammopathy of uncertain significance
How common is MGUS?
- most common premalignant condition
- 1-3% of elderly affected
- increases with age
Which type of MGUS must the patient have for progression to myeloma or lymphoma?
IgG or IgA - myeloma
IgM - lymphoma
What is the WHO diagnostic criteria for MGUS diagnosis?
- Serum M-protein <30g/L
- BM clonal plasma cells <10%
AND
- No lytic bone lesions
- No myeloma-related organ or tissue impairment
- No evidence of other B-cell proliferative disorder
Which criteria is used for risk stratification of MGUS? Describe the 3 risk factors used.
Mayo criteria
Risk factors include:
- non-IgG M spike
- M-spike >15g/L
- abnormal serum free light chain (FLC) ratio
Define smouldering multiple myeloma.
Both criteria must be met:
- Serum monoclonal protein (IgG/A) >30g/L OR urinary >500mg/24hr AND/OR clonal BM plasma celsl 10-60%
- Absence of myeloma defining events or amyloidosis
What is the use of risk stratification in smouldering multiple myeloma?
If score is 0 or 1 then observation used; if >2 then ?treatment.
Risk factors for points:
- BM myeloma cells >20%
- M-spike >20g/L
- Serum FLD ratio >20
(2019 IMWG updated risk stratification model)
What does MGRS stand for?
monoclonal gammopathy of renal significance
Describe the clinical spectrum of myeloma and related plasma cell disorders.
Usual progression is….
- MGUS
- smouldering myeloma
- symptomatic myeloma
- remitting relapsing
- refractory
- plasma cell leukaema
…with increases in % plasma cell in BM, M-spike, organ damage and symptoms and appearance of PC in circulation and extramedullary disease.
What are the primary and secondary events in multiple myeloma?
Primary:
- Hyperploidy (60%) - additional odd number Chr
- IGH rearrangement (Chr 14q32)
- t(11,14) - IGH/CCND1
- t(4;14) IGH/FGFR3
- t(14;16) IGH/MAF
Secondary:
- Copy number abnormalities
- DNA hypomethylation
- Acquired mutations
- KRAS, NRAS
- t(8;14) IGH/MYC
- 1q gain/1p del
- del 17p (TP53)
- 13-/del 13q
What is the diagnostic criteria for multiple myeloma?
CRAB
- Calcium >2.75mmol/L
- Renal disease - Cr >177micromol/L or EGFR <40min/min
- Anaemia - Hb <100g/L or drop by 20g/L
- Bone disease - 1 or more lytic bone lesions on imaging
What are MDE (myeloma defining events)?
- BM plasma cells >60%
- Invovled:uninvolved FLC ratio >100
- >1 focal lesion on MRI (>5mm)
Where do bone lesions usually present in MM? Give some examples of bone disease in MM. What is the calcium level?
80% - usually in proximal skeleton, spine, chest wall and pelvic regions.
- OsteoLYTIC lesions (never osteoblastic)
- Osteopenia
- Pathological fractures
- Bloods show hypercalcaemia
What type of imaging is required for myeloma bone disease?
NOT plain XR films - require >30% bone mass loss to show change
So:
- CT
- CT/FDG-PET san
- diffusion-weighed MRI - shows BM cellularity, active vs treated disease.
What are the two main emergencies as a result of bone disease in MM? What is their management?
Cord compression - management includes MRI scan, dexamethasone, radiotherapy +/- neurosurgery.
Hypercalcaemia - management inclused fluids, steroids and zolendronic acid.
What is the definition of myeloma kidney disease?
- Serum creatinine >177micromol/L (>2mg/dL) or eGFR <40ml/min
- AKI and results of myeloma
20-50% will have it at diagnosis and 25% will develop it at a relapse. Only 4% will require dialysis.
What are the causes of myeloma kidney disease?
- Cast nephropathy caused by high serum FLC levels and Bence Jones proteinuria
- Hypercalcaemia
- Loop diuretics
- Infection
- Dehydration
- Nephrotoxics
What is the mechanism of FLC AKI?
- Injury to the priximal tubule causing tubular cell apoptosis
- Light chains and Tamm–Horsfall glycoproteins (THPs) accumulate in distal tubules and form casts
- Atrophy of tubules proximal to the cast
- Inflammatory cell infiltration
- Eventually interstitial fibrosis
What are the potential triggers for FLC cast formation in myeloma AKI?
- Dehydration
- Furesomide
- Contrast agents
- Infective agents
What is the main drug used in myeloma kidney disease?
Bortezomib
What factors contribute to risk of infection in myeloma?
- Immunoparesis - low serum Ig
- Myeloid, T cell and NK cell imapirment
- Chemotherapy impairs immune response
- Myeloma evades immune response
What 4 infections are myeloma patients most at risk of?
- Bacterial
- Pneumonia
- Viral
- Herpes zoster
What does the diagnostic work-up for myeloma consist of?
- Immunoglobulin studies e.g. SPE, serum FLC levels, 24hr Bence Jones protein
- BM aspirate and biopsy - IHC for CD138
- FISH analysis - for high risk abnormalities
- Flow cytometry for immunophenotyping - diagnosis, minimal residual disease detection
Which CD antigen should immunohistochemistry be done for in myeloma?
CD138
Which cytogenic abnormalites define high risk in myeloma?
- del(17p)
- t(4;14) IGH/FGFR3
- t(14;16) - IGH/MAF
Define AL amyloidosis.
= amyloid light-chain amyloidosis
Caused when misfolded free light chains aggregate into amyloid fibrils in target organs.
What is the main determinant for AL amyloidosis development?
The amyloidogenic potential of the light chains is more important than their amount
How is amyloidosis visualised?
By Congo Red staining, which showsn solid, non-branching and randomly arranged amyloid fibrils with a diameter of 7-12 nm
Which types of light chain are most commonly involved in AL amyloidosis?
Lambda light chain is involved in 60% - IGLV6-57 in kidney, IGLV1-44 in cardiac.
What are the clincal features of AL amyloidosis?
- nephrotic syndrome (70%) - proteinuria (not BJP), peripheral oedema
- unexplained heart failure
- sensory neuropathy
- abnormal liver function tests
- macroglossia
Which clinical feature of AL amyloidosis is the biggest determinant of prognosis? How can it be monitored?
Unexplained heart failure
- Raised NT-proBNP
- Abnormal echo and cardiac MRI
Define MGRS.
monoclonal gammopathy of renal significance
Applies to any B-cell clonal lymphoproliferation where there are:
- 1 or more kidney lesions caused by monoclonal Ig production
- no B cell clone contributions to tumour complications/no haematological criteria met for immediate specific therapy
What are the main classes of drugs used in treatment of multiple myeloma?
- Alkylators e.g. melphalan, cyclophosphamide
- Steroids e.g. dexamethasone and prednisolone
- Immunomodulatory drugs (IMiD) e.g. -omides like lenalidomide
- Cereblon bindings molecules
- Proteasome inhibitors e.g. bortezomib, ixazomib
- Therapeutic mAbs e.g. anti-CD38 like daratumumab and isatuximab
Emerging: anti-BCMA toxin conjugates, CAR-BCMA T cell, BiTE in myeloma,
Which alkylators and steroids are used in myeloma therapy?
- Melphalan - used until 1990s, but still used in autologous SCT
- Cyclophosphamide - widely used, immunomodulation and microenvironment
- Dexamethasone and prednisolone
Which immunomodulatory drugs are used in myeloma?
Thalidomide paved the way for immunomodulatory drugs. It was thought to inhibit angiogenesis
Lenalidomide (2005) - more potent, different toxicity, better tolerated
Pomalidomide (2013) - more potent than above
Iberdomide - awaits approval
What is the MOA of proteasome inhibitors in myeloma?
- Myeloma cells are crucial protein production factories
- The proteasome is crucial in removing misfolded proteins
- So misfolded proteins accumulate
- This causes endoplasmic reticulum stress and unfolded protein response
- Apoptosis occurs
Give 3 examples of proteasome inhibitors in myeloma.
Borte-zomib - first line or relapse, IV or SC use, neuropathy
Carfil-zomib - relapse only, IV only, potent, thrombocytopenia/cardiotoxocity
Ixa-zomib (newest) - relapse in combo, oral, less toxic
What is the target of daratumumab?
anti-CD38 which is strongly expressed in normal and malignant plasma cells, not a lineage specific marker
What is the treatment algorithm in transplant-eligible (usually fit and <65yrs) and transplant-ineligible patients (frail and >65yrs)?
Transplant-eligible:
- Induction: PI + IMiD + Dex (x4-6) (VRD, VTD) +/- daratumumab
- Autologous SCT
- +/- consolidation (x2)(VTD, VRD)
- Maintenance for 2 years with low dose lenalidomide
NB: VTD/VRD is the treatment name (e.g. Revlimid ® + Velcade ® + dexamethasone)
Transplant-ineligible:
- Lenalidomide + dex OR
- Bortezomib-cyclophosphamide-dex OR
- daratumumab - bortezomib - cyclophosphamide - pred
What is the goal of treatment for optimal outcome in myeloma?
Deep response (MRD -ve) i required for optimal outcome in high-risk myeloma
BESPOKE treatment plans are important
However, myeloma is still incurable.
