Myeloma and MGUS Flashcards
What are the key features of myeloma?
Monoclonal PCs
Paraprotein
(B) Osteolytic lesions (bone destruction)
(A) Anaemia
(R) Kidney failure
Infections/ immunosuppression
Angiogenesis
What does CRAN mean?
Calcaemia (hyper) >2.75
Renal failure Cr >177, eGFR<40
Anaemia Hb <100
N Bone pain 1+ lytic lesion
Multiple myeloma has very characteristic complications that arise from complex interactions with the tumour microenvironment (bone disease) or large-scale Ig secretion (renal failure)
What type of cells are in multiple myeloma?
Mature B cells which can make Ig
How is multiple myeloma linked to MGUS?
Transformation results from a range of numeric and structural genetic aberrations that accumulate from a pre-malignant condition (“MGUS”) to terminal progression
What is the second most common haematopoietic malignancy?
Multiple myeloma
What is the survival of multiple Myeloma?
4-7 years
Novel treatment approaches combined with “old-fashioned” chemotherapy are increasing survival rates
How do B cells mature?
- B cell encounters antigen and goes into germinal centre
- Affinity maturation: Somatic hypermutation and antigen selection
- Class switching to get correct isotype
- Plasmablast goes to bone marrow to produce antibodies
Where can mutations occur?
> Switching off cellular characteristics that are no longer required, such as cell cycling
> Activating programmes that are essential for antibody production
> Undergoing apoptosis if they do not find a receptive niche in the bone marrow
Failure to complete these programmes correctly could potentially leave active cellular processes, which may result in the features of myeloma.
What are key transcription factors in myeloma?
BCL-6, B cell lymphoma 6
BLIMP1, B lymphocyte-induced maturation protein 1
CIITA, MHC class II transactivator
ID3, DNA-binding protein inhibitor ID3
PAX5, paired box gene 5
XBP1, X box-binding protein 1.
Which cell secretes the most proteins?
Plasma Cells
What is the pathogenesis of multiple myeloma?
Insult to cell (infection/ inflammation)
MGUS
Microenvironment changes
Oncogenes and genetic changes etc.
Myeloma
What is the progression to Myeloma?
- MGUS (No CRAB)
- Smouldering Myeloma (No CRAB)
- Multiple Myeloma (CRAB)
- B Cell leukaemia
What would be seen in blood of MGUS?
Monoclonal serum protein < 30g/L
BM plasma cells < 10%
Annual risk of progression to MM 1-2%
Rare in young, increasing incidence with ag
What would be seen in blood of smouldering myeloma?
Monoclonal serum protein ≥ 30g/L
BM plasma cells ≥ 10%
Annual risk of progression to MM 10%
What is the epidemiology of myeloma?
o 4,500 new cases per year in the UK
o 15-20,000 people are living with myeloma in the UK [Incidence 5/100,000 per year]
o 15% of blood cancers and 1% of cancers
o 2x more frequent in blacks than in whites, less common in Asians
o Median age at diagnosis 65-70y -> median survival 3-4y (6-10y in patients fit for intensive treatment)
What investigations do you do for myeloma?
Electrophoresis Blood film Urine ESR BM aspirate
What would you find when investigating myeloma?
Electrophoresis: Dense ban of IgG/IgA monoclonal proteins Blood film: Rouleaux Urine: Bence Jones proteins ESR: High BM aspirate: >10% plasma cells
What is the aetiology of multiple myeloma?
Unsure
Chronic infection/ inflammation: RhA/ HHV8/ HIV - more chance for multiplication errors
What staging system is used for multiple myeloma?
Durie-Salmon staging system
Which mutations are linked to MGUS?
t(14q32) = 50%
del (Chr13) = 50%
Which mutations are linked to MM?
N-RAS, K-RAS = 30%
p16 methylation = 40%
2nd translocations = …
How can diagnostics be used in MGUS and MM?
Serum protein electrophoresis: Monoclonal gammopathy
Bone Marrow Aspirates: Large Golgi and ER (Immature cells = poor prognosis)
What is the difference between mature and immature cells?
o Mature plasmocytic myeloma cells = clumped chromatin, abundant cytoplasm, rare nucleoli
o Immature plasmoblastic myeloma cells = prominent nucleoli, reticular chromatin, less abundant cytoplasm
What would be positive/ negative in immunophenotyping?
o Positive: CD38 CD138 CD56/58 Monotypic cytoplasmic Ig Light Chain restriction (Kappa or Lambda positive)
o Negative:
CD19
CD20 (hence, Rituximab (targets CD20) cannot be used for B-cell depletion therapy)
Surface Ig
Summarise treatment in MM
o (1) “Classical” cytostatic drugs = melphalan (alkylating agents)
o (2) Proteasome inhibitors
o (3) “IMIDs” / Immunomodulatory Drugs = thalidomide, lenalidomide, pomalidomide
o (4) MoAbs / Monoclonal Antibodies = daratumumab
o Steroids
What do alkylating agents do?
o Adds alkyl ground to DNA -> crosslinks and blocks DNA replication -> lymphopenia
o Related compounds = cyclophosphamide, chlorambucil, ifosphamide
What is an autologous stem cell transplant?
§ (1) stem cells collected from blood and stored
§ (2) high dose melphalan used to kill myeloma cells
§ (3) re-infusion of stem cells to rescue blood formation
What do proteasome inhibitors do?
Causes proteins misfolded in ER to accumulate as proteasome cannot destroy them.
What is a proteasome?
Proteasome = large enzyme complex that degrades most intracellular proteins (i.e. damaged proteins) by ubiquinating (adding a functional group) and marking the protein for degradation
Prevents cell death by accumulation
Why is thalidomide good?
Targets the turnover of transcription factors that are particularly important for myeloma cell survival
(Previously used as an anti-morning sickness drug which was found to be teratogenic)
Why are MoAbs good?
I.E. Daratumumab
o Binds CD38, which then leads to cell death through different processes:
§ Initiates complement cascade (through C1q activation) and formation of MAC -> cell death
§ Binds to CTL and eventual cell death
§ Binds macrophages and eventual cell engulfment and death
§ Direct cellular apoptosis (autologous) through crosslinking
- Which of the following is NOT a typical clinical myeloma characteristic?
a. Anaemia
b. Lytic bone disease
c. Splenomegaly
d. Renal impairment
c. Splenomegaly
Which of the following IS a key histopathological myeloma marker?
a. CD19
b. CD38 / CD138
c. Surface Ig
d. CD20
b. CD38 / CD138
Myeloma cells have a very well developed and extensive …
a. Nucleus
b. Mitochondrial mass
c. ER
d. Cell membrane
c. ER
How do we detect myeloma bone disease?
MRI:
High sensitivity for marrow infiltration
Response monitoring possible
Expensive & limited availability
CT:
Detects very small lesions
Good for radiotherapy planning
Higher radiation dose
PET:
Detects active disease
High costs, limited availability
What is myeloma nephropathy?
FLCs activate inflammatory mediators in the proximal tubule epithelium
Fanconi syndrome (renal tubule acidosis) with FLC crystal deposition.
Proximal tubule necrosis
Cast nephropathy
What is the epidemiology of Myeloma?
‘Black male in his 60’s’
- 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
What is the aetiology of myeloma?
Aetiology is unknown but, myeloma is always preceded by a premalignant condition:
Monoclonal Gammopathy of Uncertain Significance (MGUS)
Risk factors • Obesity increases the risk for myeloma • Age • Genetics • Incidence in black population • Sporadic cases of familiar myeloma
What is 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
- IgG or IgA MGUS → myeloma
- IgM → lymphoma
What are the risk factors for MGUS?
Risk factors
• Non-IgG M-spike
• M-spike >15g/L
• Abnormal serum free light chain (FLC) ratio
What is smouldering myeloma?
2 criteria:
- Serum monoclonal protein (IgG or IgA)>30g/l
- Absence of myeloma defining event and amyloidosis
- Low, intermediate risk: observation
- High risk (≥2 factors): ? treatment
What are primary events in MM?
• Hyperdiploidy (60%)
- additional odd number Chr
• IGH rearrangements (Chr 14q32)
- t(11;14) IGH/CCND1
- t(4;14) IGH/FGFR3
- t(14;16) IGH/MAF
What are secondary events in MM?
- KRAS, NRAS
- t(8;14) IGH/MYC
- 1q gain / 1p del
- del 17p (TP53)
- 13- / del 13q
How does MM occur?
Clonal advantage - competition selection for BM niche - migration and founder effect
What is the clinical presentation of bone disease - 80% of pts?
- Proximal skeleton
- Back (spine), chest wall and pelvic pain
- Osteolytic lesions, never osteoblastic
- Osteopenia
- Pathological fractures
- Hypercalcaemia
How is imaging used in MM?
• Plain XR films (skeletal surveys): are now obsolete
– Low sensitivity, require >30% bone mass loss
- Whole body CT scan low-dose
- CT / FDG-PET scan
- Whole-body diffusion-weighted MRI
- Bone marrow cellularity
- Active vs treated disease
What are emergencies in myeloma?
Cord compression
Hypercalcaemia (• Presents with drowsiness, constipation, fatigue, muscle weakness, AKI
• Fluids, steroids, zolendronic acid)
What is myeloma kidney disease and what is cast nephropathy?
– Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI)
– Acute kidney injury and result of myeloma
Cause 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
How does kidney disease determine prognosis?
Early mortality in severe kidney disease is an area on unmet clinical need
• 12% early death (<2 months)
• Prolonged hospital stay, lethal infections
• Nephrotoxic or renal excreted myeloma drugs: eg zoledronic acid, lenalidomide
Myeloma kidney disease should be treated as an emergency
Why do infections happen in myeloma?
- Immunoparesis: low serum normal Igs
- Myeloid, T cells and NK cells impairment
- Chemotherapy impairs immune response
- Myeloma immune evasion
What is in a myeloma diagnostic workup?
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
• MRD
How is myeloma linked to AL amyloidosis?
MGUS or myeloma in the background
Misfolded free light chains aggregate into amyloid
fibrils in target organs
The amyloidogenic potential of light chains is more
important than their amount
Amyloid fibrils stain with Congo Red, are solid, nonbranching and randomly arranged with a diameter of
7 – 12 nm
Lambda light chain is involved in 60%
- IGLV6-57 in kidney
- IGLV1-44 in cardiac
What does AL amyloidosis do?
Common target organs: kidney, heart, liver, neuropathy
Clinical presentation:
• 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 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) and
- the underlying B cell clone does not cause tumor complications or meet current
hematological criteria for immediate specific therapy”
What is the pathology 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 is myeloma therapy?
Alkylators and steroids Thalidomide IMiD or Cereblon Binding Molecules Proteasome inhibitors moAbs Daratumumab
How can thalidomide be used in MM?
• Thalidomide in combination with cyclophosphamide and dexamethasone was established in the
treatment of relapsed myeloma
• It was later replaced older therapies as a front line treatment prior to autologous SCT
What is IMiD?
Thalidomide lead the way for the development of a new class of anti-myeloma drugs Immunomodulatory drugs (IMiD)
- Lenalidomide - 2005: more potent, different toxicity profile, better tolerated
- Pomalidomide – 2013 : even more potent than Lenalidomide
- Iberdomide – awaits approval
How are proteasome inhibitors used in MM?
Myeloma cells are protein production factories
Proteasome is crucial in removing misfolded protein
Accumulation of misfolded protein → endoplasmic reticulum
stress and unfolded protein response → apoptosis Alteration of NF-κB pathway
Which moabs can be used?
anti-CD38: Daratumumab and Isatuximab
Daratumumab is the first therapeutic moAb approved for multiple myeloma (2015)
• CD38 is strongly expressed in
normal and malignant plasma cells
• Not a lineage specific marker
What is the treatment algorithm for MM?
See picture notes
What are emerging treatments in MM?
Belantamab mafodotin
Anti-BCMA toxin conjugate
30% response rate in refractory myeloma
anti-myeloma activity of CAR-BCMA T cells
BCMA
BiTE in myeloma
CD3-BCMA and CD3-FcRL5
BiTE under development
The different types of bispecific antibodies
Which immunoglobulins are linked to MM?
IgA and IgG
Excess of monoclonal light chains in serum (kappa or lambda)
What does MGUS cause?
higher incidence of osteoporosis, thrombosis and
bacterial infection compared to general population
What is the clinical spectrum of myeloma?
MGUS Smouldering myeloma Symptomatic myeloma Remitting relapsing disease Refractory Plasma cell leukaemia
(see picture notes)
How do you manage cord compression?
- Diagnosis & treatment within 24hrs
- MRI scan
- Ig and FLC studies +/- biopsy
- Dexamethasone
- Radiotherapy
- Neurosurgery: rarely required
- Stabilise unstable spine
- MDT meeting
How are alkylators and steroids used?
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
Which proteasome inhibitors are used in 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
What is anti-myeloma activity of CAR-BCMA T cells
BCMA?
B cell maturing antigen, specific for plasma cells (normal and malignant) ➢6 patients with refractory disease and extensive BM infiltration were treated ➢1 patient obtained a very good partial remission ➢1 patients achieved stringent CR (undetectable disease)
What is the most common cytogenetic abnormality in myeloma?
Hyperdiploid karyotype
Which of these is not a typical myeloma characteristic: Anaemia Lytic bone disease Splenomegaly Renal impairment
Splenomegaly
How does excess free light chains cause cast nephropathy
Proximal tubule take up light chains and put them back in circulation
At some point when overwhelmed they are stressed and undergo inflammation and fibrosis and re modelling
They form material within tubules (Casts) and this with inflammation leads to kidney injury
What diseases may you get in MM?
Chest infections
Fungal infections (in later stages)
Viral infections - Herpes zoster
What is the key histopathological myeloma marker?
CD138
