Multiple Myeloma and related plasma cell disorders Flashcards
Define Multiple Myeloma
Malignancy of bone marrow plasma cells, the terminally differentiated and immunoglobulin (Ig) secreting B cells
Myeloma plasma cells:
- home and infiltrate the bonemarrow
- 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
Describe the epidemiology of myeloma.
- The second most common haematological malignancy, 19th in all cancers
- 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? What are the risk factors?
Aetiology is unknown …
Risk factors
• Obesity increases the risk for myeloma (SIGNIFICANT)
- Age
- Genetics
- Incidence in black population
- Sporadic cases of familiar myelom
… but, myeloma is always preceded by a premalignant condition:
Monoclonal Gammopathy of Uncertain Significance (MGUS)
What is 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
MGUS:higher incidence of osteoporosis, thrombosis and bacterial infection compared to general population
What is the diagnostic criteria for MGUS?
- Serum M-protein <30g/L
- Bone marrow clonal plasma cells <10%
- No lytic bone lesions
- No myeloma-related organ or tissue impairment
- No evidence of other B-cell proliferative disorder
How do we calculate the chance of progression from MGUs to myeloma
Define smouldering myeloma.
What is the progression of myeloma?
Describe the primary and secondary genetic events of myeloma?
- Primary events
- 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
Common secondary events
- KRAS, NRAS
- t(8;14) IGH/MYC
- 1qgain/1pdel
- del 17p (TP53)
- 13- / del 13q
Describe the patterns of the driver genetic events in myeloma.
How do myeloma cells interact with bone marrow microenvironment?
What is the diagnostic criteria of multiple myeloma?
MDE - new criteria
How does myeloma present?
80% of myeloma patients present with bone disease
- Proximal skeleton
- Back (spine), chest wall and pelvic pain
- Osteolytic lesions, never osteoblastic
- Osteopenia
- Pathological fractures
- Hypercalcaemia
How do we use imaging in myeloma?
What is the most COMMON cytogenetic abnormality is myeloma?
Hyperdiploid karyotype
Which of the following is NOT a typical clinical myeloma characteristic?
- Anameia
- Lytic bone disease
- Splenomegaly
Splenomegaly
What are the emergencies in myeloma?
Cord compression
- Diagnosis & treatment within 24hrs
- MRI scan
- Ig and 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
Define myeloma kidney disease
– Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI)
– Acute kidney injury and result of myeloma
- 20-50% acute kidney injury at diagnosis
- 2-4% of newly diagnosed patients will require dialysis
- 25% develop renal insufficiency at relapse
What causes 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
How does myeloma kidney diases develop?
- Cells in PCT take up light chains
- This becomes overwhelming
- Cells go into stress and inflamed
- Form a gelantinous material –> cast
- Leads to acute kidney injury
Why is kidney disease a determinant of prognosis?
- Patients with severe kidney disease (eGFR <30ml/min) have a much worse outcome
- 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
How do you treat myeloma kidney disease?
Myeloma kidney disease should be treated as an emergency
Bortezomib-based therapy is the cornerstone of myeloma kidney disease treatment
What is the relation between infections and myeloma?
Complex humoral and cellular immunodeficiency
- Immunoparesis: low serum normal Igs
- Myeloid, T cells and NK cells impairment
- Chemotherapy impairs immune response
- Myeloma immune evasion
What are the investigations for myeloma?
Immunoglobulin studies
- Serum protein electrophoresis
- Serum free light chain levels - screening
- 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
Which of the following is a key histological myeloma marker?
- CD19
- CD138
- Surface Ig
- CD20
CD138
What is the international staging system for myeloma?
What causes Amyloidosis? How do we detect it? What light chains are involved?
- 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, non- branching 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 is the clinical presentation of amyloidosis?
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
Define Monoclonal Gammopathy of Renal Significance (MGRS)
Definition
“…MGRS applies specifically to any B-cell clonal lymphoproliferation where there are:
- 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”
Describe MGRS pathology?
- 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
How has myeloma been treated in the past? How about now?
Melphalan
- Nitrogenmustardderivate,inusesincethe1960’s
- Backboneofmyelomatherapyuntillate1990’s
- High-dosemelphalan200mg/m2stillinuseinAutologousSCT
Cyclophosphamide
- Widelyusedincombinationwithsteroidsand/orotherdrugs
- Immunomodulationandmicroenvironment
Dexamethasone and Prednisolone
- Induceapoptosisinmyelomacells
- Strongsynergy,partofalmostallcombinationregimens
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
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 does lenalimdomide work
Cereblon Binding Molecules -A new mechanism of action
Selective degradation of IKZF1 and IKZF3
Describe the use of proteasome inhibitors in myeloma
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
Describe the use of moABs in multiple myeloma-
Daratumumab monotherapy in relapsed/refractory myeloma
36% of patients with multiple previous treatments and refractory disease to standard myeloma therapies responded to daratumumab
How do we treat multiple myeloma?
What is the treatment algorithm in new diagnosis of myeloma?
What is the objective of myeloma therapy?
MRD negativity may be required at least in high-risk disease
What are the emerging treatment in myeloma?
Monoclonal antibodies
- Belantamab mafodotin - Anti-BCMA toxin conjugate
- CAR-BCMA T cell therapy
BCMA: B cell maturing antigen, specific for plasma cells (normal and malignant)
