JC46 (Medicine) - Multiple Myeloma Flashcards
Define gammopathy
2 types
Gammopathy: over-production of ≥1 classes of immunoglobulin
→ Polyclonal gammopathy: occurs in association with acute or chronic inflammation, eg. infection, sarcoidosis, A/I diseases, some malignancies
→ Monoclonal gammopathy: Ig from a single clone of plasma cells
Markers for clonal plasma cells
Kappa or Lambda light chain over-production - Serum free light chain assay
Serum IgG, IgA, IgM level (heavy chain) - Serum M-protein assay
List neoplasms involving clonal expansion of plasma cells
Plasmacytoma: solitary lesion of neoplastic proliferation of plasma cells
Multiple myeloma (MM): multiple lesions of neoplastic proliferation of plasma cells
Primary (AL) amyloidosis: clonal plasma cell proliferation leading to organ deposition of amyloid proteins consisting of monoclonal light chains
Light/heavy chain deposition disease: similar light chain production as AL amyloidosis but cannot form amyloid fibrils, non-amyloid organ deposition only
Plasma cell leukaemia (PCL): aggressive MM variant with circulating plasmablast
Malignant causes of monoclonal gammopathies
Multiple myeloma (MM)
Waldeström’s macroglobulinemia (WM)
Other lymphoproliferative disease:
Indolent B cell lymphoma
Primary (AL) amyloidosis
Light and heavy chain deposition disease
Plasma cell leukaemia
Benign causes of monoclonal gammpathies
MGUS (can be premalignant)
Solitary plasmacytoma
Chronic cold haemagglutinin disease
Rheumatic diseases, eg. RA, PMR
Infections, eg. HIV
Gaucher disease
Compare and contrast: Malignant vs benign causes of monoclonal gammopathies
Bence-Jones proteinuria
Serum paraprotein levels
Serum free light chain ratio
Immunoparesis
Other features
Top 3 most common monoclonal gammopathies
MGUS (60%)
Multiple myeloma (18%)
Amyloidosis (9%)
Most frequently detected antibody in monoclonal gammopathies
IgG (60%)
Describe structure of immunoglobulin
Light chain: forms half of variable domain → contributes to specificity
→ Types: only two, i.e. lambda (λ) and kappa (κ)
Heavy chain: apart from half of variable domain, also forms the constant domain → determines type of Ig and therefore its role in immune response (eg. IgA in mucosal immunity)
→ Types: gamma (γ) = IgG, alpha (α) = IgA, delta (δ) = IgD, mu (μ) = IgM, episilon (ε) = IgE
Relevance: an M protein can consist of intact Ig (eg. IgG, IgM, IgA) or free light chain (λ, κ)
Outline the spectrum of monoclonal gammopathies from Normal plasma cells to plasma cell leukaemia
Classification of monoclonal gammopathies *
- Non-IgM producing: Non-IgM MGUS, Smoldering Multiple Myeloma, Multiple Myeloma
- IgM producing: IgM MGUS, Smoldering WM, WM, IgM Multiple Myeloma
- Light-chain producing: Light chain MGUS, Idiopathic Bence-Jones proteinuria, Light chain Multiple Myeloma
Definition of Non-IgM MGUS, smoldering MM and Multiple myeloma
Non-IgM MGUS: ALL of
(1) Serum M protein <3g/dL
(2) Clonal BM plasma cells <10%
(3) No end-organ damage PLUS no myeloma-defining biomarkers
Smoldering MM: ALL of
(1) Serum M protein ≥3g/dL and/or clonal BM plasma cells ≥10%
(2) No end-organ damage PLUS no myeloma-defining biomarkers
Multiple Myeloma: Clonal BM plasma cells ≥10%
PLUS ONE of
(1) End-organ damage, defined as ≥1 of CRAB = Hypercalcemia (corr. Ca ≥2.75 mmol/L), Renal impairment (Cr >176.8, CrCL<40), Anaemia (NcNc >2 below LLN or <10g/dL) and Bone lesion (lytic /osteopenic)
(2) ≥1 of MM-defining biomarkers: ≥60% clonal BM plasma cells, free light chain ratio ≥100, MRI >1 focal bone lesion
Definition of IgM MGUS, Smoldering WM, WM and IgM Multiple myeloma
Investigations for monoclonal gammopathies
- Clinical features (e.g. CRAB in MM)
- Serum protein: evident as reversed A:G ratio with high globulin level
- Serum + urine protein electrophoresis: identify M protein
- Immunofixation: find exact type of M protein
- Serum free light chain assay: Kappa and Lambda assay
- Investigate underlying cause
Serum + urine protein electrophoresis
Indication
Sample needed
Method
Findings
Limitation
Indication: identify M protein
Sample needed: serum (SPEP) or 24h urine (UPEP)
Method: uses electrophoresis to separate serum/urine protein → allow detection and quantification of M protein
Finding:
- Monoclonal gammopathy: single, narrow peak at γ-globulin area → a/w plasma cell neoplasms
- Polyclonal gammopathy: broad-based peak or band at γ-globulin area → a/w infectious/inflammatory ds
Note: ~50% light chain MM –ve by SPEP → must do UPEP
Immunofixation for M protein
Indication
Method
Findings
Indication: Follow +ve SPEP/UPEP, to differentiate between type of M protein
Method: each sample electrophoresed in 5 lanes → then each lane overlaid with different specific Ab, i.e. anti-γ, anti-μ, anti-α, anti-κ, anti-λ → after precipitation of Ag-Ab complex and washout, the resultant gel is stained
Finding: sharp, well-defined band with similar mobility (i.e. same position on gel) staining +ve for one heavy chain and one light chain (eg. IgG-κ)
Serum free light chain assay
Indication
Findings
Role: can detect low concentration of monoclonal free light chains in the serum
Findings: more sensitive than urine immunofixation for monoclonal FLCs
- Free serum κ light chains = 3.3-19.4mg/L normal
- Free serum λ light chains = 5.7-26.3mg/L normal
- κ:λ FLC ratio = 0.26-1.65 normal
Investigations for underlying causes of monoclonal gammopathies
General: CBC, PBS, Hemolysis markers, SPEP/UPEP with immunofixation, Serum FLC assay
Plasma cell dyscrasias → serum Ca, RFT, whole-body PET/CT ± BM if suspicious
Lymphoproliferative diseases → CBC for WCC and lymphocyte count ± PBS, BM exam MCICM
AL amyloidosis → urinalysis, urine protein:creatinne ratio, LFT and liver USG, cardiac MRI, EMG/NCV for nerve infiltration
MGUS
Definition
Clinical presentation
Investigation results
MGUS: paraproteinaemia not related with underlying disease, eg. MM/SMM, lymphoma, amyloidosis, WM
Clinical presentation: by definition asymptomatic
Investigations:
□ Incidental finding of M protein
□ Laboratory artifacts: circulating M protein may interfere with other lab tests, eg. spuriously low HDL-C level, high bilirubin level, altered inorganic phosphate level
□ Blood: reversed A:G ratio with ↑globulin, ↑ESR
□ CBC/PBS: normal ± rouleaux formation
□ BM: <10% clonal plasma or lymphoplasmacytic cells
Diagnostic criteria of MGUS
□ M protein <3g/dL
□ <10% clonal plasma or lymphoplasmacytic cells in BM
□ No end-organ damage, eg. CRAB symptoms
MGUS
Progression into which diseases
□ Non-IgM MGUS: 0.8%/y risk of progression → MM, plasmacytoma, AL amyloidosis
□ IgM MGUS: 2%/y in first 10y, then 1%/y → WM, AL amyloidosis, NHL, CLL
□ LC MGUS: 0.3%/y risk of progression into idiopathic Bence Jones proteinuria (i.e. LC-SMM)
Management of MGUS
Risk stratification: determines intensity of F/U
→ Risk factors: serum M protein ≥1.5g/dL, non-IgG MGUS, abnormal FLC ratio
Monitoring for progression: routine F/U with Hx and P/E plus
→ Annual SPEP, serum FLC/UPEP for quantification of M protein
→ CBC, serum Cr, serum Ca for development of myeloma complications
Monitoring for complications:
Fractures: evaluate for osteoporosis with DEXA ± vit D/Ca supplements ± Tx of osteoporosis
Thromboembolism
Second malignancies
Multiple Myeloma
Definition
Diagnostic criteria
Multiple (plasma cell) myeloma: Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacyoma + one of more of following:
- BM clonal plasma cell infiltration: ≥10% of BM cellularity
- Serum M protein: ≥3g/dL
- ≥1 end-organ damage including hypercalcemia, acute renal failure, anaemia and skeletal destruction with osteolytic lesions, pathological fractures and bone pain
Any one biomarker of malignancy:
- Clonal bone marrow plasma cells ≥ 60%
- Involved: Uninvolved serum free light chain ratio ≥ 100 with involved free light chain ≥ 1–mg?L
- One or more focal lesion on MRI scan ( ≥5mm)
Pathogenesis of MGUS
Aberrant response to Ag stimulation: unknown Ag stimulus produces abnormal, sustained proliferative signal for plasma cells → ↑proliferative rate → ↑risk of mutation results in cytogenetic abnormalities
Primary cytogenetic changes (eg. IgH translocation, trisomy) → creation of plasma cell clone
Pathogenesis of Multiple Myeloma from MGUS
SECONDARY cytogenetic change (eg. IgH translocation, Δ17p13 (TP53), RAS mutation, NFκB activating mutation)
>> cell cycle dysregulation (overactive cyclin D), immortalization of plasma cell
Changes in BM microenvironment → favours myeloma cell growth with homing/ migration to BM
- ↑induction of angiogenesis
- Paracrine/cytokine loop: MM cells bind to BM stromal cells → interaction and activation of signal transduction pathways stimulate proliferation and develop malignant features
Pathogenesis of CRAB end-organ damage in Multiple Myeloma
Purely osteolytic bone lesion: osteoblast suppression + osteoclast activation (↑RANKL:OPG ratio)
Hypercalcemia due to osteoclast activation: ↑bone resorption → ↑calcium release into blood
Renal dysfunction:
* Cast nephropathy (most common): precipitation of light chains in tubules → bind with uromodulin, formation of obstructing casts → induce giant cell reaction → interstitial nephritis and fibrosis
- Hypercalcaemia leading to nephrogenic DI, dehydration and pre-renal failure
- AL amyloidosis or light/heavy chain deposition disease → presents with nephrotic syndrome
NcNc anaemia: malignant BM infiltration, disruption of BM microenvironment, renal impairment
Further progression of Multiple Myeloma
Extramedullary plasmacytoma: myeloma cells undergo further genetic changes → no longer require BM microenvironment to survive
Plasma cell leukaemia: when myeloma transform into leukaemic state with circulating plasmablasts
Clinical presentation of Multiple Myeloma
- NcNc anaemia: fatigue, pallor
- Bone: Bone pain, vertebral collapse, cord compression, pathological fracture
- Renal disease: Cast nephropathy, Hypercalcaemia, Amyloidosis with nephrotic syndrome
- Hypercalcemia
- Extramedullar plasmacytoma
- Infections (encapsulated or gram-negative organism)
- Neurological: Radiculopathy by plasmacytoma, Cord compression, Peripheral neuropathy
Causes of neurological signs in Multiple Myeloma
→ Radiculopathy: usu T/L/S-spine due to compression by paravertebral plasmacytoma (or rarely by collapsed bone itself)
→ Cord compression due to extramedullary plasmacytoma or vertebral collapse
→ Peripheral neuropathy: uncommon in MM alone, usu a/w amyloidosis
Investigations for Multiple Myeloma
- Basic blood test: CBC (NcNc anaemia), LFT (reversed A:G ratio), RFT (↑Cr), CaPO4 (↑Ca), LDH (prognostic)
+ Pre- Tx tests: glucose, CRP, HBsAg, anti-HBs, anti-HBc, G6PD - PBS: rouleaux (>50%) ± leukopenia (20%), thrombocytopenia (5%), circulating plasma cells
- Urine:
→ Dipstick: +ve if nephrotic syndrome
→ Serum + urine electrophoresis for monoclonal gammopathy + immunofixation for type
→ Serum free light chain (FLC): free κ, free λ and κ:λ ratio (90% abnormal) - BM examination:
→ ≥10% plasma cells infiltration: diagnostic
→ Morphology: generally round, eccentric ‘clock-face’ nucleus with marked perinuclear cytoplasmic clearing
→ Immunophenotyping for CD138, κ/λ light chain expression
→ Cytogenetics FISH: ~50% hyperdiploid (HRD), ~50% non-HRD
How to detect bony damage by multiple myeloma
Common sites: areas of active haematopoesis, incl vertebra bodies, skull, thoracic cage, pelvis, proximal humerus/femur
Skeletal survey: conventional 1st line imaging to detect lesions
- Includes: PA chest, AP/lateral C/T/L-spine, AP/lateral femur/humerus, AP/lateral skull, AP pelvis
- Findings: punched out lytic lesions (60%), diffuse osteopenia, pathological fractures (20%)
- Options: WB low-dose CT, WB MRI (or spine/pelvis), WB PET/CT (usually preferred in QMH)
Prognostic markers for Multiple Myeloma
Patient: Age, Comorbidities (e.g. renal failure, cord compression)
Tumor factors:
- ISS staging*****
- Any extramedullary disease/ plasmacytomas
- Any plasma cell leukaemia
- Serum LDH ≥2×ULN
- Cytogenetic abnormalities on FISH: Hypodiploidy, high risk mutations
- High proliferation rate: Labelling index (LI) on cytology
- Gene expression profiling
- β2-microglobulin
High risk = Add adjunctive radiotherapy and Anti-resoprtives
ISS staging for multiple myeloma
Smoldering MM
Diagnostic criteria
Risk of progression
Management
Criteria: Paraprotein IgG/A ≥3g/dL and/or 10-60% BM plasma cell
Urine paraprotein >500mg/24 hours
but no myeloma defining events/ CRAB symptoms
Clinical course: a/w 10%/y risk of progression into symptomatic MM, median time 4.8y
Management:
Observe Q4-6mo as in MGUS if low/intermediate-risk
Consider lenalidomide ± dexamethasone if high-risk → prevent end-organ damage
General Management of Multiple Myeloma
General: well hydrate + allopurinol 300mg daily (TLS),
correct hyperCa,
dialysis if indicated
± consult ONCO/ORTHO if presenting with skeletal Cx (pathological #, spinal cord compression)
Treatment options for Multiple Myeloma
Autologous HSCT: (ASCT)
proven to ↑overall survival, ↑progression-free survival, ↑complete remission → considered standard therapy in young, transplant-eligible MM patients
Triple therapy:
Proteasome Inhibitors: bortezomib (V), daratumumab (D), carfilzomib (K)
Immunomodulatory drugs (IMiD): lenalidomide, pomalidomide
Dexamethasone
Novel agents:
Monoclonal antibodies: daratumumab (anti-CD38 Ab), elotuzumab
Nuclear Cytoplasmic Transport Receptor Inhibitor: Selinexor
BCL-2 Inhibitors: Venetoclax (t(11;14) positive)
MoA of Triple Therapy for Multiple Myeloma
Proteasome inhibitors (PI):
Examples: bortezomib (V), daratumumab (D), carfilzomib (K)
MoA: prevent degradation of pro-apoptotic factors (eg. p53) → activation of intrinsic (mitochondrial) pathway of apoptosis
S/E: ↑risk of infection (require acyclovir ± septrin prophylaxis), peripheral neuropathy
Immunomodulatory drugs (IMiD):
Examples: lenalidomide, pomalidomide
MoA:↓tumour angiogenesis, ↓tumour secreted cytokines, induce caspase-8 → activation of extrinsic (death-receptor) pathway of apoptosis
S/E: ↑risk of thrombosis (require anticoagulant/antiplatelet prophylaxis), myelosuppression
Which type of HSCT is used to treat multiple myeloma
Autologous HSCT
Allogeneic HSCT is NOT used in MM due to high treatment-related mortality (TRM)
Pathogenesis of anaemia due to Multiple Myeloma
Marrow infiltration by plasma cells
Rouleaux formation due to high paraproteinemia
Dilution by paraproteins
Renal damage > Low EPO
Pathogenesis of Hypercalcemia in Multiple Myeloma
Increase Osteoclast activity by lymphokines (cytokines , Macrophage inflammatory factor and tumor necrosis factors)
Positive feedback bone resorption by IL-6 - IL6 released from bone resorption causing more myeloma activity
Renal failure - decrease Ca reabsorption, Vit D3 formation and increase PO4 retention
