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
