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Q1: Definitions and the IgM-paraprotein spectrum (2 min)
- Define MGUS: an asymptomatic clonal disorder with a serum monoclonal protein under 30 g/L, bone-marrow clonal plasma cells under 10 percent, and no end-organ damage (CRAB) or amyloidosis attributable to the disorder. Common (over 3 percent of people over 50); 1 percent per year lifelong progression risk — monitor, do not treat.
- Define Waldenstrom macroglobulinaemia: a lymphoplasmacytic lymphoma (post-germinal-centre B-cell) secreting a monoclonal IgM paraprotein; marrow infiltration over 10 percent plus end-organ damage (anaemia, hyperviscosity, lymphadenopathy/splenomegaly, neuropathy, cryoglobulinaemia).
- Distinguish IgM MGUS (asymptomatic, under 30 g/L, under 10 percent) from smouldering/asymptomatic Waldenstrom (over 30 g/L or over 10 percent, no symptoms) from symptomatic Waldenstrom (end-organ damage).
Q2: Pathophysiology and mechanism (3 min)
- Cell of origin: post-germinal-centre B-cell with plasmacytic differentiation; immunophenotype surface IgM+, CD19+, CD20+, CD5-, CD10-, CD23-, CD138-.
- Molecular hallmark: MYD88 L265P mutation in over 90 percent — drives constitutive NF-kB signalling via IRAK; the basis of BTK-inhibitor dependence. CXCR4 (WHIM-like) mutation in 30 to 40 percent, associated with higher IgM and hyperviscosity.
- Why IgM causes hyperviscosity: IgM is a 970-kDa pentamer (five subunits plus J-chain), about 80 percent intravascular; raises serum viscosity steeply above 30 to 40 g/L; symptomatic threshold around a relative serum viscosity of 4 (water = 1).
- Mechanism of the hyperviscosity triad: thickened blood sludges in small vessels — engorged friable capillaries bleed (mucosa); retinal veins dilate into 'sausage-string' veins with haemorrhages and papilloedema (vision); microvascular sludging in the brain (neurology).
- Paraneoplastic IgM phenomena: type I cryoglobulinaemia (cold-precipitating IgM; purpura, acrocyanosis, glomerulonephritis); cold agglutinin disease (IgM anti-I, complement-mediated haemolysis, C3-positive Coombs); anti-MAG neuropathy (chronic distal demyelinating sensorimotor neuropathy).
Q3: Investigations (3 min)
- First-line bloods: FBC/film (normocytic anaemia, rouleaux, high ESR), U&E, creatinine, calcium (normal — unlike myeloma), LDH, beta-2 microglobulin (prognostic), quantitative immunoglobulins (raised IgM, suppressed IgG/IgA).
- Paraprotein workup: serum protein electrophoresis + immunofixation (IgM M-band), serum free light chains (kappa/lambda ratio).
- Serum viscosity — measured when IgM is high or symptoms suggest hyperviscosity.
- Bone-marrow aspirate and trephine — lymphoplasmacytic infiltration over 10 percent with the characteristic immunophenotype; MYD88 L265P PCR to confirm.
- Contrast-enhanced CT (nodes, spleen) — a skeletal survey is NOT required.
- Special tests: cryoglobulins (sample kept WARM at 37 degrees C), cold-agglutinin titre and Coombs, anti-MAG antibodies and nerve-conduction studies.
- Reproduce the MGUS risk-stratification (IMWG): adverse factors are M-protein at least 15 g/L, non-IgG isotype, abnormal free-light-chain ratio; 20-year progression risk from about 5 percent (0 factors) to over 50 percent (3 factors).
Q4: Management — resuscitation and definitive (3 min)
- Hyperviscosity syndrome = EMERGENCY PLASMAPHERESIS (plasma exchange) — 1 to 1.5 plasma volumes, daily or alternate-day; reverses symptoms within hours; do NOT transfuse first (worsens viscosity); watch for citrate hypocalcaemia.
- Definitive therapy is indicated for SYMPTOMATIC disease: rituximab-based chemoimmunotherapy — BR (bendamustine + rituximab) or DRC (dexamethasone + rituximab + cyclophosphamide) for 4 to 6 cycles; OR a BTK inhibitor — zanubrutinib 160 mg twice daily (preferred after ASPEN), ibrutinib 420 mg daily, continuous until progression.
- Autologous stem-cell transplant reserved for younger, fit patients with chemosensitive relapsed disease.
- MGUS: no treatment; lifelong monitoring (SPEP/FLC every 6 to 12 months), risk-stratify, educate on red flags.
- Cryoglobulinaemia / cold agglutinin disease: treat the underlying Waldenstrom with rituximab; cold avoidance; sutimlimab for refractory CAD.
Q5: Complications, pitfalls and prognosis (2 min)
- Disease complications: hyperviscosity (the signature emergency), anaemia/cytopenias, infection (immune paresis), cryoglobulinaemia, cold agglutinin haemolysis, anti-MAG neuropathy, Bing-Neel syndrome (CNS infiltration), amyloidosis, and transformation to DLBCL (Richter-like, poor prognosis).
- Treatment pitfalls: rituximab IgM flare (delay rituximab or plasmapheresise first when IgM is over 40 g/L); BTK-inhibitor toxicities (bleeding, atrial fibrillation more with ibrutinib, hypertension, infection); transfusing before plasmapheresis in hyperviscosity.
- Diagnostic pitfalls: attributing anaemia/neuropathy to "old age"; drawing the cryoglobulin sample cold; forgetting MYD88 testing; confusing MGUS with myeloma.
- Prognosis: median survival 5 to 10 years, improving with BTK inhibitors; IPSSWM stratifies by age, haemoglobin, platelets, beta-2 microglobulin and LDH. MGUS: 1 percent per year lifelong progression — never truly discharged.