Waldenstrom macroglobulinaemia and amyloidosis

• Waldenstrom macroglobulinaemia (WM) is a slow-growing B-cell lymphoplasmacytic lymphoma that secretes an IgM paraprotein. The IgM itself, not just the tumour, causes most of the trouble: thickened blood (hyperviscosity), tissue amyloid deposits, autoimmune effects and nerve injury.
• About 90 per cent or more of WM carries a MYD88 L265P mutation, which activates B-cell signalling; up to about 40 per cent also carry a CXCR4 mutation, which is linked to higher marrow burden, hyperviscosity and a slower response to BTK inhibitors. ^[1]
• WM differs from multiple myeloma: it is usually an IgM disease, causes lymphadenopathy and hyperviscosity rather than osteolytic bone lesions, and is treated with BTK inhibitors and with combinations of rituximab and chemotherapy rather than proteasome-based myeloma regimens. ^[1][5]
• Amyloidosis is not one disease. It is the deposition of misfolded proteins in organs. AL amyloid comes from immunoglobulin light chains; AA amyloid comes from chronic inflammation; ATTR amyloid comes from transthyretin and may be inherited or age-related. ^[3][4]
• AL amyloidosis is confirmed on tissue biopsy and Congo red (apple-green birefringence), then typed by mass spectrometry. The standard first-line treatment is a daratumumab-based regimen (Dara-CyBorD), with stem-cell transplant in selected patients. ^{[1][2][4] [3]}
• ATTR cardiomyopathy is treated with transthyretin stabilisation (tafamidis: 80 mg VYNDAQEL or 61 mg VYNDAMAX once daily) and, for neuropathy, transthyretin gene silencers such as patisiran or inotersen. ^[6][7]
• AA amyloidosis is treated by controlling the underlying inflammatory disease, together with organ support. ^[3]

By the end of this page you should be able to:

1. Define WM, describe the lymphoplasmacytic infiltrate and the IgM paraprotein, and state the roles of MYD88 L265P and CXCR4 mutations.
2. Recognise and manage hyperviscosity, peripheral neuropathy, cold agglutinin haemolysis and IgM-related amyloid in WM.
3. Plan the initial investigations and distinguish WM from IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and from multiple myeloma.
4. Choose between fixed-duration chemoimmunotherapy and continuous BTK inhibitor therapy, and know where each is preferred.
5. Classify amyloidosis as AL, AA, ATTR (hereditary and wild-type) or dialysis-related, and match each to its treatment.
6. Interpret Congo red staining, fat-pad biopsy and mass-spectrometry typing, and recognise the cardiac, renal, neurologic and hepatic patterns of amyloid organ involvement.

Waldenstrom macroglobulinaemia (WM) is a low-grade B-cell lymphoplasmacytic lymphoma of the IgM subtype: clonally related small lymphocytes, plasmacytoid lymphocytes and plasma cells infiltrate the bone marrow and secrete monoclonal IgM. ^[1]

For a disorder to be called WM rather than IgM MGUS, the Mayo clinic criteria require clonal lymphoplasmacytosis of at least 10 per cent of marrow cellularity with ruling out of other B-cell lymphomas with plasmacytic differentiation, such as marginal zone lymphoma.^[1] The IgM size and the marrow burden do not move in parallel, so a large IgM does not mean heavy marrow infiltration. ^[1]

Both forms of IgM MGUS recognised in the International Consensus Classification exist, an IgM MGUS not otherwise specified that progresses to WM, and an IgM MGUS of plasma cell type that progresses to IgM myeloma. AL amyloidosis can result from either. ^[1]

WM is rare and age dependent. In the United States it accounts for about 2 per cent of newly diagnosed non-Hodgkin lymphoma and is diagnosed in roughly 2,300 new cases of lymphoplasmacytic lymphoma each year. ^[1]

Age-adjusted incidence is 0.92 per 100,000 person-years in males and 0.30 per 100,000 person-years in females, and the disease is rarely seen below age 30. Older age, male sex, white race and family history are established risk factors. ^[1]

No modifiable risk factor is known. A family history of lymphoma or chronic lymphocytic leukaemia is the best established risk. Chronic antigenic stimulation (for example hepatitis C), immune dysfunction and some occupational exposures are postulated. ^[1]

Two mutations dominate. MYD88 L265P is present in over 90 per cent of patients: a gain-of-function change in the TLR/IL-1 receptor adaptor that drives NF-kappa B signalling and lymphoma survival. ^[1] The mutation helps separate WM from IgM myeloma, in which it is absent, and from marginal zone lymphoma. ^[1]

CXCR4 mutations, present in up to 40 per cent of patients (almost always with an underlying MYD88 mutation), are associated with higher marrow burden, symptomatic hyperviscosity and resistance to several therapies. ^[1] Their presence lowers response and shortens progression-free survival with BTK inhibitors. ^[1]

Symptoms come from two sources: marrow infiltration (cytopenias, organomegaly) and the large circulating IgM (hyperviscosity, autoantibody effects, amyloid deposition). The IgM pentamer has a molecular weight of about 1 million, which is why blood flow becomes sluggish when levels are high. ^[1]

Fatigue, weight loss, drenching night sweats, fever, lymphadenopathy and hepatosplenomegaly are common. Many patients have an IgM MGUS-like or smouldering course and need only observation. ^[1]

Hyperviscosity syndrome is seen in up to 15 per cent of patients with WM and usually presents with epistaxis, gingival bleeding, blurred vision, papilloedema, retinal haemorrhage, headache, light-headedness, ataxia, somnolence or, rarely, heart failure. ^[1] Symptoms may occur even when the measured viscosity is under 4 centipoise. ^[1] Only one to three plasmapheresis sessions are usually needed to reverse symptoms, with a 25 per cent reduction in IgM eliminating most symptoms. ^[1] Red-cell transfusion is withheld in haemodynamically stable patients until viscosity has normalised, because expanded plasma volume may mask anaemia. ^[1]

Peripheral neuropathy occurs in a substantial minority of patients and has four mechanisms: immune-mediated damage by IgM autoantibodies against nerve antigens (classically anti-MAG demyelinating sensory neuropathy); cryoglobulinaemic vasculitic neuropathy; amyloid deposition; and direct lymphomatous infiltration (neurolymphomatosis). ^[1]

IgM cold agglutinins are produced in some patients and cause chronic haemolysis, acrocyanosis, Raynaud-like phenomena and, in severe cases, gangrene. Laboratory markers are an anaemia with raised bilirubin, LDH and reticulocytes, a positive direct antiglobulin test for C3d, and a cold agglutinin titre of 64 or greater. ^[1]

About 7.5 per cent of patients with WM develop ALH amyloidosis from the IgM clone. ^[1] This presents with fatigue, weight loss, macroglossia, easy bruising (periorbital purpura), jaw claudication, bilateral carpal tunnel syndrome, dyspnoea, oedema, autonomic or sensory neuropathy and renal involvement. ^[1] It is treated by rapidly attaining a very good partial response, not with BTK inhibitors (which are poorly tolerated and increase bleeding and cardiotoxicity). ^[1]

Baseline testing includes full blood count, LDH, albumin, renal profile, serum protein electrophoresis with immunofixation, 24-hour urine, serum free light chains, IgA, IgG and IgM, beta-2 microglobulin, a dilated eye examination and bone marrow biopsy with immunophenotyping and MYD88 and CXCR4 studies. ^[1] Serum viscosity, cold agglutinin titre, cryocrit and hepatitis status are added when clinically indicated. ^[1]

A two-dimensional echocardiogram with cardiac biomarkers (troponin and NT-proBNP) is used to look for amyloid organ infiltration. ^[1] Electrocardiography and CT of the chest, abdomen and pelvis assess extramedullary disease and possible histological transformation. ^[1]

Active WM requires evidence of end-organ damage attributable to the lymphoma: cytopenias, constitutional symptoms, hyperviscosity, symptomatic lymphadenopathy or hepatosplenomegaly. ^[1]

Staging uses the International Prognostic Scoring System for WM: age over 65, haemoglobin, platelet count, beta-2 microglobulin and IgM level. ^[1] Response now uses the simplified IWWM-11 criteria based on IgM reduction (complete response: undetectable monoclonal protein and normal marrow; very good partial response: at least a 90 per cent reduction). ^[1]

The important differential is IgM myeloma. WM usually shows lymphoplasmacytic morphology, absent lytic bone lesions, CD20 positivity and MYD88 mutation; IgM myeloma shows pure plasma-cell morphology, osteolytic lesions in most cases and the myeloma immunophenotype. ^[1][5]

Smouldering WM is watched. Treatment is started when there is end-organ damage: symptomatic anaemia or cytopenias, hyperviscosity, troublesome lymphadenopathy or organomegaly, or WM-related neuropathy. ^[1]

Immediate plasmapheresis plus rapidly acting cytoreductive therapy, and rituximab deferred until viscosity normalises. ^[1] BTK inhibitors are avoided for hyperviscosity because their onset is too slow, particularly in patients with CXCR4 nonsense mutations. ^[1]

Anti-MAG neuropathy is managed with regimens active against WM (rituximab-based or BTK inhibitor-based), assessing the response with disability scores; axonal neuropathy from amyloid deposition is treated as ALH amyloid (below). ^[1]

Rituximab monotherapy gives responses in about 50 per cent of patients; rituximab plus bendamustine is more effective, with an overall response around 71 per cent. ^[1] Keeping warm, treating the underlying clone and avoiding cold exposure support these therapies. ^[1]

Fixed-duration rituximab-based chemotherapy (bendamustine-rituximab, or dexamethasone/cyclophosphamide/rituximab) remains standard. In a subset analysis, bendamustine-rituximab produced a median PFS of 69.5 months versus 28.1 months with rituximab-CHOP. ^[1] Dexamethasone/cyclophosphamide/rituximab is well tolerated and is preferred for frail patients; a randomised trial added bortezomib to this backbone and improved early responses but not 2-year PFS. ^[1]

Continuous BTK inhibitor therapy is the second main approach. Ibrutinib 420 mg daily was the first approved; in an iNNOVATE sub-study it added benefit to rituximab. ^[1] Zanubrutinib is now preferred where available on safety and efficacy grounds, and is active even in patients without MYD88 mutation. ^[1] Acalabrutinib and tirabrutinib/orelabrutinib have shown activity in single-arm studies. ^[1] Response is faster and deeper in MYD88-mutated, CXCR4-wild-type disease. ^[1]

The non-covalent inhibitor pirtobrutinib (200 mg daily) is active after prior covalent BTK inhibitor failure, with a higher major-response rate in BTK inhibitor-naive (88 per cent) than in exposed patients (67 per cent). ^[1]

Bortezomib-based regimens are rapid IgM reducers and are highly effective in concomitant ALH amyloidosis, but carry a risk of peripheral neuropathy (mitigated by weekly or subcutaneous dosing). ^[1] Carfilzomib-based and ixazomib-based combinations are options. ^[1] Venetoclax is active, especially in CXCR4-mutated disease, but co-treatment with ibrutinib has produced ventricular arrhythmias and this combination is not standard. ^[1] Plasma-cell-directed therapy is used for WM-related ALH amyloid. ^[1]

Autologous stem cell transplantation is reserved for relapsed or refractory disease in fit patients. ^[1]

After WM-associated stroke, early resection-level control of lymphoma is aimed for; anticoagulation alone does not remove the embolic source. ^[1] ALH amyloidosis is treated to a rapid very good partial response, using melphalan-conditioned transplant or bortezomib-based regimens (R-CyBorD), since stem-cell-based approaches appear particularly useful in the IgM amyloid setting. ^[1]

• Histological transformation to diffuse large B-cell lymphoma in 4 to 6 per cent (higher in MYD88-wild-type disease). ^[1]
• Hyperviscosity-related stroke and bleeding. ^[1]
• Neurolymphomatosis, Bing-Neel syndrome (CNS infiltration), and transformation. ^[1]
• Treatment-related myeloid neoplasms with purine-analogue and alkylator regimens. ^[1] WM is incurable but commonly indolent; 5-year survival ranges from 36 per cent in high-risk to 87 per cent in low-risk IPSS-WM groups. ^[1]

Amyloidosis is the extracellular deposition of misfolded fibrillar proteins (about 10 nm, beta-pleated sheet) in organs; all fibrils stain with Congo red and show apple-green birefringence. ^[3][4]

The major systemic types are:

AL, AA and ATTR together account for about 98 per cent of all amyloid diseases. ^[4]

AL amyloidosis is the commonest type in developed countries (about 9 cases per million person-years in the Mayo series); AA amyloidosis is probably the most common type worldwide and is relatively commoner in developing countries (about 1 to 2 cases per million person-years in European registries). ^[3] ATTRwt is common in the very elderly (deposits in about a quarter of people over 85 at autopsy). ^[8]

All types share a common endpoint: a precursor protein is produced in excessive or abnormal form, becomes misfolded, aggregates into fibrils, deposits in the extracellular space, and causes tissue injury and organ failure. ^[3][4] Transthyretin is a liver-derived transport protein for thyroxine and retinol; most TTR mutations destabilise the tetramer and promote monomer misfolding and aggregation. ^[6]

Constitutional: fatigue, weight loss, oedema, possible hepatic or splenic enlargement. ^[2]

Organ involvement is similar across types, but with tendencies:

• Heart: restrictive cardiomyopathy, diastolic heart failure, atrial fibrillation, conduction disease, low limb-lead ECG voltage with thick walls, "apical sparing" on strain imaging. Troponin and NT-proBNP are elevated and prognostic. ^[2][4][6]
• Kidneys: proteinuria (often nephrotic), renal impairment. In AA amyloidosis renal involvement is the earliest and most frequent manifestation, present in up to 95 per cent of patients. ^[3]
• Nerves: symmetric small-fibre or autonomic neuropathy, orthostatic hypotension, carpal tunnel syndrome, gastrointestinal dysmotility. Carpal tunnel may predate ATTR diagnosis by years. ^[6]
• Liver: hepatomegaly with cholestatic enzyme pattern. ^[3]
• Gastrointestinal tract: diarrhoea, malabsorption, pseudo-obstruction, bleeding. ^[3][4]
• Soft tissues and tongue: macroglossia, jaw claudication, periorbital purpura (a clue to AL), "shoulder pad" sign. ^[1][3]

In AL amyloidosis, median overall survival from the revised 2012 Mayo staging system is 94.1, 40.3, 14 and 5.8 months for stages I to IV, driven mainly by the degree of cardiac involvement. ^[2]

Tissue is essential. Congo red shows the deposit; under polarised light it gives apple-green birefringence (often described as red-green or other colours in practice), and the finding alone without this optical effect is not diagnostic. ^[3][4]

Biopsy site affects yield. Fat aspiration is first-line because it is simple, with specificity of 93 to 100 per cent but sensitivity from 0 to 90 per cent (about 57 to 82 per cent in most series). ^[3] Rectal, minor salivary gland (83 to 100 per cent), skin and eventually organ biopsies are used when fat aspiration is negative. ^[3][6]

Typing must be definitive, because therapy differs. Immunohistochemistry is first-line; mass spectrometry after laser microdissection is the gold standard. ^[4] Non-invasive clues include: serum/urine immunofixation and FLC in AL; SAA elevation in inflammation; genetic testing in suspected ATTR; bone scintigraphy (technetium 99m DPD/PYP/HMDP) uptake for ATTR cardiomyopathy. ^[4] Note that bone scans can be positive in AL cardiac amyloidosis too, and that some TTR mutations scan-negative. ^[6]

Staging:

• AL cardiac staging (Mayo 2012): NT-proBNP, troponin and the difference between involved and uninvolved free light chains. ^[2]
• AL renal staging (Palladini): eGFR and 24-hour proteinuria; high proteinuria over 5 g per 24 hours with eGFR under 50 mL/min gives a 60 to 85 per cent risk of dialysis dependence at 3 years. ^[2]

First-line induction is the only licensed regimen: daratumumab plus cyclophosphamide, bortezomib and dexamethasone (Dara-CyBorD). ^[2] In the ANDROMEDA trial (stage I to IIIA disease) this improved the haematological complete-response rate to 53.3 per cent versus 18.1 per cent for CyBorD alone, and improved survival free from major organ deterioration (hazard ratio 0.58, 95 per cent confidence interval 0.36 to 0.93). ^[2]

Response is monitored by serum free light chains every 3 months; a very good partial response is dFLC under 40 mg per litre and is often required before transplant. ^[2]

Autologous stem cell transplant (melphalan conditioning) is offered to selected, fit patients for deep and durable responses, particularly with t(11;14), and can be used as consolidation or salvage. ^[2] Careful patient selection has reduced post-transplant mortality. ^[2]

Solid organ transplant (heart or kidney) has a small evidence base and is reserved for selected candidates after haematological control. ^[2]

In relapsed or refractory disease, options include a bortezomib or carfilzomib-based regimen if a proteasome inhibitor was not used before, daratumumab in anti-CD38-naive patients, pomalidomide-based therapy, venetoclax (particularly with t(11;14)), and, in trials, anti-BCMA chimeric antigen receptor T cells. ^[2]

There is no specific therapy against the deposits. Control the underlying inflammatory disease, thereby lowering serum amyloid A: treat infection, remove a localised inflammatory tumour surgically, use colchicine 1.5 to 2 mg per day in familial Mediterranean fever, and use anti-cytokine or immunosuppressive therapy in rheumatoid arthritis and inflammatory bowel disease. ^[3] Supportive care covers orthostatic hypotension, gastrointestinal dysautonomia and, when control is achieved, organ support including transplant. ^[3] The colchicine dose cited is the published treatment dose for familial Mediterranean fever. ^[3]

ATTR cardiomyopathy is treated by transthyretin stabilisation or reduction. Tafamidis, a transthyretin tetramer stabiliser, reduces mortality and cardiovascular hospitalisation in ATTR cardiomyopathy (hereditary or wild-type). ^[6][7] The recommended dose is VYNDAQEL 80 mg orally once daily or VYNDAMAX 61 mg orally once daily (the formulations are not interchangeable milligram for milligram). ^{[7] [1]}

Polyneuropathy is treated by gene silencers that reduce transthyretin production: the ASO inotersen and the siRNA patisiran (approved for mild-to-moderate ATTR polyneuropathy), vutrisiran, and the ligand-conjugated ASO eplontersen. ^[6] Liver transplantation was the first disease-modifying therapy and prolongs survival in early Val30Met disease, but progression can continue from wild-type production by the eye and choroid plexus. ^[6] Diflunisal stabilises transthyretin and has off-label use; new oral stabilisers (acoramidis) and gene editing approaches are in late development. ^[6]

Activity ranges:

• Patisiran 0.3 mg per kilogram intravenously every 3 weeks improved neuropathy and quality of life in the APOLLO trial. ^[6]
• Inotersen 200 mg subcutaneously once weekly requires monitoring of platelets and renal function because of thrombocytopenia and glomerulonephritis. ^[6]

• WM: a basic blood count, serum protein electrophoresis and, where possible, a marrow biopsy establish the diagnosis; an eye examination screens for hyperviscosity. Referral and plasmapheresis where available; wherever a BTK inhibitor or bendamustine is unavailable, chlorambucil, cyclophosphamide or (where safe) fludarabine combined with rituximab, plus supportive transfusion and antimicrobial care, are fallback options. Cold agglutinin and neuropathy are recognised clinically rather than with specialist serology. ^[1]
• Amyloidosis: diagnosis in much of the world rests on clinical organ patterns plus a cheap indirect biopsy (abdominal fat or rectal mucosa) stained with Congo red, which is inexpensive and widely available, with awareness of its false-negative rate. Typing by mass spectrometry is restricted to reference centres, so typing by immunohistochemistry, clinical context, genetics and organ scanning remains the practical route. Tafamidis and gene silencers are expensive and often inaccessible; control of the underlying inflammation in AA and locally available supportive care (diuretics, antiarrhythmics, dialysis, symptom control) are the realistic mainstay. ^[3][4]
• Across both conditions, delayed diagnosis is the main avoidable driver of poor outcomes; any patient with proteinuria plus chronic inflammation, or heart failure with thick walls and low ECG voltage, should be referred for typing and specialist care. ^[3][6]

• WM is an IgM-secreting lymphoplasmacytic lymphoma; the IgM (pentamer, ~1,000,000 Da) produces hyperviscosity, autoimmune phenomena, cryoglobulinaemia, cold agglutinin haemolysis, neuropathy, and tissue amyloid.
• MYD88 L265P in over 90 per cent of WM, absent in IgM myeloma; CXCR4 in up to 40 per cent, predicting hyperviscosity and relative BTK inhibitor resistance.
• Hyperviscosity: epistaxis, visual disturbance, papilloedema, neurology; one to three plasmapheresis sessions, plus cytoreductive therapy; avoid rituximab until viscosity normalises.
• WM has no osteolytic lesions in the classic picture; IgM myeloma usually has them. ^[5]
• First-line WM therapy: bendamustine-rituximab (median PFS 69.5 months) or dexamethasone/cyclophosphamide/rituximab; BTK inhibitors used continuously and preferred by many for MYD88-mutated disease and for relapse; zanubrutinib favoured over ibrutinib for tolerability. ^[1]
• IgM-related ALH amyloid (about 7.5 per cent) is not treated with BTK inhibitors; aim for a rapid VGPR/CR with ASCT or R-CyBorD. ^[1]
• Amyloidosis means organ deposition of misfolded protein. AL from light chains (plasma cell clone), AA from chronic inflammation (SAA), ATTR from transthyretin (inherited or wild-type/age-related), dialysis-related from beta-2 microglobulin.
• Congophilic (Congo red) fibrils give apple-green birefringence; tissue typing by mass spectrometry is the gold standard. Fat-pad aspiration is simple but can be falsely negative.
• AL first-line treatment: Dara-CyBorD (haematological CR 53.3 per cent versus 18.1 per cent over CyBorD alone); stem-cell transplant in selected fit patients; relapsed disease has pomalidomide, proteasome inhibitors, CD38-directed therapy, venetoclax and upcoming cellular therapy.
• AA amyloid is treated by treating the underlying disease, with colchicine 1.5-2 mg daily in familial Mediterranean fever.
• ATTR: tafamidis 80 mg VYNDAQEL or 61 mg VYNDAMAX orally daily for cardiomyopathy; patisiran, inotersen and other silencers for neuropathy; liver transplant in selected cases.
• Involvement is heart, kidney, nerve, liver, autonomic system; periorbital purpura and macroglossia point to AL.

• Polycythemia and blood disorders; multiple myeloma; lymphomas; acute leukaemias; coagulation disorders.
• Nephrotic syndrome; chronic kidney disease; heart failure; carpal tunnel syndrome.
• Familial Mediterranean fever; inflammatory arthritis; chronic inflammation.
• Clinical biochemistry: protein electrophoresis, free light chains, immunofixation.