Waldenström macroglobulinemia (WM)

Pathology and Biology

• Definition: lymphoplasmacytic lymphoma (LPL) with IgM monoclonal protein and bone marrow infiltration by IgM-secreting lymphoplasmacytic cells with constitutive B-cell receptor signaling (Bruton tyrosine kinase, BTK, is a critical component).
• Cell of origin: B cell arrested after somatic hypermutation in the germinal center and before plasma cell differentiation (mutated IGHV; recurrent IGH translocations are typically absent).
• MYD88 L265P: mutated in >90% of WM (L265P in 93 to 95% of patients). MYD88 (a component of IL-1 and Toll-like receptor signaling) activates hematopoietic cell kinase, which transactivates BTK, adding prosurvival signals. Non-L265P MYD88 mutations add ~2%.
• CXCR4 mutations (~30 to 35%): WHIM-like C-terminal truncations; constitutive CXCR4 signaling promotes ibrutinib resistance through enhanced AKT/ERK signaling; associated with high IgM/hyperviscosity. Very rare in other lymphoproliferative disorders.
• Cytogenetics: 6q deletion most frequently reported (significance unclear).

Diagnosis and Immunophenotype

• Abnormal lymphoplasmacytic aggregates in marrow with clonal B cells and plasma cells, plus IgM monoclonal protein of any concentration.
• Immunophenotype: sIgM+, CD19+, CD20+, CD22+, CD138+, CD5 (+/-), CD10−, CD23−. CD5, CD10, or CD23 may be positive in 10 to 20% and does not exclude the diagnosis.
• MYD88/CXCR4 testing supports the diagnosis; LPL may be rendered even when aggregates are <10% of cellularity.

Differential Diagnosis

• Presence of B cells with lymphoplasmacytic differentiation OR an IgM paraprotein is not itself diagnostic of WM.
• IgM MGUS: IgM paraprotein with <10% marrow plasma cells and no lymphoplasmacytic aggregates sufficient for LPL; asymptomatic. Plasma-cell type (no B-cell component, wild-type MYD88 or t(11;14), implies progression toward MM) vs NOS (MYD88-mutated, monoclonal B cells without WM-level aggregates). IgM MGUS carries a relative risk ~262 for progression to WM (~16-fold for progression to any lymphoid disorder).
• IgM multiple myeloma: t(11;14), lytic bone lesions.
• SMZL and CLL: distinguished by immunophenotype.
• Primary cold agglutinin disease: lacks MYD88 mutation; trisomies 3, 12, 18 and KMT2D/CARD11 mutations.

Clinical Features and Presentation

• Tumor-infiltration symptoms: cytopenias, constitutional symptoms, lymphadenopathy/organomegaly (20 to 40%), marrow involvement required for diagnosis (essentially universal).
• Circulating IgM effects: hyperviscosity (~15%; blurred vision, vertigo, mucosal bleeding when viscosity >4 cP), cryoglobulinemia, cold agglutinin disease.
• Tissue IgM effects: peripheral neuropathy (anti-MAG IgM antibodies), amyloidosis, IgM deposits causing renal failure, macroglobulinemia cutis.
• Hypercalcemia (~4%) and lytic bone lesions (~2%) are uncommon (contrast with MM).
• Bing-Neel syndrome: CNS involvement by WM; rare but severe (confusion, ataxia, cranial nerve palsies); treat with CNS-penetrant therapy: ibrutinib (BTK inhibitor, commonly preferred) or high-dose methotrexate-based regimens, cytarabine, or fludarabine.
• Schnitzler syndrome: chronic urticaria associated with IgM gammopathy.

Prognosis and Risk Models

• Risk of progression from asymptomatic to symptomatic WM: BM infiltration ≥70%, IgM ≥4500 mg/dL, β2m ≥4 mg/L, albumin ≤3.5 g/dL; MYD88 wild-type carries higher progression risk (HR 2.7).
• WM IPSS: risk factors are age >65, Hb ≤11.5 g/dL, platelets ≤100 × 10⁹/L, β2m >3 mg/L, M protein >7 g/dL. Low risk = 0 to 1 factor (except age); intermediate = 2 factors or age >65; high = >2 factors. rIPSSWM (Kastritis, Leukemia 2019) uses age categories, beta-2-microglobulin, albumin, and LDH (original IPSSWM: Morel, Blood 2009); not validated in BTK-inhibitor-treated patients.
• Revised IPSSWM (rIPSSWM, Kastritis Leukemia 2019): age (66 to 75 = 1 point, ≥76 = 2), β2m ≥4 mg/L, LDH ≥250 IU/L, albumin <3.5 g/dL; very low to very high risk. (MIPI is the mantle cell lymphoma index, not a WM score.)

Indications for Therapy

• Disease-related Hb ≤10 g/dL or platelets <100,000/µL, bulky (≥5 cm) or symptomatic adenopathy, symptomatic hepatosplenomegaly, symptomatic hyperviscosity, neuropathy, amyloidosis, cryoglobulinemia, cold agglutinin disease, B symptoms.
• Asymptomatic disease is observed (watch-and-wait; median time to treatment ~5 yr).

Treatment

• Rituximab: IgM flare in ~half of patients, can persist ~4 mo and is associated with reduced response. Perform plasmapheresis for symptomatic hyperviscosity and before rituximab if IgM >4000 mg/dL (alternatively, hold rituximab for the initial cycles while IgM is high); monitor IgM and repeat plasmapheresis for symptomatic hyperviscosity; for an asymptomatic IgM flare on rituximab, monitor rather than exchanging on the IgM level alone.
• Bortezomib: rapid rise in serum IgM on cessation (mechanism unclear, possibly ER stress). Discordance between marrow and paraprotein can occur; do not change therapy for this alone.
• Ibrutinib (response by genotype): MYD88-mut + CXCR4-WT gives the best response (ORR ~100%); MYD88-mut + CXCR4-WHIM ORR ~80%; double wild-type (MYD88-WT + CXCR4-WT) ~60%. INNOVATE (PCYC-1127, ibrutinib-rituximab vs placebo-rituximab): PFS benefit was independent of MYD88/CXCR4 genotype (unlike single-agent ibrutinib). Atrial fibrillation occurred mainly in patients ≥75 (~55% of AF cases); CHF ~3% (vs 0% rituximab alone).
• Ibrutinib resistance: median time to discontinuation ~2 yr; rapid IgM rise on discontinuation in ~60% (some symptomatic hyperviscosity). BTK C481S found in some; C481S did not affect time to discontinuation or survival, but TP53 mutations (~15%) were associated with worse survival. 5-yr OS ~44%.
• Zanubrutinib (Brukinsa): FDA Aug 31, 2021 for WM; now preferred first-line over ibrutinib. ASPEN trial (Tam CS et al, Blood 2020;136(18):2038-2050): zanubrutinib vs ibrutinib in MYD88 L265P WM; superior tolerability (fewer atrial events, fewer bleeding events), numerically higher VGPR rates (not statistically significant).
• Other agents: carfilzomib/ixazomib (proteasome inhibitors, useful if neuropathy is a concern), acalabrutinib, everolimus, obinutuzumab, idelalisib, venetoclax, ulocuplumab (CXCR4 antagonist, in development).
• Plasmapheresis: urgent treatment for symptomatic hyperviscosity; bridge to systemic therapy.

Relapsed/Refractory

• BTK inhibitor switch: for intolerance, another covalent BTKi (zanubrutinib/acalabrutinib) is reasonable; for covalent-BTKi resistance (e.g., BTK C481S), use a noncovalent BTKi (pirtobrutinib), an alternative active class, or a trial.
• Pirtobrutinib (BRUIN WM cohort, Palomba ML et al, ASH 2023 / JCO 2024): non-covalent reversible BTKi; major response rate ~67% (ORR ~80%) in covalent-BTKi-exposed R/R WM including BTK C481S mutants. NCCN 2026 R/R option post-cBTKi; not yet FDA-approved for WM.
• BGB-16673 (BTK degrader) (Shadman M et al, ASH 2024 / NEJM 2025): oral BTK-targeting chimeric degrader; active in R/R WM/CLL/MCL after covalent BTKi and pirtobrutinib. Phase 3 CaDAnCe planned.
• Mavorixafor (Xolremdi): CXCR4 antagonist, FDA Apr 26, 2024 for WHIM syndrome (NOT for WM); a phase 1b mavorixafor plus ibrutinib study in MYD88/CXCR4-mutant WM (NCT04274738) has completed; no approved role in WM.
• Venetoclax + rituximab: synergy, emerging option.

Treatment Summary. NCCN preferred primary regimens: bendamustine/rituximab and zanubrutinib. Other recommended: bortezomib/dex/rituximab, rituximab/cyclophosphamide/dex, ibrutinib +/- rituximab.

• Bendamustine/rituximab
• Bortezomib/dexamethasone/rituximab or cyclophosphamide/dexamethasone/rituximab
• Ibrutinib +/- rituximab
• Zanubrutinib (preferred BTK inhibitor)

High-Yield Pearls

• MYD88 L265P in >90%; test CXCR4 status (mutations predict slower, less deep BTKi responses, especially to ibrutinib, not class-wide resistance).
• Zanubrutinib is preferred first-line over ibrutinib: fewer atrial fibrillation and cardiovascular toxicities (ASPEN).
• Bing-Neel syndrome (CNS) is rare but serious; treat with CNS-penetrant therapy (ibrutinib or high-dose methotrexate-based regimens).
• Plasmapheresis is urgent for symptomatic hyperviscosity and precedes rituximab when IgM >4000 mg/dL (or hold rituximab for initial cycles; avoid IgM-flare-driven hyperviscosity).
• Best ibrutinib responders: MYD88-mutated, CXCR4 wild-type; double wild-type responds least.