Blood & Lymphoreticular

Waldenstrom macroglobulinemia: diagnosis and management

Clinical Overview and When to Suspect Waldenström Macroglobulinemia

— Hyperviscosity syndrome (headache, blurred vision, epistaxis, mucosal bleeding, confusion)

— Cryoglobulinemia (type I or II) with Raynaud, acrocyanosis, ulcers

— Cold agglutinin disease with hemolysis worsened by cold

— IgM-mediated peripheral neuropathy (anti-MAG, demyelinating, distal symmetric)

— AL or non-AL amyloidosis

— Older patient with unexplained anemia + elevated total protein/IgM spike

— Hyperviscosity signs: "sausage-link" retinal veins, dilated tortuous fundus vessels, papilledema, epistaxis

— Peripheral neuropathy + monoclonal IgM

— B symptoms (fevers, drenching sweats, weight loss) + lymphadenopathy/splenomegaly with an IgM paraprotein

— Incidental SPEP showing IgM spike during workup of fatigue, neuropathy, or recurrent epistaxis

— IgM MGUS: IgM <3 g/dL, <10% marrow LPL, no end-organ damage

— Smoldering WM: marrow ≥10% LPL or IgM ≥3 g/dL, but asymptomatic

— Symptomatic WM: above plus attributable cytopenia, hyperviscosity, neuropathy, amyloid, or organomegaly

Board pearl: An older man with anemia, epistaxis, blurry vision, and total protein 10 g/dL is WM with hyperviscosity until proven otherwise — even before SPEP results return.

Definition: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma (LPL) with bone marrow involvement and a monoclonal IgM gammopathy. It is an indolent, incurable B-cell neoplasm of older adults (median age ~70, male predominance, more common in Whites).

Pathobiology: Clonal small B-lymphocytes, lymphoplasmacytoid cells, and plasma cells secrete monoclonal IgM. MYD88 L265P mutation is present in >90% and CXCR4 mutations in ~30–40% — both shape prognosis and therapy.

Why IgM matters clinically: IgM is a large pentameric molecule confined largely to the intravascular space, driving the hallmark complications:

When to suspect WM on Step 3:

Spectrum to recognize:

Presentation Patterns and Key History

— Fatigue and exertional dyspnea from normocytic anemia (marrow infiltration ± hemodilution from expanded plasma volume)

— Recurrent infections from hypogammaglobulinemia of uninvolved isotypes

— B symptoms in ~25%: drenching night sweats, weight loss, low-grade fever

— Classic triad: mucosal bleeding (epistaxis, gingival), visual changes (blurring, vision loss), neurologic symptoms (headache, vertigo, ataxia, somnolence, seizures, coma)

— Ask specifically about nosebleeds, blurry vision when reading, headaches worse with bending forward

— Distal symmetric sensorimotor demyelinating neuropathy — slowly progressive numbness/gait imbalance, often anti-MAG antibody positive

— Bing–Neel syndrome: rare CNS infiltration by LPL — focal deficits, cognitive change, seizures

— Cryoglobulinemia: purpura, livedo, ulcers, arthralgia, renal involvement

— Cold agglutinin disease: acrocyanosis, hemolysis after cold exposure

— Lymphadenopathy, splenomegaly, hepatomegaly (less prominent than CLL)

— GI involvement → diarrhea/malabsorption; pulmonary infiltrates/effusions

— Duration of fatigue and pace of progression (indolent)

— Cold sensitivity, Raynaud

— Sexual/family history: ~20% of WM patients have a first-degree relative with a B-cell disorder

— Medication review: avoid rituximab monotherapy initiation when IgM is very high without plasma exchange — risk of IgM flare

Step 3 management: In the ambulatory clinic, an unexplained IgM monoclonal protein on routine SPEP with no end-organ damage = IgM MGUS or smoldering WM — observe with serial CBC, SPEP, and clinical assessment every 3–6 months, not treat.

Constitutional/cytopenia-driven (most common):

Hyperviscosity syndrome (HVS) — usually when serum viscosity >4 cP or IgM >4 g/dL (threshold varies by patient):

Neurologic:

Cold-related symptoms:

Organ infiltration:

Amyloidosis features: nephrotic-range proteinuria, restrictive cardiomyopathy, macroglossia, autonomic neuropathy, carpal tunnel

Historical clues to pin down:

Physical Exam Findings and Hemodynamic Assessment

— Pallor from anemia; cachexia if advanced

— Acrocyanosis or livedo reticularis on cold exposure (cryoglobulinemia, cold agglutinins)

— Funduscopic exam is essential. Look for:

— Dilated, tortuous, "sausage-link" or "boxcar" segmented retinal veins

— Flame hemorrhages, dot/blot hemorrhages

— Papilledema

— Cotton wool spots, exudates

— Mucosal oozing — gingival bleeding, recent epistaxis crusting

— Macroglossia → suspect concomitant AL amyloidosis

— Cervical, axillary, inguinal lymphadenopathy (~15–20%)

— Splenomegaly (~10–20%); hepatomegaly less common

— Volume overload from expanded plasma volume (IgM holds water intravascularly): elevated JVP, S3, bibasilar crackles, peripheral edema — can mimic CHF, especially after RBC transfusion

— In amyloid cardiomyopathy: low-voltage ECG with thick walls on echo, S4

— Stocking-glove sensory loss, reduced vibration/proprioception, areflexia, sensory ataxia

— Cranial nerve or focal deficits → suspect Bing–Neel

— Altered mental status in HVS

— Palpable purpura (cryoglobulinemic vasculitis)

— Waxy papules around eyes (amyloid)

— Raynaud phenomenon

— Hypertension can be unreliable; pseudohyponatremia and pseudohypoxemia/spurious lab values common due to high protein

— Transfusion in untreated severe HVS can precipitate stroke or CHF — viscosity rises further

CCS pearl: In a CCS case with suspected hyperviscosity, order a dilated fundus exam early — retinal findings often confirm clinical HVS before serum viscosity result returns, and they trigger urgent plasmapheresis consultation.

General appearance:

HEENT — the highest-yield exam in suspected WM:

Lymphoreticular:

Cardiopulmonary:

Neurologic:

Skin:

Hemodynamic pitfalls:

Diagnostic Workup — Initial Labs, Imaging, and Biomarkers

— Normocytic normochromic anemia is most common

— Thrombocytopenia, leukopenia variable

— Rouleaux formation on peripheral smear — RBCs stacked like coins

— Look for spherocytes/agglutination if cold agglutinin disease

— Spuriously elevated total protein (often 9–12 g/dL) with normal albumin → large gamma gap (>4 g/dL)

— Pseudohyponatremia from high protein (true Na is normal — measured by direct ISE)

— BUN/Cr to assess renal involvement; LDH, uric acid, calcium for tumor burden

— LFTs for hepatic involvement

— Reticulocyte count, haptoglobin, LDH, indirect bilirubin, direct Coombs (DAT) — C3d positive in cold agglutinin

— Monoclonal IgM spike — typically κ light chain predominance

— Quantitative immunoglobulins (IgG, IgA, IgM) — IgM elevated, others often suppressed

— Serum free light chains and ratio

— 24-hour urine for protein and UPEP/UIFE — Bence Jones less common than in myeloma

— Normal 1.4–1.8 cP

— Symptoms typically >4 cP, but no strict cutoff — treat the patient

— CT chest/abdomen/pelvis for nodes, splenomegaly, organ involvement

— Not all patients need PET — useful if transformation suspected

Board pearl: A patient with total protein 11, albumin 3.8, Na 128, anemia, and rouleaux — calculate the gamma gap (~7 g/dL) and order SPEP + IFE + serum viscosity before chasing hyponatremia.

CBC with differential and smear:

Chemistries:

Hemolysis labs (if cold agglutinin/AIHA suspected):

Serum protein electrophoresis (SPEP) + immunofixation (IFE):

Serum viscosity:

Coagulation: PT/PTT, fibrinogen — IgM can coat platelets and clotting factors → acquired vWD-like bleeding

Cryoglobulin and cold agglutinin titer (transport warm)

Hepatitis B and C, HIV serologies (HCV-associated cryoglobulinemia mimic; HBV reactivation risk with rituximab → screen and prophylax)

Imaging:

Cardiac/renal screening for amyloid: NT-proBNP, troponin, ECG, echo, urine albumin/Cr

Diagnostic Workup — Advanced and Confirmatory Studies

— ≥10% clonal lymphoplasmacytic infiltrate (small lymphocytes, plasmacytoid lymphocytes, plasma cells)

— Pattern: intertrabecular, often with mast cell increase

— Immunophenotype by flow: CD19+, CD20+, CD22+, CD5– (usually), CD10–, CD23– (usually), surface IgM+, monotypic light chain

— Distinguishes WM from CLL (CD5+/CD23+), mantle cell (CD5+, cyclin D1+), marginal zone, and multiple myeloma (CD20–, CD138+, CD56+)

— MYD88 L265P — present in >90% of WM, supports diagnosis; absence should prompt re-review for IgM myeloma, marginal zone, or other LPL

— CXCR4 mutations (WHIM-like) — ~30–40%; predict resistance to BTK inhibitor monotherapy and more hyperviscosity at presentation

— Karyotype/FISH: del(6q) common; assess for del(17p), TP53 mutations affecting therapy

— IgM monoclonal gammopathy of any concentration

— Bone marrow infiltration by LPL ≥10%

— Typical immunophenotype

— Exclusion of other lymphomas

— CSF flow cytometry for clonal B cells, MYD88 PCR on CSF, MRI showing leptomeningeal/parenchymal enhancement

— EMG/NCS: demyelinating sensorimotor neuropathy

— Anti-MAG IgM antibodies (myelin-associated glycoprotein)

— Anti-GM1, sulfatide antibodies in subsets

— Fat pad or organ biopsy with Congo red — apple-green birefringence

— Mass spectrometry to type amyloid (AL vs other)

— Cardiac MRI, NT-proBNP, troponin for staging

Key distinction: IgM multiple myeloma is rare, lacks MYD88 L265P, shows CD138+ plasma cells without lymphoplasmacytic component, and is often associated with lytic bone lesions — features absent in WM. MYD88 status is the discriminator.

Bone marrow biopsy and aspirate — required for diagnosis:

Molecular testing on marrow (high yield):

Diagnostic criteria for WM (consensus):

Lymph node biopsy if extramedullary disease dominates or transformation suspected (to diffuse large B-cell lymphoma in ~5%)

CSF studies + MRI brain/spine if Bing–Neel suspected:

Nerve studies and antibodies:

Amyloid workup if suspected:

Risk Stratification and First-Line Management Logic

— Symptomatic hyperviscosity

— Hemoglobin ≤10 g/dL or platelets <100k attributable to WM

— Bulky/symptomatic adenopathy or organomegaly

— Constitutional B symptoms

— Symptomatic cryoglobulinemia, cold agglutinin disease, or AIHA

— Moderate-to-severe IgM-related peripheral neuropathy

— Bing–Neel syndrome

— AL amyloidosis secondary to WM

— Renal dysfunction from WM

— International Prognostic Scoring System for WM (IPSSWM) — variables: age >65, Hb ≤11.5, plt ≤100, β2-microglobulin >3, IgM >7 g/dL → low/intermediate/high risk

— Revised IPSSWM (rIPSSWM) incorporates LDH and age strata

— Genotype: MYD88-mutated/CXCR4-wildtype = best response to BTK inhibitors; MYD88-wildtype = worse prognosis, atypical drug response

— Hyperviscosity emergency → urgent plasmapheresis first, then systemic therapy

— Need for rapid cytoreduction (bulky disease, profound cytopenias) → chemoimmunotherapy (e.g., bendamustine–rituximab, BR)

— Older/frail, comorbidities, AFib risk → BTK inhibitor (zanubrutinib preferred over ibrutinib for cardiac safety) or rituximab-based combos

— Concern for secondary MDS/AML or stem cell preservation (younger candidate) → favor BTK inhibitor over alkylators

— Anti-MAG neuropathy dominant → rituximab-based, BTK inhibitor

— Screen HBV/HCV/HIV before rituximab; HBV prophylaxis with entecavir if HBsAg+ or anti-HBc+

— Vaccinate (pneumococcal, influenza, shingles non-live, COVID) before therapy when feasible

Step 3 management: A 72-year-old with WM, Hb 9, fatigue, no HVS — start systemic therapy (commonly BR or zanubrutinib); a 72-year-old with IgM 5 g/dL but no symptoms and Hb 13 — observe with q3–6 month follow-up.

First decision: Does the patient need treatment now? WM is incurable and indolent — observation is appropriate for asymptomatic disease regardless of IgM level.

Indications to initiate therapy (any one):

Do NOT treat based on IgM level alone unless rising rapidly with end-organ threat.

Prognostic tools:

Choosing first-line therapy — patient-centered factors:

Address pre-treatment risks:

Pharmacotherapy — First-Line Regimens

— Zanubrutinib — preferred over ibrutinib: similar/better efficacy, lower rates of atrial fibrillation, hypertension, and bleeding (ASPEN trial)

— Ibrutinib ± rituximab — historical first oral option; AE: AFib, HTN, bruising, diarrhea, infection

— Best response in MYD88-mutated, CXCR4-wildtype patients

— Monitor: AFib, bleeding (hold around procedures 3–7 days), HTN, infections (PJP/HBV reactivation), cytopenias

— Continuous therapy until progression or intolerance

— Bendamustine + rituximab (BR) — highly effective, ~6 cycles; well-tolerated; AE: cytopenias, infusion reactions, infections, secondary MDS risk

— Dexamethasone + rituximab + cyclophosphamide (DRC) — gentler, good for frail patients

— Bortezomib-based (BDR: bortezomib, dex, rituximab) — useful for rapid IgM reduction, amyloid, renal involvement; risk of peripheral neuropathy (use weekly SC dosing, avoid if pre-existing neuropathy)

— IgM "flare": rituximab can transiently raise IgM 25–300% in ~50% — do NOT use rituximab monotherapy if IgM >4 g/dL or symptomatic HVS until IgM lowered (e.g., plasmapheresis or other agent first)

— Single-agent rituximab reserved for low-burden disease or IgM neuropathy

— Pre-meds: acetaminophen, diphenhydramine; HBV screening mandatory

— Bortezomib, carfilzomib (less neuropathy, cardiac risk), ixazomib (oral)

— Particularly useful when amyloidosis coexists

— PJP prophylaxis (TMP-SMX) with bendamustine, prolonged steroids, or BTK inhibitors in high-risk patients

— Antiviral (acyclovir) with bortezomib or BR

— IVIG for recurrent infections with hypogammaglobulinemia

— Avoid live vaccines on therapy

— Switch BTK inhibitor class, add venetoclax (BCL2 inhibitor — caution tumor lysis), nucleoside analogs (fludarabine, cladribine — limit due to MDS), autologous stem cell transplant in select younger patients

Board pearl: Never start single-agent rituximab in a patient with IgM >4 g/dL or hyperviscosity symptoms without first lowering IgM (plasmapheresis or alternative induction) — the IgM flare can precipitate stroke, retinal hemorrhage, or CHF.

BTK inhibitors (oral, continuous):

Chemoimmunotherapy — fixed duration:

Rituximab — central but with caveats:

Proteasome inhibitors:

Supportive pharmacology:

Relapsed/refractory options:

Procedures and Acute Interventions — Plasmapheresis and Beyond

— Indication: symptomatic hyperviscosity (visual changes, neurologic symptoms, mucosal bleeding) or impending HVS with very high IgM

— Mechanism: IgM is largely intravascular (~80%), so TPE efficiently removes it — 1–1.5 plasma volumes per session

— Typical regimen: 1–2 sessions to relieve symptoms, then daily or every other day until viscosity <3 cP

— TPE is a bridge — it does not treat the underlying clone. Always couple with systemic therapy initiation

— Access: large-bore peripheral or temporary central line (avoid permanent if possible)

— Replacement: albumin (or FFP if coagulopathy/bleeding)

— Monitor: ionized calcium (citrate chelation), magnesium, K+, fibrinogen, platelet count

— Admit to monitored bed/ICU if neurologic symptoms

— STAT serum viscosity, CBC, type & screen, coags, fundus exam

— Hold transfusions until after plasmapheresis if possible — transfusing PRBCs increases viscosity and can precipitate stroke

— Hydration with isotonic saline to reduce viscosity while preparing TPE

— Avoid diuretics that further concentrate plasma proteins

— Consult apheresis service and hematology immediately

— Bone marrow biopsy — diagnostic cornerstone (chunk 5)

— Lumbar puncture with flow cytometry/MYD88 PCR for Bing–Neel

— Tissue biopsy with Congo red when amyloid suspected (fat pad, kidney, heart)

— Splenectomy — rarely indicated, occasionally for symptomatic splenomegaly or refractory cytopenias

— Autologous hematopoietic stem cell transplant (auto-HCT) — select younger patients in chemosensitive relapse; allogeneic reserved for highly selected refractory patients

— CAR-T and bispecifics — emerging in relapsed/refractory disease

— Hold BTK inhibitors 3–7 days before/after surgery depending on bleeding risk

— Check for acquired von Willebrand if mucosal bleeding (high IgM can bind vWF)

— Avoid epidural anesthesia with severe thrombocytopenia or coagulopathy

CCS pearl: In a WM patient who arrives with Hb 6 and HVS symptoms, order plasmapheresis first, then transfuse PRBCs slowly after viscosity drops — reversing the usual reflex to transfuse for anemia immediately.

Plasmapheresis (therapeutic plasma exchange, TPE) — the emergency lever:

CCS-style management of acute HVS:

Other procedures relevant to WM:

Periprocedural pearls for any WM patient:

Special Populations — Elderly and Renal/Hepatic Impairment

— Median age ~70 — performance status, frailty, polypharmacy dominate decisions

— Apply geriatric assessment (G8, CGA) before initiating therapy

— Favor agents with manageable oral schedules and limited cumulative marrow toxicity

— Zanubrutinib preferred over ibrutinib in elderly given lower AFib, HTN, and bleeding rates (ASPEN trial showed AFib ~2% vs 15%)

— Avoid prolonged alkylator exposure (bendamustine, cyclophosphamide) when secondary MDS risk and infection risk are major concerns; if used, limit cycles and add antimicrobial prophylaxis

— Fall risk + bleeding risk on BTK inhibitor → counsel patients and caregivers; reassess concurrent anticoagulation

— Vaccination status: pneumococcal (PCV20 or PCV15+PPSV23), annual influenza, RSV (≥60), shingles (Shingrix, non-live), COVID boosters — ideally before therapy

— Causes in WM: light chain cast nephropathy (less common than myeloma), AL amyloidosis, cryoglobulinemic membranoproliferative GN, IgM deposition disease, tubulointerstitial infiltration

— Workup of new renal dysfunction in WM: UA, urine protein/Cr, serum/urine IFE, free light chains, complement levels (low C4 in cryo), renal biopsy if persistent proteinuria or unexplained AKI

— Bortezomib-based regimens preferred when myeloma-like renal involvement

— Bendamustine: dose-adjust if CrCl <40 mL/min; avoid if CrCl <30

— Zanubrutinib/ibrutinib: no dose adjustment for renal impairment

— Avoid nephrotoxins; ensure hydration; treat hypercalcemia or hyperuricemia

— Tumor lysis is uncommon but monitor with high tumor burden, venetoclax use

— Ibrutinib: avoid in severe (Child-Pugh C); dose-reduce in mild/moderate

— Zanubrutinib: reduce dose in severe hepatic impairment

— Bendamustine: avoid if bilirubin >3

— Rituximab — monitor LFTs; HBV reactivation prophylaxis essential (entecavir or tenofovir) for HBsAg+ or anti-HBc+ patients, continued ≥12 months after last dose

Step 3 management: Before starting any rituximab-containing regimen, document HBsAg, anti-HBc, anti-HBs, and HCV Ab — Step 3 commonly tests reactivation prevention in immunosuppression.

Elderly patients (the majority of WM):

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Younger Patients, and Other Subgroups

— WM in pregnancy is exceedingly rare given disease demographics, but vignettes appear

— Symptomatic disease during pregnancy: prioritize maternal stabilization

— Plasmapheresis is safe in pregnancy for hyperviscosity

— Rituximab can be used after the first trimester if essential; risk of transient neonatal B-cell depletion — coordinate vaccination delays

— Avoid bendamustine, fludarabine, and BTK inhibitors in pregnancy (teratogenic/limited data); bortezomib data limited

— Steroids and IVIG generally safe

— Counsel on effective contraception during BTK inhibitor therapy and for 1 week after last dose; longer for cytotoxic regimens (per package inserts)

— Most managed with chemoimmunotherapy (BR, DRC) or BTK inhibitors

— Stem cell collection considerations: if future autologous HCT is plausible, limit lenalidomide and prolonged alkylator exposure that impair mobilization

— Auto-HCT in chemosensitive relapse can extend remission; allo-HCT reserved for highly selected refractory cases

— Fertility counseling and sperm/oocyte preservation before gonadotoxic therapy

— First-degree relatives have ~20-fold increased risk of WM and other B-cell disorders

— Routine genetic testing not recommended, but maintain low threshold to evaluate symptomatic relatives with SPEP/CBC

— Optimize antiretroviral therapy; monitor CD4 closely during chemoimmunotherapy

— Aggressive infection prophylaxis (PJP, antifungal, antiviral)

— Higher incidence in White populations; somewhat lower MYD88 mutation frequency reported in Black patients — important when selecting BTK-based therapy; confirm genotype

— On BTK inhibitor: prefer DOAC over warfarin; avoid warfarin with ibrutinib (high bleeding risk per label)

— Reassess CHA₂DS₂-VASc vs HAS-BLED; consider stopping/switching BTKi if bleeding intolerable

Key distinction: Compared to multiple myeloma, WM lacks lytic bone lesions and hypercalcemia is uncommon — a young patient with monoclonal IgM, lytic lesions, and hypercalcemia points to IgM myeloma, not WM.

Pregnancy:

Younger/transplant-eligible patients (<65–70, fit):

Family screening:

HIV and immunosuppressed:

Race/ethnicity:

Patients with concurrent anticoagulation needs (AFib, VTE):

Complications and Adverse Outcomes

— Visual loss from retinal hemorrhage/vein occlusion, stroke, seizure, coma, mucosal hemorrhage

— Highest risk when IgM >5–6 g/dL but individualized — some symptomatic at lower levels

— Anemia from marrow infiltration, hemodilution, hemolysis, hepcidin upregulation

— Hypogammaglobulinemia → encapsulated organism infections (pneumococcus, H. influenzae); recurrent sinopulmonary infections

— Therapy-related neutropenia compounds infection risk

— Acquired von Willebrand syndrome (IgM binds vWF); platelet dysfunction; thrombocytopenia; BTK inhibitor effect on platelet aggregation

— Manifests as epistaxis, easy bruising, mucosal bleeding, postoperative hemorrhage

— Progressive sensorimotor demyelinating neuropathy with disabling sensory ataxia

— Bing–Neel syndrome — CNS involvement with focal deficits, cognitive decline; requires CNS-penetrant therapy (ibrutinib, bendamustine-rituximab + intrathecal options)

— Stroke (HVS-related, cryoglobulinemia)

— Cold agglutinin disease → cold-induced acrocyanosis, hemolysis

— Type I and II cryoglobulinemia → vasculitic skin lesions, glomerulonephritis

— AL amyloidosis → cardiomyopathy, nephrotic syndrome, autonomic neuropathy, hepatomegaly — independent prognostic driver

— Cryoglobulinemic MPGN, light-chain deposition, amyloid, tubulointerstitial infiltration

— ~5% transform to diffuse large B-cell lymphoma — rapid clinical deterioration, B symptoms, rising LDH, new bulky masses → biopsy for confirmation; treat as aggressive lymphoma (R-CHOP)

— Ibrutinib: atrial fibrillation, hypertension, bleeding, diarrhea, arthralgia, infections, sudden cardiac events

— Zanubrutinib: lower cardiac AEs, still neutropenia, infection risk

— Bendamustine: prolonged lymphopenia (CD4 may stay <200 for 6–12 months), secondary MDS/AML, infections

— Rituximab: infusion reactions, HBV reactivation, late-onset neutropenia, PML (rare)

— Bortezomib: peripheral neuropathy (mitigate with weekly SC dosing), herpes zoster reactivation (acyclovir prophylaxis)

Board pearl: Mucosal bleeding in a WM patient with normal platelet count and INR — think acquired von Willebrand syndrome from IgM — check vWF activity and factor VIII.

Hyperviscosity syndrome:

Cytopenias and infections:

Bleeding:

Neurologic complications:

Immune-mediated complications:

Renal complications:

Transformation:

Therapy-related complications:

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Symptomatic hyperviscosity with neurologic symptoms (altered mental status, stroke-like deficits, seizures, severe headache with focal signs)

— Acute visual loss from retinal hemorrhage or central retinal vein occlusion

— Active mucosal bleeding requiring transfusion or airway protection

— Hemodynamic instability from anemia + plasma volume expansion → CHF

— Severe AIHA with hemodynamic compromise

— Tumor lysis (rare; with venetoclax or high tumor burden)

— Suspected stroke or intracranial event in patient with very high IgM

— Hematology/oncology — confirm diagnosis, plan systemic therapy

— Apheresis service — for plasmapheresis activation

— Ophthalmology — fundus documentation and management of retinal hemorrhage

— Neurology — when neuropathy, Bing–Neel, or stroke-like symptoms

— Nephrology — AKI or new significant proteinuria

— Cardiology — concern for amyloid cardiomyopathy or BTK-inhibitor-associated arrhythmia

— Admit to monitored bed

— NPO if mental status compromised; IV access ×2 (large bore)

— STAT: CBC with smear, CMP, LDH, uric acid, serum viscosity, SPEP/IFE, quantitative Igs, free light chains, type & screen, coags, fibrinogen, cryoglobulins (warm transport), DAT, NT-proBNP, troponin

— Imaging: CT head if neuro symptoms; ECG; chest X-ray

— IV NS at maintenance, hold transfusions until after TPE if possible

— Consult hematology and apheresis emergently

— Begin glucocorticoids if cryoglobulinemic vasculitis or severe AIHA

— Start HBV screening results review before any rituximab

— Resolution of HVS symptoms, serum viscosity <3 cP

— Stable hemoglobin, stable mental status

— Outpatient hematology follow-up within 1–2 weeks for treatment plan

— Patient counseling: signs to return (vision change, neuro symptoms, bleeding, fever)

Step 3 management: A WM patient in clinic with new headache, blurred vision, and epistaxis is a same-day ED referral, not "schedule plasmapheresis next week" — call ahead for STAT viscosity and apheresis activation.

Immediate ICU or step-down admission criteria:

Urgent same-day consultations:

CCS-style order set for acute HVS admission:

Inpatient → outpatient transition triggers:

Key Differentials — Same-Category B-Cell/Plasma Cell Disorders

— IgM <3 g/dL, bone marrow LPL <10%, no end-organ damage

— Watchful waiting; 1–2%/year progression to WM, AL amyloid, or B-cell lymphoma

— Distinguishing feature: by definition no WM-defining symptoms

— Marrow ≥10% LPL or IgM ≥3 g/dL but no symptoms

— Observe; risk of progression ~6–12%/year early, declining over time

— Clonal plasma cells (CD138+, CD20–, cyclin D1 sometimes+) without MYD88 L265P

— Lytic bone lesions, hypercalcemia, renal failure more typical

— Light chains and IgG/IgA isotypes more common; IgM myeloma is rare and often has t(11;14)

— Key distinction: MYD88 mutation status and CD20 expression separate WM from IgM myeloma

— CD5+, CD23+, CD20 dim, often absolute lymphocytosis on CBC

— Lacks robust IgM paraprotein; rouleaux uncommon

— Smudge cells on smear

— CD5+, cyclin D1+, t(11;14), often more aggressive

— Can have leukemic phase; lacks IgM paraprotein typically

— Can produce IgM monoclonal protein and infiltrate marrow — overlaps clinically

— Typically MYD88-wildtype; bone marrow pattern and lymph node histology distinguish

— HCV association (especially splenic MZL)

— Pancytopenia, splenomegaly, no lymphadenopathy; CD11c+, CD25+, CD103+, BRAF V600E mutation

— No IgM paraprotein

— Rare LPL variants secreting IgG or IgA; treated similarly when symptomatic; not classified as WM

— Can be independent or secondary to WM/MGUS

— Look for organ deposition pattern; tissue biopsy confirms

— Treatment combines plasma cell–directed therapy ± clone-specific approach

Key distinction: WM = LPL in marrow + IgM monoclonal protein + MYD88 L265P. CLL is CD5+/CD23+; mantle cell is CD5+/cyclin D1+; myeloma is CD20–/CD138+ with no MYD88. These four immunophenotype/genetic anchors resolve nearly every Step 3 stem.

IgM MGUS:

Smoldering (asymptomatic) WM:

Multiple myeloma (especially IgM myeloma):

Chronic lymphocytic leukemia (CLL):

Mantle cell lymphoma:

Marginal zone lymphoma (splenic, nodal, MALT):

Hairy cell leukemia:

Lymphoplasmacytic lymphoma without IgM:

AL amyloidosis (primary):

Key Differentials — Other-Category Mimics

— Chronic infection (HIV, HCV, TB), autoimmune disease (SLE, Sjögren), chronic liver disease

— SPEP shows broad-based gamma elevation without discrete M-spike

— Immunofixation negative for monoclonal band

— HCV-associated mixed cryoglobulinemia (type II/III) — most common cause overall; treat underlying HCV with DAAs

— Connective tissue disease–related cryoglobulins

— Distinguish by viral serologies and absence of dominant IgM monoclonal LPL

— Primary CAD is itself a clonal LPL-like disorder (often MYD88-mutated) but with low marrow involvement; treated with sutimlimab (C1s inhibitor), rituximab-based regimens

— Secondary CAD: Mycoplasma, EBV, lymphoma

— Overlap with WM exists; classify carefully

— Atherosclerotic, embolic, hypertensive — but absence of paraprotein and rouleaux on smear should redirect

— Diabetic, B12 deficiency, alcohol, paraneoplastic, CIDP — CIDP in particular overlaps with anti-MAG neuropathy; SPEP/IFE is essential to find IgM

— Anti-MAG titer differentiates IgM neuropathy from idiopathic CIDP

— Hypertensive heart disease, HCM, restrictive cardiomyopathy of other etiology

— Suspect amyloid when low-voltage ECG with thick walls on echo, granular sparkling myocardium, apical sparing on strain imaging, discordant NT-proBNP/troponin elevation

— Pyrophosphate scan and biopsy distinguish AL from ATTR

— Severe hyperlipidemia, hyperproteinemia (WM, myeloma) — confirm with direct ion-selective electrode Na measurement; do not treat with hypertonic saline

— Warm AIHA (IgG-mediated) vs cold (IgM/C3d) — DAT pattern distinguishes; cold AIHA in WM patient supports cold agglutinin pathway

Board pearl: A patient with HCV + palpable purpura + glomerulonephritis + low C4 has HCV-associated mixed cryoglobulinemia, not WM. Check HCV before attributing cryoglobulinemia to a B-cell clone.

Polyclonal hypergammaglobulinemia mimicking paraproteinemia:

Cryoglobulinemia from other causes:

Cold agglutinin disease (CAD):

Stroke and visual loss from non-WM causes:

Peripheral neuropathy mimics:

Heart failure mimics for amyloid:

Other causes of pseudohyponatremia:

Autoimmune hemolytic anemia (warm AIHA):

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Initiated systemic therapy plan (BTK inhibitor or chemoimmunotherapy schedule) with clear dosing instructions

— Antimicrobial prophylaxis as indicated:

— TMP-SMX for PJP (bendamustine, prolonged steroids, BTKi in high-risk)

— Acyclovir/valacyclovir for herpes reactivation with bortezomib or bendamustine

— Antifungal prophylaxis case-by-case

— HBV antiviral prophylaxis (entecavir/tenofovir) for HBsAg+ or anti-HBc+ patients on rituximab — continue ≥12 months after last dose

— Anti-emetics for chemotherapy days

— Stool softeners; antidiarrheals PRN for BTKi-related diarrhea

— Hold/coordinate anticoagulation: prefer DOAC over warfarin if on BTK inhibitor

— Pneumococcal: PCV20 (or PCV15 + PPSV23)

— Annual influenza (inactivated)

— Shingrix (non-live) — important on BTKi/bortezomib

— COVID-19 boosters per current guidance

— RSV vaccine if ≥60

— Hepatitis B if non-immune (and not on active rituximab — give before therapy when possible)

— Avoid live vaccines (MMR, varicella, yellow fever, live influenza) on therapy and for 6–12 months after

— Consider for patients with hypogammaglobulinemia (IgG <400) and recurrent serious bacterial infections — typical dose 400 mg/kg every 3–4 weeks

— Reassess every 6–12 months

— CBC, CMP, SPEP/IFE, quantitative IgM every 3 months in first year, then every 3–6 months

— Serum viscosity if IgM trending up or symptoms

— Annual screen for transformation, secondary malignancies (skin cancer, MDS)

— Bone marrow biopsy only as indicated (response assessment, suspected progression/transformation)

— Blood pressure check at every visit; treat HTN aggressively

— ECG annually or with symptoms; ambulatory monitor if palpitations

— Reassess need for anticoagulation if AFib develops; weigh against bleeding risk

— Avoid cold exposure if cryoglobulinemia/CAD

— Fall and bleeding precautions on BTKi

— Hydration; sun protection (increased skin cancer risk)

Step 3 management: At discharge, schedule a hematology follow-up within 1–2 weeks, confirm prescription pickup, document HBV/vaccination status, and provide written "return precautions" for vision change, neuro symptoms, fever, and bleeding — a frequent Step 3 transition-of-care theme.

Discharge medications after acute WM event:

Vaccinations (ideally before or between therapy cycles):

IVIG replacement:

Long-term monitoring framework:

Cardiovascular risk on BTK inhibitors:

Lifestyle counseling:

Follow-Up, Monitoring, and Counseling

— Active treatment: monthly during induction with labs each cycle (CBC with diff, CMP, IgM)

— Maintenance/observation: every 3 months for first year, then every 3–6 months indefinitely

— Stable IgM MGUS/smoldering WM: every 6 months once initial stability established

— Symptoms checklist: fatigue, vision changes, headaches, bleeding, neuropathy progression, cold sensitivity, B symptoms, infections

— Labs: CBC, CMP, LDH, quantitative IgM/IgG/IgA, SPEP ± IFE periodically

— Serum viscosity if IgM rising or new symptoms

— Blood pressure, weight, performance status

— On BTKi: ECG annually, ambulatory monitor with palpitations

— Categories: CR, VGPR (≥90% IgM reduction), PR (≥50%), MR (≥25%), SD, PD

— Use trends rather than single values; IgM can lag clinical response (and flare with rituximab)

— Reassess marrow when discordance between symptoms and IgM, or before stopping fixed-duration therapy

— Repeat CT scans only if initial bulky disease being followed, or new symptoms

— Routine PET not recommended unless transformation suspected

— Neuropathy: PT/OT for gait training, fall prevention; symptomatic pharmacotherapy (gabapentin, duloxetine); avoid neurotoxic agents

— Cardiac rehab if amyloid heart failure

— Nutrition referral for cachexia/malabsorption

— Palliative care integration early in advanced/symptomatic disease — supports symptom management even alongside active therapy

— Disease is incurable but chronic — expectation-setting; many patients live 10+ years

— Adherence to oral BTKi: avoid strong CYP3A inhibitors/inducers (grapefruit, certain antifungals, rifampin); coordinate with pharmacist

— Bleeding precautions: soft toothbrush, electric razor; hold BTKi periprocedurally per surgical team

— Infection precautions: seek care for fever >38°C; hand hygiene; mask in high-risk settings

— Cold-exposure avoidance (gloves, scarves) for cold agglutinin/cryoglobulinemia

— Discuss clinical trial options at relapse

Board pearl: Use quantitative IgM trends + symptoms + Hb, not the SPEP M-spike alone, to track WM response — the SPEP underestimates IgM and lags clinical reality, a Step 3 favorite distractor.

Visit cadence:

Key monitoring parameters at each visit:

Response assessment criteria (modified IWWM):

Imaging:

Rehabilitation and supportive care:

Patient counseling priorities:

Ethical, Legal, and Patient Safety Considerations

— BTK inhibitors are typically continuous, indefinite, expensive, and carry cardiovascular/bleeding risks — patients must understand chronicity, AE profile, and cost/insurance implications before initiation

— Document discussion of alternatives (chemoimmunotherapy with fixed duration, observation if indicated)

— Reassess goals of care annually and at progression

— WM is incurable; integrate goals-of-care conversations early, especially in elderly with comorbidities

— Document code status, healthcare proxy, advance directive at every hospitalization

— Early palliative care consultation improves symptom control and decision-making — does not preclude disease-directed therapy

— At hospital discharge after HVS: ensure scheduled hematology follow-up within 1–2 weeks, medication reconciliation (especially anticoagulation changes around BTKi), and written return precautions for vision/neuro/bleeding symptoms

— Use teach-back to confirm patient understanding of new oral chemotherapy

— Coordinate with specialty pharmacy for BTK inhibitor delivery — gaps in fills can compromise disease control

— Anticoagulation: avoid warfarin with ibrutinib; use DOAC if AFib develops on BTKi and bleeding risk acceptable

— Drug interactions: BTK inhibitors are CYP3A substrates — counsel against grapefruit, strong inhibitors (clarithromycin, ketoconazole), and strong inducers (rifampin, St. John's wort)

— Pseudohyponatremia awareness: do not give hypertonic saline reflexively in WM patients with low measured sodium — could cause iatrogenic harm

— Document vaccine refusal; revisit periodically; ensure access regardless of insurance status

— Visual loss from retinal hemorrhage can trigger driving restrictions — counsel and document per state law

— Cognitive impairment in Bing–Neel: assess decision-making capacity formally before major decisions

— Discuss availability at relapse and refractory disease; ensure equitable referral; informed consent must cover unknowns

— ~20-fold familial risk — when first-degree relatives report symptoms (anemia, neuropathy, recurrent infection), recommend SPEP/CBC; routine genetic testing not required

Step 3 management: When a WM patient is discharged on a new BTK inhibitor, stop and reassess all anticoagulants and CYP3A-interacting drugs, schedule a 1–2 week follow-up, and confirm specialty-pharmacy fill — this transition-of-care checklist is a recurring exam stem.

Informed consent for indefinite oral therapy:

Goals of care and advance directives:

Transitions-of-care safety (high-yield Step 3 theme):

Medication safety:

Vaccination ethics and equity:

Mandatory reporting and disability:

Clinical trial enrollment:

Genetic counseling:

High-Yield Associations and Rapid-Fire Clinical Facts

— MYD88 L265P in >90% — diagnostic and predictive of BTKi response

— CXCR4 mutations in 30–40% — more hyperviscosity, attenuated BTKi response

— MYD88-wildtype — worse prognosis, may not respond to BTKi

— LPL: CD19+, CD20+, CD22+, surface IgM+, CD5– (usually), CD10–, CD23– (usually), CD138+ on plasmacytic component

— Rouleaux on smear; pseudohyponatremia; large gamma gap

— IgM M-spike on SPEP; quantitative IgM elevated; IgG/IgA often suppressed

— Direct Coombs C3d+ in cold agglutinin variants

— Treat based on symptoms, not IgM number

— Plasmapheresis for symptomatic HVS — IgM is intravascular → TPE is highly effective

— Avoid rituximab monotherapy if IgM >4 g/dL or HVS — risk of IgM flare

— Zanubrutinib > ibrutinib for cardiac safety in WM

— Bortezomib SC weekly to reduce neuropathy

— Bendamustine — secondary MDS risk, prolonged CD4 lymphopenia → prophylaxis

— Anti-MAG IgM — demyelinating neuropathy

— Cold agglutinins — anti-I (Mycoplasma also), anti-i (mononucleosis)

Board pearl: "Older man, anemia, epistaxis, blurry vision, rouleaux, IgM 5 g/dL, marrow with lymphoplasmacytic infiltrate, MYD88 L265P" — Waldenström macroglobulinemia with hyperviscosity → plasmapheresis now, systemic therapy soon.

Genetics anchors:

Cell of origin / immunophenotype:

Lab signatures:

Funduscopy: "sausage-link" tortuous retinal veins — classic HVS sign

Triad of hyperviscosity: mucosal bleeding + visual changes + neurologic symptoms

Treatment thresholds:

Drug-specific pearls:

Antibody associations:

Familial risk: ~20× increased in first-degree relatives

Transformation: ~5% to DLBCL — rising LDH, new bulky disease, rapid B symptoms

Bing–Neel syndrome: CNS WM — use CNS-penetrant ibrutinib, IT therapy, MTX-based regimens

Amyloid alert: macroglossia, periorbital purpura, nephrotic syndrome, low-voltage ECG with thick walls — biopsy with Congo red apple-green birefringence

HBV reactivation prophylaxis: mandatory with rituximab if HBsAg+ or anti-HBc+ — entecavir/tenofovir, continued ≥12 months post-therapy

Vaccines: pneumococcal, influenza, shingles (non-live), COVID, RSV; avoid live vaccines on therapy

Pseudohyponatremia: confirm with direct ISE; do not give hypertonic saline

Acquired vWD: mucosal bleeding with normal platelets and INR → check vWF, factor VIII

Board Question Stem Patterns

— 70 y/o man with fatigue, epistaxis, blurred vision; fundus shows dilated tortuous retinal veins; total protein 11 g/dL, albumin 3.8, Na 128, Hb 9

— Best next step? → Plasmapheresis (after STAT viscosity), then bone marrow biopsy and systemic therapy

— Distractor: "transfuse PRBCs" — wrong, worsens viscosity

— 65 y/o woman with incidental IgM monoclonal protein 1.8 g/dL on routine SPEP, asymptomatic, Hb 13, marrow LPL 8%

— Diagnosis: IgM MGUS

— Management: Observation with serial SPEP/CBC every 6 months — not treatment

— Patient with WM, Na 124, normal serum osmolality, total protein 12

— Cause: Pseudohyponatremia from hyperproteinemia

— Best next step: Confirm with direct ion-selective electrode; do NOT give hypertonic saline

— New WM, IgM 6 g/dL, mild symptoms; physician plans single-agent rituximab

— Concern: IgM flare worsening hyperviscosity

— Best next step: Lower IgM first (plasmapheresis or combination regimen) before rituximab

— Older patient with progressive distal sensory ataxia, paraprotein, anti-MAG antibody positive

— Diagnosis: IgM-associated demyelinating neuropathy, likely WM

— Management: Bone marrow biopsy; if WM confirmed and neuropathy disabling, treat with rituximab-based regimen

— WM patient with new focal deficits and cognitive change, MRI shows leptomeningeal enhancement, CSF with clonal B cells and MYD88 L265P

— Therapy: CNS-penetrant ibrutinib ± intrathecal therapy

— Patient with positive anti-HBc starting BR

— Best step: Initiate entecavir or tenofovir prophylaxis before rituximab; continue ≥12 months after therapy

— Patient with lytic bone lesions, hypercalcemia, IgM monoclonal protein, MYD88-wildtype, CD138+/CD20– plasma cells → IgM multiple myeloma, not WM

— Patient on ibrutinib develops AFib; currently on warfarin

— Best step: Switch to a regimen that avoids ibrutinib-warfarin combination — consider zanubrutinib + DOAC if anticoagulation indicated and bleeding risk acceptable

— WM patient with mucosal bleeding, normal platelets/INR

— Diagnosis: Acquired von Willebrand syndrome — check vWF activity

Key distinction: Step 3 stems hinge on treat-the-symptom-not-the-number logic, plasmapheresis as bridge, avoiding rituximab flare, HBV prophylaxis, and pseudohyponatremia recognition — recurring motifs across question sets.

Stem 1 — Classic HVS:

Stem 2 — Asymptomatic IgM:

Stem 3 — Pseudohyponatremia:

Stem 4 — Rituximab flare risk:

Stem 5 — Anti-MAG neuropathy:

Stem 6 — Bing–Neel:

Stem 7 — HBV reactivation:

Stem 8 — Distinguishing diagnoses:

Stem 9 — BTKi complication:

Stem 10 — Acquired vWD:

One-Line Recap

Waldenström macroglobulinemia is an indolent IgM-secreting lymphoplasmacytic lymphoma diagnosed by ≥10% clonal marrow LPL with a monoclonal IgM (usually MYD88 L265P–mutated), treated only when symptomatic — with plasmapheresis as an emergency bridge for hyperviscosity, and zanubrutinib or bendamustine–rituximab as preferred first-line systemic therapy.

Board pearl: When the stem screams "older man + anemia + epistaxis + blurred vision + rouleaux + IgM spike," your reflex is plasmapheresis now, bone marrow biopsy with MYD88 testing next, systemic therapy soon — and never forget HBV screening before rituximab.

Diagnose: Bone marrow biopsy showing ≥10% clonal LPL + IgM monoclonal protein + MYD88 L265P confirms WM; check CXCR4 to predict BTKi response; exclude IgM myeloma (lytic bone, CD138+/CD20–, MYD88-wildtype) and CLL (CD5+/CD23+).

Triage: Treat only with end-organ disease — hyperviscosity, Hb ≤10, plt <100, bulky disease, B symptoms, neuropathy, cryoglobulinemia, AIHA, Bing–Neel, amyloidosis. Asymptomatic IgM MGUS or smoldering WM = observation, not therapy.

Emergency lever: Symptomatic hyperviscosity → urgent plasmapheresis (IgM is intravascular), avoid pre-TPE PRBC transfusion when possible, then initiate systemic therapy; never use single-agent rituximab when IgM >4 g/dL or HVS active — rituximab flare can be catastrophic.

Long game: Prefer zanubrutinib (less AFib/HTN than ibrutinib) or BR/DRC; screen and prophylax for HBV before rituximab; vaccinate (avoid live); monitor with quantitative IgM + symptoms + Hb every 3–6 months; counsel on bleeding precautions, CYP3A interactions, cold avoidance, and arrange close transition-of-care follow-up within 1–2 weeks of any acute event.