Waldenström's Macroglobulinemia / Lymphoplasmacytic Lymphoma

Evidence-based treatment sequencing for symptomatic Waldenström's macroglobulinemia, integrating MYD88 and CXCR4 mutational profiling to guide frontline selection between targeted BTK inhibition (zanubrutinib/ibrutinib) and chemo-immunotherapy (bendamustine-rituximab), with non-cross-resistant salvage sequencing.

Symptomatic indication and MYD88 / CXCR4 mutational profiling

• MYD88-mutant — targeted BTK pathway → BTK inhibitor — zanubrutinib or ibrutinib (± rituximab)
• Fixed-duration bendamustine-rituximab preference / MYD88 wild-type → Bendamustine + rituximab (BR)

1L: BTK inhibitor — zanubrutinib or ibrutinib (± rituximab)

Preferred frontline targeted therapy for MYD88-mutant WM, giving deep, durable responses (ASPEN/iNNOVATE). Zanubrutinib is favored over ibrutinib for its improved cardiac/tolerability profile; CXCR4 mutation can blunt or delay BTK-inhibitor response.

• Disease progression or intolerance → Disease progression or intolerance following frontline therapy

1L: Bendamustine + rituximab (BR)

Standard fixed-duration chemo-immunotherapy frontline option — preferred for patients wanting time-limited therapy, needing rapid disease control (e.g. bulky disease), or with MYD88 wild-type disease that responds poorly to BTK inhibition. Manage IgM flare risk if rituximab is used without plasmapheresis in hyperviscosity.

• Disease progression or relapse → Disease progression or intolerance following frontline therapy

Disease progression or intolerance following frontline therapy

• Alternative targeted therapy crossover → Alternative targeted class — BTK crossover or venetoclax
• Proteasome-inhibitor salvage preference → Proteasome inhibitor combination — bortezomib + rituximab + dexamethasone

2L: Alternative targeted class — BTK crossover or venetoclax

Second-line transition to an unexposed targeted mechanism — an alternative BTK inhibitor after prior chemo-immunotherapy, or venetoclax (BCL-2 inhibition) in BTK-exposed disease.

• Subsequent progression → Clinical trial referral / specialized salvage regimens

2L: Proteasome inhibitor combination — bortezomib + rituximab + dexamethasone

Cytotoxic/biologic salvage for patients needing rapid disease control or with prior BTK-inhibitor exposure; monitor for peripheral neuropathy with bortezomib.

• Subsequent progression → Clinical trial referral / specialized salvage regimens

3L+: Clinical trial referral / specialized salvage regimens

Clinical-trial evaluation or multi-agent salvage therapy for heavily pretreated refractory disease.