What is the recommended initial treatment for a patient with a hypercellular marrow (80%) showing an atypical lymphoid infiltrate, MYD88 (Myeloid Differentiation Primary Response 88) mutation, lytic lesions, and elevated Immunoglobulin M (IgM) level?

Treatment of Waldenström Macroglobulinemia with MYD88 Mutation and High IgM

For this patient with symptomatic Waldenström macroglobulinemia (WM) presenting with MYD88 mutation, lytic lesions, and markedly elevated IgM (5100 mg/dL), the recommended initial treatment is bendamustine-rituximab (BR) for 4-6 cycles, with consideration for plasmapheresis prior to rituximab administration given the very high IgM level. 1

Rationale for Treatment Selection

Why Bendamustine-Rituximab is Preferred

• BR is specifically recommended for patients with high IgM levels, symptomatic hyperviscosity, and when expeditious disease control is needed 1
• The combination is well-tolerated even in elderly patients, with four cycles appearing adequate to achieve response 1
• BR produces objective response rates >80% and demonstrates durable responses 1
• In elderly patients and those with renal impairment, dose adjustment of bendamustine should be considered 1

Critical Pre-Treatment Consideration: Plasmapheresis

Plasmapheresis should be performed immediately before initiating rituximab in this patient 1. Here's why:

• IgM level of 5100 mg/dL is well above the 4000 mg/dL threshold where rituximab can cause IgM flare 1
• Rituximab monotherapy should be avoided in patients with very high serum IgM levels 1
• Plasmapheresis prevents IgM flare and symptomatic hyperviscosity that can occur when rituximab is administered to patients with elevated IgM 1
• Always combine plasmapheresis with chemoimmunotherapy or targeted therapy—never use it as monotherapy 1

Alternative First-Line Options

Ibrutinib as Primary Therapy

Ibrutinib represents an effective option for treatment-naive patients with MYD88 mutation 1, 2, but has specific considerations:

• The MYD88 mutation status makes this patient an excellent candidate for ibrutinib, as patients with MYD88 mutation alone achieve metabolic response rates of 92% 1
• Consider ibrutinib as primary therapy for symptomatic patients not candidates for chemoimmunotherapy 1
• Important caveat: Serum IgM might increase and hemoglobin might decrease if ibrutinib is stopped, and this should not be considered treatment failure 1, 2
• Ibrutinib should not be interrupted because discontinuation leads to hemoglobin decrease and IgM increase 1, 2

Bortezomib-Based Regimens

Consider bortezomib-based combinations for patients with high IgM levels, symptomatic hyperviscosity, or in young patients to avoid myelotoxic agents 1:

• Use subcutaneous administration and weekly dosing to reduce neurotoxicity 1
• Particularly appropriate for younger patients where preservation of stem cell reserve is important 1
• Avoid in patients with pre-existing peripheral neuropathy grade >2 1

DRC (Dexamethasone-Rituximab-Cyclophosphamide)

• Consider DRC when disease burden is low (absence of extensive lymphadenopathy/extramedullary disease) 1
• DRC remains a primary choice but is less appropriate than BR when expeditious disease control is needed 1

What NOT to Use

Avoid these regimens in the frontline setting:

• Rituximab monotherapy is inferior to combination regimens 3, 4 and should be avoided in patients with high IgM levels 1
• R-CHOP is no longer considered first-line choice 1
• Fludarabine-based combinations are not recommended for primary therapy, reserved only for relapsed/refractory disease 1

Monitoring During Treatment

Response Evaluation

• Response evaluation is based on serial measurements of monoclonal IgM in serum and relative reduction of IgM 1, 2
• Bone marrow assessments are not routinely recommended for response evaluation except to establish complete response 1, 2
• Discordant results between IgM reduction and bone marrow infiltration have been reported with several agents, including BTK inhibitors 1, 2

Follow-Up Schedule

• Monitor CBC, comprehensive metabolic panel, and IgM every 3 months 2
• Watch for symptoms of hyperviscosity (visual changes, headache, bleeding, neurologic symptoms) if IgM rises above 4000 mg/dL 1, 2
• Routine imaging is not recommended unless baseline lymphadenopathy/organomegaly was present 1

Special Consideration: Lytic Lesions

The presence of lytic lesions in this patient is unusual for WM and raises important diagnostic considerations:

• Lytic bone lesions are rare in WM and should prompt consideration of transformation to higher-grade lymphoma or concurrent plasma cell disorder 1
• Ensure that multiple myeloma has been excluded, as the combination of lytic lesions with IgM paraprotein is atypical 1
• If transformation is suspected, bone marrow biopsy should be repeated before initiating therapy 1

Post-Treatment Management

On completion of primary therapy, responders should be observed periodically until disease progression or reemergence of WM-related symptoms 1:

• Rituximab maintenance therapy should not be routinely used outside clinical trials 1
• A single nonrandomized study showed improved outcomes with rituximab maintenance but at the cost of increased toxicity 1
• Nonresponders to primary therapy with persistent symptoms should be offered an alternative regimen 1

Common Pitfalls to Avoid

1. Do not start rituximab without plasmapheresis in patients with IgM >4000 mg/dL 1
2. Do not interpret IgM flare as treatment failure, particularly in the first 6 months of rituximab therapy 1, 2
3. Do not discontinue ibrutinib for elevated IgM alone without evidence of clinical progression (worsening anemia, thrombocytopenia, increasing lymphadenopathy, or new hyperviscosity symptoms) 2
4. Do not use bone marrow biopsy routinely for response assessment unless establishing complete response or when clinical concern for progression is discordant with IgM levels 1, 2
5. Do not overlook the possibility of disease transformation when atypical features like lytic lesions are present 1