Can a patient with Waldenstrom's macroglobulinemia (WM) develop myelomatous lesions?

Can Waldenstrom's Macroglobulinemia Present with Myelomatous Bone Lesions?

Yes, although extremely rare, Waldenstrom's macroglobulinemia can present with destructive bone lesions that appear myelomatous on imaging, but this finding should prompt immediate reconsideration of the diagnosis.

Critical Diagnostic Distinction

The presence of lytic bone lesions on MRI in a patient with a diagnosis of WM is highly atypical and requires urgent diagnostic reassessment. The MYD88 L265P mutation is present in approximately 90% of WM cases but is absent in IgM multiple myeloma, making this the single most important test to distinguish between these entities 1.

Immediate Next Steps

• Obtain MYD88 L265P mutation testing immediately - this mutation is found in >90% of WM but is absent in multiple myeloma, making it the definitive discriminator 1.
• Verify the immunoglobulin type - WM produces monoclonal IgM, while myeloma typically produces IgG or IgA 1.
• Perform bone marrow biopsy from the lesion site - WM shows lymphoplasmacytic cells (CD19+, CD20+, CD22+, CD79a+), while myeloma shows plasma cells 1.

Why This Presentation is Problematic

Destructive bone lesions are a hallmark of multiple myeloma but have been repeatedly emphasized as rare in WM 2. The ESMO guidelines explicitly state that imaging studies (CT or MRI) should be included in initial WM evaluation, but they do not list bone destruction as a typical feature 1.

The Rare Exception

A 2022 case report documented a patient with confirmed WM who presented with vertebral compression fracture as the first symptom 2. This case demonstrated that:

• Bone destruction may not always clearly distinguish WM from multiple myeloma 2.
• The diagnosis was confirmed through vertebral bone marrow biopsy showing lymphoplasmacytic infiltration 2.
• This represents an exceptional presentation rather than typical disease behavior 2.

Diagnostic Algorithm When Bone Lesions Are Present

1. First priority: Confirm the diagnosis is actually WM

   • Order MYD88 L265P mutation testing by AS-PCR 1
   • Review bone marrow histopathology for lymphoplasmacytic cells versus plasma cells 1
   • Confirm monoclonal IgM (not IgG or IgA) by immunofixation 1

2. If MYD88 is negative or equivocal:

   • Strongly consider the diagnosis is actually IgM multiple myeloma, not WM 1
   • IgM myeloma is rare but does exist and would explain lytic lesions
   • Treatment approach differs significantly between these entities

3. If MYD88 L265P is positive and diagnosis confirmed as WM:

   • Consider biopsy of the bone lesion to rule out transformation to aggressive lymphoma 1
   • Evaluate for secondary malignancy (WM patients have increased risk) 1
   • If truly WM with bone involvement, this represents highly atypical disease requiring aggressive therapy 2

Treatment Implications if Confirmed as WM with Bone Lesions

If the diagnosis is definitively WM (MYD88 L265P positive, lymphoplasmacytic cells, monoclonal IgM), the presence of destructive bone lesions indicates high tumor burden requiring immediate aggressive therapy 1.

• Bendamustine plus rituximab (BR) for 4-6 cycles is the primary option for high tumor burden WM 1.
• Bortezomib/dexamethasone/rituximab (BDR) is an alternative for rapid disease control 1.
• Single-agent ibrutinib may be considered if patient is ineligible for chemoimmunotherapy 1.

Critical Caveat

The far more likely scenario is diagnostic error - lytic bone lesions strongly suggest IgM multiple myeloma rather than WM 1, 2. Do not proceed with WM-directed therapy until MYD88 mutation status definitively confirms the diagnosis, as treatment approaches differ substantially between these entities.