Second-Line Therapy Options in Waldenstrom Macroglobulinemia


Steven P. Treon, MD, PhD:In this particular case, the patient then relapses 2 years later. Now we’re dealing with a patient who has a rising IgM [immunoglobulin M] level. His lymph nodes are no longer bulky. And so, this case has actually changed. When the patient now comes back to us, we no longer are dealing with an oncologic emergency. Now we have other options that we can consider in the care of this patient. What we would not want to do is add in alkylating agents because we don’t want to potentiate any damage to his stem cells. So this is really where we have some time to think about what’s best for this patient and to manage him with other treatment options.

In the second-line setting, where this patient does not need emergent therapy, we would still be mindful of using a proteasome inhibitor, potentially. I think the fact that he still has adenopathy might sway me against that. Ordinarily, proteasome inhibitors are really good at cleaning out disease in the marrow but are not so good at dealing with extramedullary disease.

I would avoid using alkylating agents in this particular case. I would also avoid a nucleoside analogue because, again, if he’s young, we don’t want to put him at risk for secondary malignancies or myelodysplasia. This is a particular patient who I would actually get very excited about using ibrutinib in at this point in time. We know he has theMYD88mutation. We also know that he has theCXCR4mutation, but we’re no longer dealing with imminent disease control that would be required. One has to understand that if one has aCXCR4mutation, you have to set expectations. You know this is not somebody who’s going to respond overnight to a drug like ibrutinib. It may take a while. That’s why it’s important for clinicians to know about the mutation status of an individual. Then you can set expectations. You won’t panic after a couple of months if you are not seeing a major response, understanding that it may take time in somebody who has aCXCR4mutation.

The fact that the patient did well for 2 years would also suggest to me to use ibrutinib along with rituximab in this particular case. One could certainly use ibrutinib alone, but since the patient did have benefit with the 2 drugs together—the bendamustine and rituximab up front—I think it would be very reasonable to use both drugs together. We know from the iNNOVATE study that the patients who got ibrutinib and rituximab together showed improvement over rituximab alone. For somebody who has aCXCR4mutation, I think the combination would be reasonable.

Transcript edited for clarity.

A 42-Year-Old Male With Relapsed/Refractory Waldenström Macroglobulinemia

September 2016

  • A 42-year old male presented with blurry vision and nosebleeds.
  • Physical examination revealed retinal hemorrhages, adenopathy, and splenomegaly.
  • Laboratories revealed a hematocrit of 18% (normal 34.8-43.6%)
    • Platelets of 50,000/mm3(normal 155,000-410,000/mm3)
    • Leukocyte count of 1,500/mm3(normal 3,800-9,200/mm3)
  • Serum total protein was high prompting a workup that revealed an IgMλ monoclonal protein and serum IgM level of 12,400 mg/dL.
  • CT scans showed bulky adenopathy (> 5 cm)
  • A bone marrow biopsy revealed that 80% of the intertrabecular space was involved with lymphoplasmacytic lymphoma.
  • Immunohistochemistry demonstrated CD20 expressing bone marrow disease.
  • Molecular diagnostic testing for MYD88 and CXCR4 is pending


  • The patient began several emergent rounds of plasmapheresis, and his vision and energy improved.
  • His retinal exam improved and repeat serum IgM level was 3,892 mg/dL.
  • The molecular diagnostic studies showed MYD88 L265P and CXCR4 nonsense mutations to be present in the tumor cells.
  • The patient received bendamustine alone for two cycles, then rituximab was added to bendamustine for 2 more cycles. He attained a major response.

September 2018

  • Two years later, he relapsed with progressive adenopathy (< 5 cm), symptomatic anemia, and his serum IgM rose to 5,459 mg/dL.
  • Patient was started on rituximab/ibrutinib combination therapy.
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