Precision Medicine in Waldenstrom Macroglobulinemia

Steven P. Treon, MD, PhD:I think it’s really important that we talk about precision medicine. Patients should be worked up. Getting theMYD88mutation is very, very important. It’s important to understand its status in patients with Waldenström. It will help in the diagnosis. It may also play a role in the prognosis. We know that patients who don’t have theMYD88mutation tend to have decreased survival, but they are also at risk for increased transformation to aggressive lymphoma. So I think from the get-go, it really helps us make the diagnosis and prognosis, and can also help with treatment. We know that with ibrutinib monotherapy, patients who don’t carry theMYD88mutation don’t show those deep responses. The 95% of patients that do, on the other hand, benefit with BTK [Bruton tyrosine kinase] inhibitors. So it’s important to know that.

The L265P mutation is the most commonMYD88mutation. You see it in almost all patients, but there’s a small handful of patients who can carry non-L265P mutations. So if somebody is getting a PCR [polymerase chain reaction] work-up for theMYD88mutation and they come back as wild type, that may be because the patient either has a low disease burden or may have one of these non-L265P mutations. In that case, you want to use Sanger sequencing or next-generation sequencing to determine that.

CXCR4is really important because it gives us a sense of disease presentation. Patients who have nonsense mutations tend to be the ones who present with very high IgM [immunoglobulin M] loads, symptomatic hyperviscosity, and need to be treated sooner than later. So I think it’s really important. And also, it impacts a lot of drugs. We’re now seeing data on ibrutinib impacting deep response attainment and time to response. It’s important to know this because it then sets expectations for the patient. If somebody needs an acute response to therapy, you would take that into account.

Also, from a development point of view, this is a targetable mutation. There’s a lot of research going on using CXCR4 antagonists. I do think that if we were to have this interview maybe 5 years from now, there would be an action for using this for aCXCR4mutation. You would specifically treat that person with the CXCR4 antagonist. I think that’s what’s really exciting in that regard.

So being able to get both mutations from the get-go helps you understand the patient and develop a comprehensive treatment strategy.

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

Treatment

• 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.