COMy 2021 | Challenges associated with Waldenström’s

There are a couple of challenges that come into my mind. I think initially, probably we have the diagnostic challenges. There are a number of indolent lymphomas that sometimes can look like Waldenström’s, specifically marginal zone lymphoma. Clinically speaking and pathologically speaking, sometimes it’s difficult to differentiate a marginal zone lymphoma from a lymphoplasmacytic lymphoma. I think this is where the discovery of the MYD88 mutation has been important, given that this mutation is prevalent in over 90% of patients with lymphoplasmacytic lymphoma or Waldenström’s, but less than 5 to 10% of patients with marginal zone lymphoma have this mutation. So in a situation which we have a patient, for example, with a B-cell lymphoma, with plasmacytic differentiation in the bone marrow, the serum IgM level is increased and you find the MYD88 mutation, I think in that scenario we will be more likely speaking of a lymphoplasmacytic lymphoma than a marginal zone lymphoma for example.

Another diagnostic challenge is sometimes IgM myeloma that can also, in the marrow, actually look very much like lymphoplasmacytic lymphoma. And these patients can have very, very high IgMs and present with clinical features similar to Waldenström’s [inaudible]. But these patients with myeloma also, they do not have MYD88 mutations, and we do a myeloma test, FISH for example. We can see that a number of patients with IgM myeloma can have translocation (11;14) or even expression of cyclin D1 which almost never are seen in Waldenström’s. So pathologically speaking, there are some tricks there that we can use to differentiate these two conditions.

Now, the other challenge that I can see is therapeutic challenges. Waldenström’s remains an incurable condition with the current treatments that we have. I mean, we have a number of very effective therapies and we have chemoimmunotherapy. We can use bendamustine or cyclophosphamide in combination with rituximab. And we have a number of agents that are not chemotherapeutic, specifically proteasome inhibitors. For example, in the United States we have three of those products available, bortezomib, carfilzomib, and ixazomib, and they are all combined with rituximab as well. We do have now the new kids on the block are the BTK inhibitors. We do have three in actual development, ibrutinib, fully approved by the FDA and the European Medical Agency. Also, we have acalabrutinib and zanubrutinib and they’re all extremely effective in treating patients with Waldenström’s.

Now, none of these treatments, as I mentioned earlier, are curative and all these treatments can provide a response. I would say over 90% of patients with Waldenström’s will respond to any of these treatments, but they all have their own problems. I mean, chemoimmunotherapy, we have the risk of infections. We have the risk of a secondary leukemia. The risk is small, but it’s there. Patients who get exposed to proteasome inhibitors, the risk of neuropathy, the risk of other cardiac and pulmonary issues with carfilzomib specifically in patients older than 65. In patients who are taking BTK inhibitors, those are treatments that are indefinite duration therapies. Taking pills every day for many years sometimes and the risk of bleeding, the risk of arrhythmias specifically atrial fibrillation. So I think moving forward, one of the biggest challenges that we have is how we develop treatments that are safer. How we develop treatments that can induce deeper responses that hopefully last longer and impact positively the quality of life of our patients. So I think that is where the new world is coming in with newer treatments in the near future.