First-Line Treatment for Waldenstrom Macroglobulinemia
Insights From: Meletios A. Dimopoulos, MD, the National and Kapodistrian University of Athens School of Medicine; Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute
Meletios A. Dimopoulos, MD: Waldenström macroglobulinemia a relatively indolent disease. From the time of initiation of treatment, the median survival exceeds 10 years. This means that the majority of the patients with Waldenström will die from something else. And because it’s an indolent disease, we want to be careful and gentle in the majority of the patients. Of course, there is a small subset of patients who have aggressive disease that needs rapid and effective disease control, otherwise the patient may succumb to these complications of the disease. But in the majority of the patients, one would like to alleviate the symptoms, improve the hemoglobin, and reduce the lymphadenopathy. This can be done with several treatments. Thus, the goal is to induce a response, and we use the measurement of serum IgM or the serum protein electrophoresis in order to follow the effectiveness of a particular treatment.
Steven P. Treon, MD, PhD: Beyond age, I think you need to look at the genomic status of a patient. I think understanding the patient’s MYD88- and CXCR4-mutation status can help you understand which therapies you have an option of considering. For patients who have the MYD88 mutation, one can consider BTK [Bruton tyrosine kinase] inhibitor therapy. The CXCR4-mutation status may provide you a hint as to the use of BTK inhibitors in patients who require immediate versus subacute disease control.
You also want to keep in mind bulky adenopathy. Proteasome inhibitors would not be appropriate for somebody with bulky adenopathy, but an alkylating drug like bendamustine might be appropriate, so it’s important to keep that in mind. Amyloidosis—our best evidence today suggests that proteasome inhibitors are probably the best drugs that we ought to be using.
And then there are the patients with IgM neuropathy. This is still a very difficult patient population to treat. We’ve relied traditionally on the use of rituximab as monotherapy, but the results have been suboptimal. Being able to consider combination therapy for these patients would be appropriate.
Meletios A. Dimopoulos, MD: Whenever we are dealing with a newly diagnosed, symptomatic patient with Waldenström macroglobulinemia, we have to take into consideration the age of the patient and the comorbidities and the need of rapid disease control or not. For example, there are some patients who present with hyperviscosity. For these patients we need to control their disease quite rapidly. There are some patients who have extensive lymph node involvement. Again, we need to have rapid disease control. Whereas, frequently, older patients present only with anemia, and we have time to control the disease.
And also, because this is an elderly patient population with a median age older than 70, frequently these patients have comorbid conditions [that] we need to take into consideration as well. If we have a young patient who needs relatively rapid disease control, one may choose a combination of cyclophosphamide, dexamethasone, and rituximab or bendamustine and rituximab. For older patients who don’t need such rapid disease control, oftentimes single-agent rituximab or dexamethasone, cyclophosphamide, and rituximab may be the treatment of choice.
Of course, ibrutinib has been also approved for the frontline setting and the relapsed setting of patients with Waldenström macroglobulinemia. Ibrutinib is a very effective drug. It is associated with a very quick reduction of monoclonal protein. It is associated with a rapid improvement of anemia or correction of their anemia. It is associated with decrease of the bone marrow infiltration. However, ibrutinib has 1 pitfall. It has to be administered continuously, because whenever we discontinue the drug, even for a few days, the monoclonal protein starts to increase back. So it is not clear yet whether, in the frontline setting, one should use 1 of the regimens that may be administered for a period of 6 months and can give the patient a progression-free survival of 3 or 4 years without any treatment; or whether ibrutinib, which is a continuous therapy, is the treatment of choice.
Steven P. Treon, MD, PhD: Traditionally, we have relied on rituximab monotherapy for the treatment of patients with Waldenström. We know based on SEER [the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program] data, as well as data from the study by Dr Christian Buske in Europe, that Rituxan monotherapy is the community favorite. But in the academic setting, and I think a more practical setting, combination therapy with rituximab has really become the mainstay of therapy. When you consider that a number of different drug combinations with rituximab have produced deeper responses and longer progression-free survival, this has been a reason why combination therapies with rituximab have been employed.
So in the modern era now, because of the MYD88 mutation advancing our knowledge of targeted therapies in Waldenström, we now have BTK inhibitors as options. Ibrutinib represents 1 of these very important new options. As monotherapy, we’ve seen response rates and even depth of response in progression-free survival in previously treated patients that is as good if not better than any of the combination therapies that have been used in the previously treated scenario. We also know from our frontline monotherapy studies that we’re getting very high responses and durability with ibrutinib alone.
Excitingly, we know from the iNNOVATE study that combined ibrutinib along with Rituxan, that overall responses, deep responses, and the progression-free survival curves also look much better with the 2 drugs over Rituxan alone.
Of course, now the big question in our field is: Is ibrutinib monotherapy as good as ibrutinib plus Rituxan? We certainly need to see more follow-up in these studies. But there may be patient populations like the CXCR4-mutated patients, in particular, where the combination may be an exciting option over ibrutinib monotherapy itself.