New Approaches to Treating Waldenström Macroglobulinemia

At the 2019 Lymphoma & Myeloma Congress, Steven Treon, MD, PhD, FACP, FRCP, Harvard University, Dana-Farber Cancer Institute, Bing Center for Waldenström Macroglobulinemia, Boston, Massachusetts, provided an update on the latest research in the treatment of Waldenström Macroglobulinemia.

Transcript

My name is Steven Treon. I'm a Professor of Medicine at Harvard Medical School in Boston. I'm currently here in New York for the Lymphoma and Myeloma Congress.

I had the opportunity to present data on new approaches to treating Waldenström's macroglobulinemia. This is actually a very exciting time for Waldenström's macroglobulinemia because genomics have given us new insights into the disease and have allowed us to be able to target therapies for this disease based on these genomic findings.

Critical to these findings has been the discovery of a mutation in the MYD88 gene. This is a mutation which is found in about 93 to 97% of patients with Waldenström's macroglobulinemia.

One of the insights that I helped share at this meeting was the pivotal role of BTK, along with HCK in mediating downstream signaling, pro-survival signaling for MYD88.

Both BTK and HCK are targeted by a number of BTK inhibitors, including ibrutinib and zanubrutinib, and so, this has given us really the opportunity to help examine the role of BTK inhibitors in Waldenström's disease.

I had the opportunity to update folks here on the pivotal trial of single agent ibrutinib in Waldenström's macroglobulinemia, which I recently presented at the ICML Congress in Lugano, noting, in fact, that 90% of patients who are actually heavily pre-treated responded to single agent ibrutinib. More importantly, I talked about the role of the MYD88 mutation in the responses.

I also talked about CXCR4 mutations. These are also mutations which are highly prevalent in patients with Waldenström's. We, in fact, see them enough -- up to 40% of newly-diagnosed patients, and 30% of those patients who have been previously treated.

These are very interesting mutations because they allow for pro-survival signaling and even for drug resistance against a number of drugs, including BTK inhibitors.

The way these mutations work is that the receptor for CXCR4 actually remains in the "on" position with these mutations, allowing it to signal for CXCL12. This provides the pro-survival signaling that also contributes to drug resistance.

As part of the update here, I discussed the role of MYD88 and CXCR4 mutations in modulating ibrutinib response. Notable, if you do not have the MYD88 mutation, you don't see major responses. If you do, you see good responses, but CXCR4 can actually have an important impact.

That impact is manifested by lower rates of deep responses., the PR or VGPRs. We also see that it takes longer to be able to respond to single agent ibrutinib if you have the CXCR4 mutation in addition to the MYD88 mutation.

Importantly, as I also mentioned, you also see early progression in those patients who are double-mutated for MYD88 and CXCR4 relative to those that only have MYD88 mutation alone.

What can we do about this? This was actually a topic that I also discussed here at the Lymphoma and Myeloma Congress. There are actually CXCR4 antagonists, thereby, giving us an opportunity to actually develop targeted therapy against CXCR4.

I talked about the trial that's ongoing with ulocuplumab, a CXCR4 antagonist that we're using in combination with ibrutinib in those patients that have the CXCR4 mutation.

More good news will probably follow because there's also an oral antagonist against CXCR4, a drug called mavorixafor, that I also spoke about in an upcoming trial of mavorixafor along with ibrutinib as anticipated in those patients that have the CXCR4 mutation.

I also had the opportunity at this meeting to update folks on other new BTK inhibitors, including acalabrutinib. A dedicated study to acalabrutinib actually showed very high response rates on par with what we have seen with ibrutinib.

Zanubrutinib also another very important, new BTK inhibitor, which is showing remarkable responses, including deep responses in attainment of VGPR. Both of these drugs showing very good side effect profiles compatible to what we have seen with ibrutinib.

I think the opportunity to be able to continue to innovate therapy in Waldenström's, based on our genomic findings, can be recognized through MYD88 and CXCR4. I had the opportunity here to present an algorithm where we can actually genotype patients for these 2 mutations and use this information in order to be able to make informed decisions on how to treat patients.

Namely, BTK inhibitors should be considered in the setting where a patient has a MYD88 mutation. For those patients that also have CXCR4 mutations, one has to be concerned because many of these patients will present with hyperviscosity crises and high IGM levels.

If you need to get an immediate response, perhaps, BTK inhibitors may not be the best therapeutic endeavor given the fact that they take time to kick in. In which case, there's alternatives such as bendamustine or proteasome inhibitors can be considered.

The tough nut to crack is those patients that truly don't have a MYD88 mutation. They constitute about 5 to 7% of all patients. They typically have shorter overall survival, a higher propensity to transform to aggressive lymphomas.

When you look at the genomics of this disease, they tend to have many mutations that parallel those that have been reported in DLBCL, diffuse large B-cell lymphoma. Those patients should be ideally handled either with a proteasome inhibitor or bendamustine-based therapy.

We also talked about the role of autologous stem cell transplant. This should be considered in patients with multiple relapses, but with chemo-sensitive disease. An important footnote is that an autologous stem cell transplant can be considered as a consolidative measure in patients who have symptomatic amyloidoisis.

Our typical approach to these patients is to use a proteasome inhibitor and then consolidate with autologous stem cell transplant. This is really exciting news I was able to share here at the Lymphoma and Myeloma Congress in New York.

I think really the opportunity to be able to continue advancing therapy in Waldenström's will continue to be realized through these important genomic advances.