Rarity of Waldenstrom's Macroglobulinemia Challenging, But Novel Combinations on Horizon

The disease occurs in roughly 4 patients per million, per year, making trials extremely difficult to cultivate, says Gertz, professor of medicine, Mayo Clinic.

“You figure about 18,000 new patients per year in the United States distributed among tens of thousands of medical oncologists, so a medical oncologist may see a new patient like this every three or four years,” says Gertz. “Meeting accrual targets and having enough activated centers so that patients can be enrolled can really be a challenge. So only a small number of centers are capable of producing these trials.”

In an interview with Targeted Oncology, Gertz discusses this and other challenges for WM, combinations with potential, and what is on the horizon for treatment of the disease.

TARGETED ONCOLOGY:What are you most excited about in the treatment paradigm of Waldenstrom's macroglobulinemia?

Gertz:

A lot of the information for Waldenstrom's has been derived from chronic lymphocytic leukaemia (CLL) data. The three newest agents that have been used in the treatment of Waldenstrom's carfilzomib (Kyprolis), which is off label, ibrutinib (Imbruvica) which was approved, and idelalisib (Zydelig), which is being investigated as both a single agent and in combination with ibrutinib and with bendamustine. I think those three agents are really pushing the edge in treatment for patients with Waldenstrom's.

TARGETED ONCOLOGY:For the drugs that are not yet approved, are there trials moving toward that you are excited about?

Gertz:

There are at least four trials listed on ClinicalTrials.gov that are looking at combinations of ibrutinib with rituximab and with bendamustine, and the same with idelalisib. This does appear to have significant activity in the treatment of Waldenstrom's macroglobulinemia. These combinations are showing promise in the elderly population regarding toxicities particularly with ibrutinib.

TARGETED ONCOLOGY:You mentioned the elderly population. Is that a large group of patients?  

Gertz:

Waldenstrom's macroglobulinemia increases with age. It actually has a median age of probably about 73. So it is an older population than for myeloma and older than the population with low-grand lymphoma. These patients have significant comorbidities, and tolerance of these medications becomes important to look at.

TARGETED ONCOLOGY:What are some of the biggest challenges that remains with Waldenstrom's macroglobulinemia?  

Gertz:

There are a lot of active drugs. I think that because it's a rare disease, it's hard to develop phase III trials that allow comparators so you understand how much better, if any, a new agent is versus an old agent. Fludarabine has been around for 30-something years and still shows significant activity, as does cyclophosphamide and bendamustine.

I think what faces most clinicians is how you make the decision between using bendamustine or ibrutinib, or carfilzomib, or so on for the treatment of Waldenstrom's macroglobulinemia. A lot of clinicians are in a quandary as to the sequencing for the treatment of this disease.

TARGETED ONCOLOGY:What needs to be done to solve this issue?  

Gertz:

We need phase III trials. Patients need to be encouraged to participate in phase III trials, or we'll never get an answer to this. The East German Lymphoma Study Group, in their LYMPHONA9 trial demonstrated that bendamustine in the Waldenstrom's subset was better tolerated than rixtuximab cyclophosphamide dexamethasone and did so with less toxicities. Without trials like that, we'll never get to the answers that we really need in terms of making selections that will benefit our patients.

TARGETED ONCOLOGY:How has ibrutinib impacted the treatment paradigm?  

Gertz:

Ibrutinib has made an important inroad in the management of Waldenstrom's macroglobulinemia. Even though there's only data for previously treated patients, it is approved by the FDA for any line of therapy in Waldenstrom's macroglobulinemia. It adds a lot convenience for this elderly population where visits to doctors can sometimes be a bit of a challenge.

TARGETED ONCOLOGY:What do you see on the horizon in this space?  

Gertz:

There's going to be a lot more in the next couple of years with idelalisib and how it will integrate into the management of patients with Waldenstrom's macroglobulinemia. The important thing, again, isn't going to be the individual agents, but how will they be combined?

Hopefully with combinations patients can achieve a deep response and be on therapy for a finite period of time, and then discontinue it. The hard part is knowing what those three agents will be and what will be that optimal combination of treatments for that population.