Shaji Kumar, MD, discusses the clinical significance of a recent clinical trial presented at ASH 2018 that involved a quadruplet multiple myeloma therapy comprising ixazomib, lenalidomide, dexamethasone, and daratumumab.

Transcript

My name is Shaji Kumar. I am a consultant in the Division of Hematology at Mayo Clinic in Rochester, Minnesota.

We were interested in examining the combination of ixazomib, lenalidomide, dexamethasone, and daratumumab for a variety of different reasons. The combination of ixazomib, lenalidomide, and dexamethasone has been studied in newly diagnosed myeloma and the combination has been shown to be quite effective—comparable to what we have seen with bortezomib, lenalidomide, and dexamethasone, but with increased convenience of an all-oral regimen.

Daratumumab has been studied in combination with both bortezomib and lenalidomide in relapsed patients, and also in combination with bortezomib, melphalan, and prednisone in newly diagnosed myeloma patients.

So we wanted to examine if we can maximize the efficacy of these 3 different classes of drugs in patients with newly diagnosed myeloma in a combination strategy to see if we can get really deep responses.

So we treated patients with newly diagnosed myeloma with a combination of ixazomib, lenalidomide, dexamethasone, and daratumumab. The median age of the patients was 62 years. About a quarter of the patients had high-risk cytogenetic abnormalities.

The dosing and schedule of the treatments were similar to what has been described for these drugs. They were given in 28-day cycles. Patients continued on all 4 drugs for 12 cycles, after which they went on a maintenance with daratumumab and ixazomib given less frequently. Patients could go to stem-cell collection after 4 cycles of therapy and then proceed to stem-cell transplant if they so desired.

At the latest data cutoff, we had administered a median of 9 cycles of therapy, with a minimum of 4 cycles of therapy in all the patients. What we found was that the combination was quite effective, with nearly all the patients having a partial response or better to the combination therapy. We did see fairly rapid responses and deep responses.

The overall response rate was 100%, with almost 16% of patients having a complete response or better at the median of 9 cycles of therapy. Three patients had progressed at 6 cycles, after 8 cycles, and after 14 cycles of treatment. An additional 6 patients had gone off to get stem-cell transplant.

The 4-drug regimen was well-tolerated, with very few patients requiring dose modifications, with most of the dose modifications limited to lenalidomide and dexamethasone.

Overall, the regimen was well-tolerated, with limited number of grade 3 and 4 adverse events. Most of it was related to neutropenia, lymphopenia, and fatigue.

The quadruplets offer the possibility that we can actually get deep responses, including minimal residual disease–negative status, in patients sooner than what we have been able to, and in more number of patients than we have been able to, with the 3-drug regimen.

If we can actually do that then there is a real possibility we can give treatments for a defined duration of time and then completely stop, unlike the current paradigm where patients continue on maintenance until disease progression.

If we are able to achieve that, then these 4-drug regimens—even though they are quite expensive—may turn out to be a better value proposition by not keeping patients long-term, both from a cost-of-treatment perspective as well as the treatment-related side effects.

So now that we have the data with the 4-drug regimen from this virtually small study, the question is what do we do next.

One of the options that we are pursuing right now is a very similar study but using less amount of dexamethasone. As we all know, dexamethasone does have significant side effects associated with it so the hypothesis is that maybe we don’t need as much of dexamethasone since these 3 drugs are so effective.

Another phase 2 trial with 38 patients is currently enrolling, where patients will have the dexamethasone discontinued after the first 2 cycles of therapy.

We hope that these results will also form the basis for future phase 3 trial designs, which will be looking at the question of limited duration of quadruplet therapy versus the current paradigm of triplet followed by maintenance.