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Usmani on Personalized Combination Treatments for Myeloma Management

Published: Wednesday, Dec 30, 2015

Saad Usmani, MD

Saad Usmani, MD

With three new drug approvals in November 2015, the treatment paradigm for multiple myeloma is rapidly evolving.

At the 2015 American Society of Hematology (ASH) Annual Meeting, results of a phase I/IIb study that explored the combination of ibrutinib and carfilzomib with or without dexamethasone in patients with relapsed/refractory multiple myeloma.

The study authors concluded that the triplet combination was found to be well tolerated with no dose-limiting toxicities, as well as no increase in severity of known toxicities for the individual drugs.

The third cohort of the study that included the higher dose of ibrutinib (840 mg/d) along with carfilzomib and dexamethasone saw the most promising results, with a preliminary overall response rate (ORR) of 58%, with one stringent complete response and three very good partial responses. Cohort 3b was established as the recommended phase II dose and is being further evaluated in the phase II portion of the study.

These phase I/IIb findings were just one of several data on combination treatments in multiple myeloma discussed at this year's meeting ASH Annual Meeting. 

In an interview with OncLive, Saad Usmani, MD, director of the Plasma Cells Disorder Program at the Levine Cancer Institute in Charlotte, North Carolina, discusses these newly approved treatments for patients with multiple myeloma, as well as the combination therapies currently being investigated in clinical trials.

OncLive: Can you discuss the combination study of ibrutinib with carfilzomib in patients with relapsed/refractory multiple myeloma?

Usmani: The carfilzomib and ibrutinib combination clinical trial is a phase Ib/II clinical trial done as a multi-institutional study in patients who are relapsed and refractory and have taken both bortezomib and an immunomodulatory drug in the past. The study summarizes the phase Ib safety, as well as the phase II expanded portion efficacy data. The median prior lines of therapy for these patients was three. About one-quarter of patients had been exposed to carfilzomib and pomalidomide in the past—truly a relapsed and refractory patient population.

The response rates that were seen with this combination, in the whole group, were about 58%. A total of 58% partial response (PR) or better were seen, and clinical benefit rates were 67%. There were a subgroup of patients [that had] less than a PR, but still benefited from being on therapy. In terms of safety, there were no significant dose-limiting toxicities seen, and the cohorts in the phase Ib portion filled up fairly quickly. Since these are very encouraging results, I believe there are plans to do a further dose expansion and perhaps plan a phase III study in the future.

Were any adverse events observed with this regimen?

There was nothing unexpected. We do appreciate, that within relapsed/refractory patients, there are infectious complications or certain complications that are already known and attributable to carfilzomib and ibrutinib, but the combination didn't see any new safety signals.

Do you think more combination therapies, such as this one, are on the horizon for treating multiple myeloma?

Yes, I believe so. The main idea is to develop different platforms from the classical immunomodulatory drug/proteasome inhibitor platform and try to approach the disease, perhaps, differently mechanistically. As malignant myeloma cells become savvy with these relapses, you find specific ways of targeting those patients with relapsed/refractory myeloma. I think the main challenge will be determing which combination works for which patient. We will be relying more on molecular profiling of patients, and determining therapies based on that.

Can you provide information about the phase II study with carfilzomib and filanesib?

The carfilzomib with or without filanesib is a randomized phase II study, again, done in a multi-institutional fashion. Jeff Zonder, MD, presented these data at the 2015 ASH Annual Meeting. The study was a 2:1 randomization between carfilzomib, along with filanesib, and the other arm was carfilzomib, or commercial carfilzomib on its own. This particular study was going to be a segue into a broader phase III study, which would have mirrored the current design.

Overall, the combination of carfilzomib and filanesib did demonstrate activity, which was approximately 48%. In the carfilzomib-only arm, which included patients with high-medium prior lines of therapy, the response rate was around 14%. In the arm with the combination of carfilzomib and filanesib, there was an overall response rate of about 35%.

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