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New Age of Myeloma Management Offers Personalized Combination Treatments: A Q&A With Saad Usmani

Sandra Kear
Published Online: 5:31 AM, Tue December 29, 2015
New Age of Myeloma Management

Saad Usmani, MD

With three new drug approvals in November 2015, the treatment paradigm for multiple myeloma is rapidly evolving. At the American Society of Hematology (ASH) 57th Annual Meeting & Exposition, Ajai Chari, MD, presented results of a phase I/IIb study that explored the combination of ibrutinib and carfilzomib with or without dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.

The study authors concluded that the combination of the three agents were well tolerated with no dose-limiting toxicities and 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.

This study was just one of several studies discussed at the ASH Annual Meeting, which currently focus on combination treatments in multiple myeloma. Targeted Oncology spoke with Saad Usmani, MD, director of the Plasma Cells Disorder Program at the Levine Cancer Institute in Charlotte, North Carolina, about newly approved treatments, as well as these combination therapies currently in clinical trials.
TARGETED ONCOLOGY: Can you detail the findings of the combination study of ibrutinib with carfilzomib in patients with relapsed, or 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 a quarter of the 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, the whole group, were about 58%. A total of 58% partial response (PR) or better, and 67% clinical benefit rates. 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 (DLT) 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.
T.O.: Were there adverse events (AEs) experienced by patients in the study?
USMANI: 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.
T.O.: Do you think more combination therapies, such as this one, are on the horizon for treating multiple myeloma?
USMANI: 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 the myeloma cells, 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, “Which combination works for which patient?” We will be relying more on molecular profiling of patients, and determining therapies based on that.
T.O.: Can you provide information about the phase II study with carfilzomib and filanesib?
USMANI: The carfilzomib with or without filanesib is a randomized phase II study, again, done in a multi-institutional fashion. Jeff Zonder, MD, will be presenting these data at ASH this year. The study was a 2-to-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 have activity. I think it was around 48%. In the carfilzomib-only arm, which included patients with high-medium prior lines of therapy, the response rate was around 14%. The combination of carfilzomib and filanesib [arm] saw an overall response rate of about 35%.

In terms of safety, I think myelosuppression has been recognized as a side effect of filanesib. There were grade 3 anemias, thrombocytopenias, and neutropenias that were seen in about one-quarter of patients, but they were, for the most part, reversible. Neutropenia was certainly reversible. The regimen was quite efficacious, and even in patients with high-risk cytogenetic features. The main question in follow-up to the study, now that we're seeing different dosing of carfilzomib coming out (in fact, in many studies being presented at ASH this year), is which would be the right carfilzomib dose to pick for the next phase III study with this combination?
T.O.: There will definitely be a phase III study, correct?
USMANI: Yes, and I do want to highlight the fact that this is yet another example of a different platform. Filanesib is a kinase and spindle protein inhibitor. Even though, intuitively, myeloma is a less proliferative disease, when it comes to relapsed/refractory disease, that proliferative component tends to be much higher, especially in high-risk patients. It [the combination] does certainly have its place in the field, and I think this combination is the right step forward. Finding the right carfilzomib dose will be the next question.

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