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

Sandra Kear

Saad Usmani, MD, discusses newly approved treatments, as well as these combination therapies currently in clinical trials.

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) 57thAnnual 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.

Can you detail the findings of the combination study of ibrutinib with carfilzomib in patients with relapsed, or relapsed/refractory multiple myeloma?

TARGETED ONCOLOGY:

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.

USMANI:

This study was just one of several studies discussed at the ASH Annual Meeting, which currently focus on combination treatments in multiple myeloma.Targeted Oncologyspoke 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.

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.

Were there adverse events (AEs) experienced by patients in the study?

T.O.:

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.

USMANI:

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

T.O.:

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.

USMANI:

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

T.O.:

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.

USMANI:

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?

There will definitely be a phase III study, correct?

T.O.:

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.

USMANI:

What is the mechanism of action for filanesib? How does the drug work, and what kind of research still needs to be done with this drug?

T.O.:

We know quite a lot about this drug. Outside of myelosuppression, honestly, we don't see a lot of major safety signals. The way this drug is supposed to work is to stop the cell during mitosis, or cell division, by binding to the kinase and spindle protein, a specific kinase and spindle protein called KSB5. If we know about its mechanism of action, I think it's [the challenge is] finding the right partner and the dosage. I think adding it to the proteasome inhibitor (PI) platform is a good idea. It would be worthwhile to check it with other platform drugs such as immunomodulatory drugs (IMiDS), and now monoclonal antibodies.

USMANI:

Can you give an overview of the daratumumab as monotherapy study?

T.O.:

Sure. Daratumumab just got FDA approved less than a week ago. The current abstract talking about the clinical efficacy of daratumumab monotherapy is actually a combined analysis of two clinical trials. One is the phase II registration study that led to this drug's approval, and the other is a subset of patients from the original phase I/II trial, the GEN501 trial, where a subset of patients received the currently approved dose at 16 milligrams per kilogram.

USMANI:

A total of 148 patients were evaluated for response and safety signals, and the overall response rate that was found was around 31%. These patients had a median of 5 prior lines of therapy. Almost half of the patients who were exposed to both carfilzomib and pomalidomide, regardless of the prior lines of therapy—the kind of drugs they were exposed to—the overall response rates were very similar. All subsets of patients benefited.

The only safety signal in the side effect profile was perhaps infusion reactions the first time the patients get the infusion. That appears to happen in less than half of the patients, mostly grade 1 and grade 2 infusion reactions that are mitigated by standard of care, supportive care measures. The patients are able to complete the infusions, and then it doesn't happen the second or the third time around. So it's once and done.

The key highlight of this presentation is not just that the patients who were on daratumumab and responding were benefiting, it appears that patients who even get a minimal response or stable disease, they appear to have some overall survival (OS) benefit, PFS, and OS benefit.

Do you foresee any ongoing trials? Should there be any more done with other combinations of daratumumab?

T.O.:

There are several large phase III trials, both in the upfront setting, as well as in the first relapse setting that are ongoing. Daratumumab in the upfront setting, has been combined with BTD, or with RVD, with VMP in the first, in the transplant ineligible setting. There's a large randomized phase III study looking at daratumumab with len/dex versus len/dex. The same holds true for the first-line setting as well. There's a combination trial comparing daratumumab with len/dex versus len/dex and daratumumab, bortezomib/dex versus bortezomib/dex. There's a lot of effort being put forth in developing this drug and trying to move it to the upfront setting. There's also a provocative phase II trials in a smaller group of myeloma patients that is being initiated.

USMANI:

In many ways the anti-CD38 monoclonal antibodies are an extremely promising new platform drug that are being combined with available regimens, and the advantage here is the safety profile.

Can you comment on the recent approval of daratumumab for multiple myeloma, and the significance of it?

T.O.:

When patients get to a double-refractory stage or beyond three prior lines of therapy, their PFS with each subsequent line of therapy tends to be shorted, and we're generally running out of options.

USMANI: