Usmani on Personalized Combination Treatments for Myeloma Management

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.

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

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.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.

Were any adverse events observed with this regimen?

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

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

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.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.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.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%.

There will definitely be a phase III study, correct?

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?

Can you give an overview of recent findings which showcased the benefit of daratumumab as monotherapy?

In terms of safety, 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?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. The combination does certainly have its place in the field, and this combination is the right step forward. Finding the right carfilzomib dose will be the next question.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, then the challenge is finding the right partner and the dosage. Adding it to the proteasome inhibitor (PI) platform might be a good idea. It would be worthwhile to check it with other platform drugs such as immunomodulatory drugs (IMiDS), and now monoclonal antibodies.Daratumumab was recently FDA approved. 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.

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 receive the infusion. That appears to occur in less than half of the patients, mostly grade 1 and grade 2 infusion reactions that are mitigated by standard of care and supportive care measures. The patients are able to complete the infusions, and then it doesn't happen the second or the third time around. Therfore, it is a once and done occurrence.

Do you foresee any ongoing trials? What other combinations with daratumumab would you hope to be investigated?

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 PFS and OS benefit.There are several large phase III trials ongoing, both in the upfront setting and first relapse setting. In the upfront setting, daratumumab 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 lenalidomide and dexamethasone versus lenalidomide and dexamethasone. The same holds true for the first-line setting, as well. There's a combination trial comparing daratumumab with lenalidomide and dexamethasone versus lenalidomide and dexamethasone and daratumumab, bortezomib and dexamethasone versus bortezomib and dexamethasone. 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 trial in a smaller group of patients with myeloma that is being initiated.

Can you comment on the significance of the recent FDA approval of daratumumab for multiple myeloma?

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 is the safety profile.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 shortened, and we're generally running out of options.

With daratumumab's approval, this gives us another option for patients that appears to be not simply efficacious, but also doesn't impact their quality of life. That is a landmark, in many ways, where we have a monoclonal antibody in myeloma for the first time that's been approved. It's our first biologic, and it has single-agent activity. There are patients who benefit from it, and then those benefits are sustainable. It is an exciting time from that perspective. There are several monoclonal antibodies, and other immunotherapeutic approaches that are being developed. This is just one facet of what potentially immunotherapy can be—the way an immunotherapy can be employed for patients with myeloma in the future.