ONCAlert | 2017 San Antonio Breast Cancer Symposium

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

Sandra Kear
Published Online: 12:31 AM, Tue December 29, 2015
T.O.: 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?
USMANI: 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.
T.O.: Can you give an overview of the daratumumab as monotherapy study?
USMANI: 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.

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.
T.O.: Do you foresee any ongoing trials? Should there be any more done with other combinations of daratumumab?
USMANI: 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.
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.
T.O.: Can you comment on the recent approval of daratumumab for multiple myeloma, and the significance of it?
USMANI: 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.

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. I think that 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. I think 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, you know, the way an immunotherapy can be employed for myeloma patients in the future.

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