Insights From: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai; Andrzej Jakubowiak, MD, PhD, University of Chicago; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Andrzej Jakubowiak, MD, PhD: Venetoclax is another very promising agent, approved already for other hematologic malignancies, but also finding its way into myeloma treatment. It is insured a new drug for the reason of mechanism of actions, though not similar to any prior previously approved drugs. And this drug is specifically working through BCL2 inhibition, which is an important complement of the apoptotic pathway for self-destruction of cells, which we try to stimulate in malignant cells. We have found that this drug can be active on its own in myeloma in over 20% of patients, and what I think appears to be most exciting about the promise of the drug in combination with some other class of drugs, particularly with proteasome inhibitors.
There have been quite promising results presented and published in part for this combination with bortezomib, and now we have not published but presented at meetings and will be updated at ASH [the American Society of Hematology meeting] in a couple of weeks, results of a combination of venetoclax with carfilzomib.
The activity of this combination is exceeding what we would have expected these patients would have achieved with using only carfilzomib and dexamethasone. While this needs to be still validated and proven, the drug appears to be enhancing activity of proteasome inhibitors.
Sagar Lonial, MD: One of the interesting areas is that, as we’ve made these advances in myeloma therapy, we haven’t really focused on precision medicine in myeloma. And the role of venetoclax, particularly in the 11;14 subset of myeloma, represents the first attempt at precision medicine. And so what we know about venetoclax is that the responses are enriched in 11;14 myeloma. About 40% to 50% single-agent activity, jumps up to 65% activity in combination with dexamethasone, and that represents a huge step forward for us in the context of using a genetic marker, the 11;14 translocation, in trying to pick a therapy-based drug.
Andrzej Jakubowiak, MD, PhD: There’s a lot of other newer drugs that have made tremendous difference in some other hematologic malignancies like BTK [Bruton tyrosine kinase] inhibitors like ibrutinib. That drug has been slowly taken into the myeloma field, although the data are not necessarily giving as much promise in terms of how well this drug will be working in myeloma as many of us have hoped. I wouldn’t discount that drug completely, but I think that a jury is out whether this will be a valid addition to our armamentarium and treatment of myeloma.
Sagar Lonial, MD: Other precision medicine approaches that are being tested in myeloma right now are the use of MDM2 inhibitors, particularly in patients with 17p deletion. That’s a trial that’s being run through the MMRC [Multiple Myeloma Research Consortium] right now, where it’s the MDM2 inhibitor alone, and then in combination with ixazomib, with the intent of trying to overexpress normal p53 in patients who either have p53 deletion or p53 mutation.
This I think does represent an important clinical trial idea because we know that loss of p53 occurs more frequently in relapsed and refractory patients. And so strategies to overcome this really are very important.
Other molecular approaches that will be tested in a larger trial through the MMRC called MyDRUG include mutations such as BRAF, mutations such as IDH1 and IDH2, as well as the NRAS and KRAS mutations by targeting MEK. And so these are all in development right now.
There’s anecdotal data here and there about targeting BRAF with a BRAF inhibitor, similar to what’s done in melanoma or in colorectal cancer, but we don’t have a large series of patients that have been treated in a trial, and hopefully MyDRUG will be able to give us that.