Shaji Kumar, MD
The burst of single agents and combination regimens approved by the FDA in multiple myeloma in recent years has had a practice-changing effect on the field—filled with monoclonal antibodies, proteasome inhibitors, and histone deacetylase inhibitors.
“The past year was historical, in that there have been several drug approvals and many new classes of drugs have been approved,” said Shaji Kumar, MD, professor of Medicine, Mayo Clinic.
Although these have had positive impacts on patient outcomes, Kumar adds that with so many therapies available for both patients with newly diagnosed and relapsed disease, the optimal sequence of agents remains an ongoing challenge.
Kumar chaired the 2017 OncLive
State of the Science Summit on Hematologic Malignancies, where he also lectured on newly approved agents for patients with multiple myeloma. In an interview during the meeting, he discussed these novel therapies in detail, the sequencing challenges ahead, and which current agents pose the greatest challenge.
OncLive: Looking back on the past year, what do you consider to be some key advancements?
: Broadly, we think about it as 2 sets of drugs. One is that we are seeing new drugs of the same class, which have some distinct advantages, and we are also seeing some brand-new classes of drugs. The new classes of drugs are particularly exciting because you have the first monoclonal antibodies that have been approved for treatment in myeloma. You have daratumumab (Darzalex), a monoclonal antibody directed against CD38, which is presented on most of the plasma cells. The results that we saw with single-agent daratumumab were quite striking in a group of patients who were very heavily pretreated.
This was followed by 2 large phase III studies, both of which showed that adding daratumumab to commonly used regimens like lenalidomide/dexamethasone or bortezomib/dexamethasone significantly improved progression-free survival (PFS). One of the interesting aspects of the results was the proportion of patients who became minimal residual disease–negative. This is something that we have not seen in the relapsed setting, at least to a significant degree. Having a totally new class of drugs has the potential to change the therapeutic approach to this disease in both newly diagnosed and relapsed populations.
The other new drug is another monoclonal antibody, elotuzumab (Empliciti). That also has been studied in combination; however, in contrast to daratumumab, it does not work by itself. It has to be used in combination and has been combined with a variety of different drugs. The phase III trial looked at the agent with lenalidomide/dexamethasone. That combination clearly improved PFS and overall survival (OS) when comparing it with lenalidomide/dexamethasone alone in a group of patients who have had 1 to 3 prior lines of therapy.
Now, there are obviously other studies that are ongoing, so we hope to hear some other results, both in terms of combinations of elotuzumab with other drugs, but also the combination with lenalidomide in the newly diagnosed myeloma setting—which would also be exciting to see what that would turn out to be. We also have another new class of drugs that has been not been used in this space before, which are the non-selective histone deacetylase inhibitors. There have been trials with other drugs of the same class. Vorinostat (Zolinza) was studied several years ago, but panobinostat (Farydak) has been studied in combination with bortezomib and dexamethasone, and that combination clearly improved PFS. In particular, the group of patients who had the maximum benefit of panobinostat were those who had previously been exposed to bortezomib and lenalidomide. These are the patients who clearly need different types of therapy and, in that group of patients, it seemed to benefit adding panobinostat to bortezomib/dexamethasone. Now, the other big drugs that have been recently approved have been new drugs of the same class. We have ixazomib (Ninlaro), which is the first oral proteasome inhibitor to be introduced in the clinic. That also has single-agent activity, and there is increased activity with dexamethasone. Ixazomib has also been combined with a variety of different drugs; in particular, a lenalidomide combination has been studied in both relapsed and newly diagnosed disease.
In the relapsed setting, it improves PFS. We still don’t have data on OS. In the newly diagnosed setting, the trials are still ongoing. There are a couple of very interesting things with ixazomib we have seen. There is the convenience of being an oral drug; it’s 1 pill a week. It also has very manageable toxicities, and we have seen that in combination with lenalidomide. It seems to be quite effective to what we have seen in the past with the bortezomib/lenalidomide/dexamethasone combination.