Shaji Kumar, MD, discusses novel therapies for patients with multiple myeloma in detail, the sequencing challenges ahead, and which current agents pose the greatest challenge.
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.
OncLive: Looking back on the past year, what do you consider to be some key advancements?
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.Kumar: 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.
The other excitement is in the newly diagnosed setting. In the clinical trials, patients managed to stay on the drug for long periods of time without any cumulative toxicities. It also raises the possibility of using this is as a maintenance drug, especially now that the field is moving into maintenance [strategies] for the majority of patients.
Lenalidomide/dexamethasone and bortezomib/dexamethasone are fairly standard backbones to these newer agents. Will they continue to be part of the newer combinations?
The final 2 drugs, which are not quite new compared with these drugs, are carfilzomib (Kyprolis) and pomalidomide (Pomalyst). They have been approved for several years now, but we are starting to learn more about the different combinations and the different doses of carfilzomib that have been studied in phase III trials.It is a good question. The reason why they were chosen as backbones is we had [a lot of data already from] their approvals, but going forward, that could very well change because many of these new classes of drugs have single-agent activity. It is possible that you could have those drugs replaced by another drug of the same class, or maybe even replaced with other drugs that belong to different classes.
Do you foresee physicians in this field facing any sequencing challenges?
2016 was a practice-changing year for the multiple myeloma landscape. What could happen this year?
For example, we have other monoclonal antibodies and even checkpoint inhibitors that are going through clinical trials, such as pembrolizumab (Keytruda), so it is not unreasonable to think that we could have drug combinations that do not include any immunomodulatory drug (IMiD) or proteasome inhibitor. That is going to take a lot of time for that data to come out, because most of what we know from the past decade and a half has been based on the IMiDs and proteasome inhibitors. Absolutely. The biggest question that we have in the field today is: How do we put all of these drugs together? Obviously, 1 strategy is to try and keep combining them to see if we can come up with regimens that are very effective, but we have multiple drugs in the same class, as well. Eventually, we have to figure out what is the best way to sequence them because patients with myeloma are still not being cured. We continue to need new treatments, so we need to figure out which combination is the best to use in the upfront setting to get the maximum response for the longest period of time—and what combination comes after that. A lot of other drugs are going through clinical trials; the BCL-2 inhibitor venetoclax (Venclexta) is quite interesting. The initial data alone and in combination with bortezomib seem to be quite encouraging. Selinexor is of a different class of drugs that also seems to have single-agent activity, and there are combination trials that are ongoing.
How could CAR T-cell therapy potentially fit into this paradigm?
Which of these newer agents do practitioners have the most questions and challenges with?
As previously mentioned, with the checkpoint inhibitors, the data look pretty interesting, as well. In addition, we have all of the other immune therapies, bispecific antibodies, and chimeric antigen receptor (CAR) T cells. They all could hold significant potential.It all depends on what kind of data we get from these clinical trials. Some of these immune therapies are very early on; it is still too early to say anything definite. Some of them do carry significant toxicity, so they might not necessarily be the ideal thing to use in the upfront setting. Maybe we continue to use some of the other modalities we use before we go onto that one. Eventually, it is going to be the data related to toxicity and efficacy and the balance [of the 2].With the monoclonal antibodies, there are a lot of questions that still need to be answered. Can we keep reusing them? What are the best drugs to be combined with? These new checkpoint inhibitors are a totally open field.
You chaired this State of the Science Summit. What is the importance of attending this type of event?
The question is: Do we use these drugs sequentially, or are there particular drugs that can be combined to give us such a deep response that, maybe, we can cure some of these patients? The whole hematology field—and cancer in general—is exploding, in terms of what we learn about the disease biology, how we select therapy for a given patient based on some of the tumor characteristics, and these different drugs and toxicity profiles and efficacy, and even the way we measure responses with these medications can be different than what we have conventionally done.
It is hard for everyone to keep track of everything that is happening in the field. Having these kinds of symposiums, where you have a whole group of experts and distill the information and give the most important aspects that are useful from a clinical standpoint, makes it much easier for community oncologists to deal with the wide array of patients that they see.