Emerging Combination Therapies for Myeloma

Transcript:Heinz Ludwig, MD: Trials are ongoing with ixazomib. I think there are 3 important ones, but when you look at the clinical trials registry of the NCI, you’ll find 46 studies with ixazomib—so there are a lot ongoing. I’ll just mention the important ones. TOURMALINE-2 is a study with ixazomib/lenalidomide/dexamethasone as compared to lenalidomide/dexamethasone in patients who are not eligible for transplant. Patients are exposed to the triple combinations for 18 cycles at full dose, and then after 18 cycles, the dose of ixazomib/lenalidomide will be reduced and dexamethasone will be discontinued. In the lenalidomide/dexamethasone arm, lenalidomide will be reduced and dexamethasone will be discontinued after cycle 18, so that’s very clear.

Then, we have the TOURMALINE-3 study, which tests the question of whether or not ixazomib maintenance therapy benefits patients after stem cell transplantation. Those patients receive ixazomib for 26 cycles, approximately 2 years, and their outcome is compared to patients who receive placebo for the same time—very important. Hopefully, our expectations will be fulfilled that maintenance therapy is highly effective.

The same protocol is followed in elderly patients, or let’s say a similar one, which achieved partial remission or better. They are stratified according to the quality of response and then randomized to either maintenance for 26 cycles or placebo for 26 cycles. Again, that’s an important question, which combines 2 major goals: to maintain treatment for a certain period, which we think is important, but also to stop treatment at a different point of time, which is important for the patient and may also lead to better or higher activity of rescue treatments that may subsequently be needed.

Shaji Kumar, MD: There are several new classes of drugs that are currently going through clinical trials. Some are similar to what we have right now—new monoclonal antibodies, new proteasome inhibitors, and new immunomodulatory drugs. But what is more exciting is the fact that we have several new classes of drugs that are going through clinical trials. We have small molecule inhibitors of specific proteins. We also have immune checkpoint inhibitors, like the PD-1 inhibitors, that are currently going through trials.

This gives us the opportunity to develop novel combinations. So, can these new drugs be combined with some of the newer drugs that we have been using in the clinic until recently? In particular, the combination of a checkpoint inhibitor with an immunomodulatory drug seems to be quite interesting. There have been data presented on combining pembrolizumab with both lenalidomide and pomalidomide, and the data look quite promising. Obviously, phase III trials are ongoing.

We know that we can combine the monoclonal antibodies with immunomodulatory drugs. Daratumumab and elotuzumab have been combined with both pomalidomide and lenalidomide. We have some very interesting data readout in terms of efficacy. We also have the proteasome inhibitors. Both ixazomib and carfilzomib have been combined with pomalidomide in the relapsed setting, and that also appears to be quite effective. So, we have several mutations and combinations of these new drugs, as well as drugs in development, that could make a difference to patients with myeloma.

Now, some of the interesting drugs that have been studied in recent trials also include selinexor, which is an inhibitor of the nuclear export protein. There’s also venetoclax, which is a BCL-2 inhibitor. We know that these drugs have single-agent activity, but what is also quite exciting is the fact that these drugs can be combined with some of the existing drugs to give an even better outcome.

For example, we know venetoclax can be combined with bortezomib, and that combination has shown significant efficacy. Selinexor has been combined with both carfilzomib and bortezomib, and that combination with a proteasome inhibitor also appears to be quite effective. So, I think there are several of these new novel combinations going through clinical trials that will probably further improve the outcome of patients with myeloma.

Transcript Edited for Clarity