Proteasome Inhibitors Paving Promising Path for Myeloma Treatment

Several novel agents have emerged in the treatment paradigm for multiple myeloma. A key class of agents that is helping to improve patient outcomes is the proteasome inhibitors.

With bortezomib (Velcade) as a standard backbone in combination regimens, additional proteasome inhibitors have become FDA approved, including carfilzomib (Kyprolis) and ixazomib (Ninlaro).

“There are lots of options, and so that’s not a problem—that's really a solution,” said Kenneth H. Shain, MD, of Moffitt Cancer Center. “That is an important thing to think about: knowing what the drugs are, what their toxicities are, and seeing the patient across [from you] who is going to let you give the right drug or combination to them.”

OncLive: You spoke on multiple myeloma at this meeting. What did you discuss specifically?

We saw data with subcutaneous use of the monoclonal antibody daratumumab (Darzalex) come out at the 2016 ASH Annual Meeting. What are your thoughts on subcutaneous administration of novel treatments in myeloma?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Shain spoke on the emergence of proteasome inhibitors in multiple myeloma and whether these agents will be best used as monotherapy or in combination regimens.Shain: I spoke to our colleagues about proteasome inhibitors and their use in relapse/refractory multiple myeloma. I mentioned, essentially, the spectrum of proteasome inhibitors from intravenous (IV), subcutaneous, and oral use. For certain drugs, it’s going to be really important. We’ve learned, with the proteasome inhibitors specifically, that subcutaneous use changed how we take care of patients—not only our patients’ way to get medicine, but also to mitigate some toxicities. That’s with bortezomib, and it has been groundbreaking and changed the practice in our ability to give that drug.

It’s going to take just a little while to give, maybe 9 hours the first day, so you have to bring a book—a long book. But if you can start giving it subcutaneously, it will increase the ability to deliver it to patients.

How have you seen the class of proteasome inhibitors in the last year have an impact on the field of myeloma?

It’s not going to be quite as simple, because it’s going to be something that’s going to take time. It’s going to take some more work, because it’s a lot of volume that has to go in there. There are some stumbling blocks and hurdles we have to overcome to make that a really usable thing for patients. It is more of a delivery change versus a mitigation of toxicity change, and those will be important.It has been an amazing change. Bortezomib was the initial proteasome inhibitor approved as an IV formulation. By itself, it changed the cornucopia, or pantheon, of myeloma treatment. Then came the new IV formulations with carfilzomib, subcutaneous bortezomib, and now oral ixazomib.

What factors do you take into consideration when deciding between 1 proteasome inhibitor over another?

Are there any emerging proteasome inhibitors moving through the pipeline?

These are options our patients never had to themselves before. We are able to control disease in a much better way. We are able to better sequence therapy and tailor treatments for our patients. Patient “X” might need this kind of therapy—this delivery—so it gives you that more personalized approach to treating your patient. It is an amazing change in our field, and it has been huge in that setting.You have to make it very patient-specific and disease-specific. So, on certain cases […] you might pick an IV formulation, such as carfilzomib, but that patient lives 2 hours from the clinic. With oral formulations, [patients] don’t have to come in all the time so it is much more feasible. That is where ixazomib, an oral proteasome inhibitor, would make a very big difference. It allows you to pick a patient-to-drug regimen. Absolutely. One is called oprozomib, which is an oral version of the drug carfilzomib or, at least, it is made by the same company. It’s an irreversible inhibitor, and there’s a lot of excitement around it. It already had some very nice data. It terms of efficacy, it needed some reformulation to make it a little bit more tolerable, and we are excited about seeing how these new formulations work. That’s one that is going to be very exciting. It has a good activity in high refractory patients. Again, it is an oral formulation.

Bortezomib is a fairly common backbone now with other treatments in myeloma. Could some of these other proteasome inhibitors be explored in combination or as backbones of other regimens?

Then, there is a second proteasome inhibitor. It is a little bit more difficult to deliver, but we are learning about an IV formulation of marizomib. It also has exciting data. It inhibits the proteasome in more than 1 way so, in theory, it will be able to overcome the resistance to these other proteasome inhibitors when it develops in patients. It’s been looked at alone and also in combination with other drugs, and the data are exciting. In terms of efficacy, we are going to have to learn a little bit more about it in terms of its tolerance and how to deliver it; however, it is definitely something on the horizon.We don’t think of drugs by themselves. As bortezomib is partnered with lenalidomide (Revlimid) or with [cyclophosphamide] or with pomalidomide (Pomalyst)—off-label, obviously—the same is going to happen [with other proteasome inhibitors). Carfilzomib is approved with lenalidomide and it’s approved with dexamethasone. I use it frequently with other drug combinations.

Ixazomib is also approved with lenalidomide, but it might partner better with other drugs. The way things work in multiple myeloma today is, you are kind of an “alphabet soup”—trying to figure out how to mix these drugs together in the right combination.

Anecdotally, how have you seen this class of drugs have an impact on quality of life?

However, proteasome inhibitors serve as a really great backbone for myeloma therapy in combination. Again, by themselves, or with dexamethasone, it is a very reasonable thing to do in the right patient. However, combinations with 3 drugs are probably the best way to go, so you’re mixing in those different targeted aspects of the therapy. It’s amazing when you think about what we did 10 or 15 years ago. Survival was [predicted] at 2 to 3 years. Now, we don’t not just have proteasome inhibitors, but also drugs and sequencing of therapy. It has markedly changed how our patients do with therapy. These drugs are very effective and generally very well tolerated for most individuals.

We are learning how to give these drugs in the right way to maximize patients’ quality of life, and it’s not data-driven—that’s anecdotal. By controlling disease and the fact that these are so well delivered in terms of their efficacy and tolerability, it makes patients do very well for long periods of time. They can stay on these drugs that control their disease.

What do you hope community oncologists took away from your presentation that they can apply to clinical practice?

The nice thing that you also think about is you have options. It’s the same target, but drug “X” is a little bit [less] tolerable, so we can move on to drug “Y” and so on and so forth. It gives you options to fall back on. The fact that we have multiple agents in the same class markedly affects our ability to control patients’ disease and then provide them longer, higher-quality life. What we all need to take away from the use of proteasome inhibitors is, first, to always recognize the right way to deliver it, and the toxicities that may come from it so you can educate your patients. A patient who knows what is going to happen is much better at helping you take care of them, turning down doses, etc. Then, [you want to identify] what drug to partner with at the right time. We have approved combinations.

There is a whole pantheon of drugs that have been approved in early relapse-like settings. A lot of them are proteasome inhibitor—based, and [it is important] to recognize that you need to see your patient across from you and use that combination you see that fits them the best—because there isn’t a right or wrong combination, for the most part. It’s what is right for that patient across from you. That’s what I really want to make sure that they took away from this.