Proteasome Inhibitors Paving Promising Path for Myeloma Treatment

Jonathan Alicea and Gina Columbus
Published Online: Monday, Jul 17, 2017

multiple myeloma
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.”

In an interview during the 2017 OncLive® State of the Science SummitTM 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.

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

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.   

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?

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.

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.

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

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.

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.

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

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. 

Are there any emerging proteasome inhibitors moving through the pipeline?

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.


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