Nuclear Export Inhibition in RRMM

Paul G. Richardson, MD: Hello, and thank you very much for joining this Targeted Oncology™ presentation entitled, “Advancing Survival in Relapsing and Refractory Multiple Myeloma.”

In recent years, the treatment for heavily pretreated relapsed and refractory multiple myeloma has evolved to include multiple, new effective treatment options for second and subsequent lines of therapy. Today we’re going to talk about a novel therapeutic target for treatment, specifically, exportin 1 [XPO1]. In fact, it is the first selective nuclear export inhibitor to enter clinical use for patients who have developed relapsed and refractory myeloma after both immunomodulatory and proteasome inhibitor-based therapies as well as exposure to CD38 monoclonal antibodies.

My name is Dr Paul Richardson. I am from the Dana-Farber Cancer Institute in Boston, Massachusetts. I serve as the director of clinical research and as a clinical program leader. It’s my privilege and pleasure to welcome Dr Cristina Gasparetto, who serves as the director of the myeloma program at Duke University Medical Center in Durham, North Carolina. And in that context, it’s my pleasure to welcome Cristina and to thank you so much for joining us. So please, let’s begin.

Cristina Gasparetto, MD: Thank you, Paul.

Paul G. Richardson, MD: It’s my pleasure, Cristina.

As you had discussed before, Cristina, in terms of our discussion outline, there are a few things we need to cover today. If I may, I wanted to start by asking for your thoughts on the rationale for treating with a nuclear export inhibitor in relapsed/refractory multiple myeloma.

Cristina Gasparetto, MD: Well, as you know, in the relapsed setting the number of patients who are penta-exposed or are triple-refractory is increasing, unfortunately. And so, we need different targets. We definitely need to attack the myeloma at a different level. Selinexor is a new agent that attacks the myeloma differently. It is an inhibitor of exportin 1, which is a very important protein overexpressed in many cancer cells, overexpressed in myeloma. In fact, the overexpression of this protein correlates with a poor prognosis in myeloma, and selinexor blocks this protein.

To talk briefly about the mechanism of action, this protein carries out of the nucleus what we call the cargo, right? Tumor suppressor or oncoprotein. It carries these cargos out of the nucleus to the cytoplasm, and the cells don’t die. They keep proliferating. Selinexor blocks these proteins so the cargos don’t leave the nucleus. And eventually, cells go into apoptosis. So it’s a different mechanism of action. We didn’t have these targets in myeloma before, so it’s definitely new and is very interesting.

Paul G. Richardson, MD: I agree. I’ve heard a description of this that I developed in my own way to provide a metaphor for my patients as to how we describe this. It’s basically as if within the nucleus of the cancer cell, and this is analogous to the home, there’s a rave going on. The parents have left the house. Essentially, what happens is by blocking the departure of the parents, not only do the parents stay at home and convert the rave to a much more civilized wine-and-cheese event, but at the same time, and this is just as important, it blocks the social media that the kids are using to invite other people to join the rave. Of course, it’s not simply just the retention of tumor suppressor proteins, but as you pointed out so nicely, Cristina, it’s the inhibition of key cargo proteins that then move out into the cytosol and can further control proliferation, survival, and growth. I absolutely agree with you. It’s a fascinating and novel mechanism that is very important in myeloma biology.

Transcript edited for clarity.