Selinexor for RRMM

Paul G. Richardson, MD: Let’s think forward, Cristina, if I may. Perhaps you can share with me your perspective on the development of selinexor? Obviously, this has been a long and very productive journey. I’d love for you to perhaps touch on some of the preclinical milestones, and at the same time, talk about some of the early studies that you’ve been involved in.

Cristina Gasparetto, MD: Yes. We do have preclinical data in vitro showing that selinexor clearly is capable of causing cell apoptosis, cell death, with and without dexamethasone. This was in an in vitro model using myeloma cell lines, but also in a mouse model. That led to the initiation of the work in humans using the selinexor for heavily pretreated patients, and using, like you said, a different mechanism of action.

We can talk a bit about the early study, the STORM study. The results were published last year in The New England Journal of Medicine, with Ajai Chari, MD, as the leading author. This trial was designed to test the combination of selinexor with dexamethasone in heavily pretreated patients. The primary end point was the overall response. It was a multicenter, phase 2 study, and they were able to enroll more than 100 patients.

There are some interesting things about this study that I want to share. Number 1, it was specifically for heavily pretreated patients. These patients were penta-exposed. They were exposed to lenalidomide, pomalidomide, carfilzomib, bortezomib, and daratumumab. They were triple-refractory and to all of the classes of the different drugs that we use. In fact, 83 patients were penta-refractory. They were refractory to all of these agents. Many of these patients were progressing very rapidly. In fact, many of these patients, if I remember correctly, were even progressing from the time of screening to enrollment. They allowed patients with low blood counts, myelosuppression, and some patients had renal impairment. This was very important because this is real life. We deal with the patients to the end, when they fail all of these therapies. The fact that the clinical trial was designed to include these patients was very important.

As I mentioned, patients received selinexor in combination with dexamethasone in this study, and selinexor was given at 80 mg twice a week—on day 1 and day 3—and dexamethasone was given weekly. That was important. It was almost a loading dose to try to decrease the tumor burden very quickly. With time, it was clear that after achieving the response, making proper dose modifications was OK to mitigate toxicity, but we were able to keep some of the responses.

I like that it included elderly patients. There were patients with penta-refractory disease with an overall survival, as you know, that was between 2 and 3 months. So heavily pretreated patients with renal impairment, some counts compromised, and there was a good signal. The overall response was 26%, with a clinical benefit of close to 40%.

Clearly, the oral combination was effective in this elderly pretreated population. If you look at the patient characteristics, the median number of prior lines of therapy was 7. And so, quite advanced. Many patients had, of course, ascites, cytogenetics, but whether we know that at this point, the majority of patients had high-risk disease in the relapsed setting.

It was outstanding for this population of patients to have that signal of 26% response rate with, if I correctly recall, a progression-free survival that was close to 4 months. And the overall survival for the entire population was more than 8 months, compared to the historical control where we see an overall survival of a couple of months for these patients. So a different mechanism of action. Definitely a signal as used in an oral combination. What do you think about the toxicity, in your opinion? I think that is one of the major concerns for the physician in the community.

Paul G. Richardson, MD: I completely agree with you, Cristina. The biggest challenge for selinexor, particularly in the STORM trial, was the tolerability profile. But I think once you’re able to establish a response in a patient and then dose reduce, that was obviously a key step.

The second step was supportive care, which was everything. In our patients, for example, we used an aggressive approach to hydration. We were very proactive with antiemetics. For example, we would use ondansetron and olanzapine together before anything. In other words, we wouldn’t necessarily react to nausea. Rather, we would start, for example, with Zofran and Zyprexa at night to basically anticipate the nausea, the fatigue, the anorexia, and so forth that would characterize unsupported administration of the drug twice a week.

I think what’s really important to note is that the GI [gastrointestinal] adverse effects have obviously been an important consideration, certainly for community colleagues. But particularly speaking, one of my colleagues who I work with in western Massachusetts has a very busy and broad practice that includes colorectal cancer patients and so forth. He shared with me that he’s very comfortable with the strategy because he basically embraces the sort of strategies that he uses in solid tumor patients to be preemptive about the antiemetic strategies, hydration, and serum sodium. I echo the points that he shared with me because I think that’s exactly right.

Transcript edited for clarity.