Selinexor for RRMM: Safety and Efficacy

Paul G. Richardson, MD: I agree with you 100%, Cristina. I think you made a very important point. A key secondary end point was the incidence of neuropathy. That was comfortably met with a highly statistically significant reduction in the severity of neuropathy for the 3-drug arm compared with the 2-drug arm. That was, again, a very crucial part of the design of the study, because we were able to demonstrate that the weekly bortezomib preserved efficacy with selinexor. But most important, we were able to reduce neuropathy. It may have been more than just simply the weekly administration in the mix. There is compelling preclinical evidence that selinexor may have anti-inflammatory effects. In the context of reducing these inflammatory signals, this may have a favorable impact on the incidence and severity of neuropathy. This is something we’ve known for many years thanks to our studies with bortezomib. Hence, the importance of partnering bortezomib with dexamethasone on the day of administration or the day after. It was very nice to see in this study that, in fact, the addition of selinexor with this weekly schedule substantially reduced neurotoxicity.

Having said that, there were still obviously adverse effects associated with the 3 drugs compared with the 2 drugs that were important. The GI [gastrointestinal] toxicity was there, but it was much less severe, much less challenging, and much less broad in terms of overall numbers compared with the challenges we saw in STORM. It’s worth sharing, though, that in the study we were dealing with centers that were relatively inexperienced with giving selinexor. At the same time, in the protocol, we were very permissive. We recommended supportive care in the form of ondansetron and so on, but recognized that in the international setting prescriptive strategies for antiemetics could be more challenging. We left it very much to investigator discretion as to how readily they might use, for example, olanzapine, depending on availability in the countries where the study was being performed. In any event, that’s why I feel very confident in the results from BOSTON. They essentially reflect what you nicely put as real-world practice.

I was particularly struck by the efficacy seen for selinexor in high-risk patients. I thought that was particularly impressive.

Cristina Gasparetto, MD: Yeah, I think so too. We are always looking for this combination to determine if there is a difference between high risk and standard risk. Of course, in the relapsed setting, it’s a little more confusing. Now we’re dealing with patients with more resistant clones, probably some changing. So we see that the number of patients with high-risk disease who were included was pretty high. It’s absolutely important that we choose the right combination for the right patient based on comorbidities, type of myeloma, prior lines, and also cytogenetics. I would love to see a dissection between deletion 17, the different translocations. We know that bortezomib and the proteasome inhibitor [PI] are conforming very well with the different translocations, so I would love to see a dissection. Unfortunately, it’s sometimes difficult. Some of these genetics come together. But I’d love to see that. Absolutely, that’s a very good combination also targeting some patients with more aggressive clones.

Paul G. Richardson, MD: I think that’s right. The hazard ratio being so striking for the high-risk group really reinforced, in my mind anyway, what I’ve always been impressed by from the early days in the preclinical development of selinexor. The observation was made about its effects on 17p deletion. That’s very gratifying to see.

The other thing that struck me, and you pointed this out nicely, was that in elderly [patients], the frailty index was formally assessed and the hazard ratio for benefit was preserved. That was really important information because they basically said, “Look, this isn’t a drug that just has to be reserved for the Lance Armstrongs of our patients,” if you’ll excuse the metaphor. “It’s a drug that can be legitimately offered to all patients.” In fact, in the STORM study, 1 of my patients who actually derived significant benefit from selinexor that hadn’t responded to anything else, for that matter, was age 86. Knowing this can actually help elderly patients, which is very important.

That was also suggested by another interesting observation, which was in the group of patients entering the study who were actually proteasome inhibitor-naïve. Remember, this was first relapse and beyond. Patients could be exposed to a proteasome inhibitor, but they had to be responsive. They couldn’t be refractory. But in the patients who had never received a proteasome inhibitor—in other words, older patients just receiving immunomodulatory treatments such as lenalidomide and dexamethasone—the hazard ratio there was really impressive. You might say, “Well, those folks who are just treated with a PI with dexamethasone do just as well.” No. Actually, the 3 drugs really did perform better, and the hazard ratio was quite striking for that group. I think we’ve got the highest level of evidence from a phase 3 multicenter international trial, with true real-world characteristics and efficacy as demonstrated.

Transcript edited for clarity.