Selinexor With Backbone Therapy for Triple-Class Refractory Multiple Myeloma

Suzanne Lentzsch, MD, PhD: Selinexor is a very interesting drug that was developed and designed based on extensive laboratory research. The mechanism is very interesting, because it inhibits a protein that shuttles other proteins from the nucleus into the cytosol. By doing this, it basically stops cell cycle. Without having any proteins going from the nucleus to the cell cycle, the cell cannot grow or produce more proteins. It’s a very elegant mechanism of action. Interestingly, high-risk cytogenetic multiple myeloma seems to be especially sensitive to selinexor; for instance, patients with 17p deletion. We saw on the BOSTON trial that patients benefited very well and to a higher extent from the selinexor-bortezomib combination in comparison with other patients who had normal-risk cytogenetics. I found that mechanism very interesting.

Peter Voorhees, MD: Selinexor and dexamethasone were approved for use in patients with relapsed/refractory multiple myeloma who had gone through the 5 primary drugs, specifically CD38 antibodies; the 2 IMiDs [immunomodulatory imide drugs], lenalidomide and pomalidomide; as well as 2 proteasome inhibitors. The way that it was initially FDA approved, selinexor 80 mg was given twice weekly with dexamethasone concurrently. The idea behind including dexamethasone with selinexor, even though the overwhelming majority of the patients treated with this regimen have dexamethasone-refractory disease, has to do with the mechanism of action of selinexor. Selinexor basically blocks exportin-1, which is a shuttle that moves proteins out from the cell nucleus into the cytoplasm. One of those proteins happens to be the glucocorticoid receptor that dexamethasone binds to in the nucleus. The idea behind the combination of selinexor and dexamethasone is that the selinexor can trap a glucocorticoid receptor–bound dexamethasone in the nucleus, where it mediates its action.

What we have learned, and we knew this from early on in the STOMP study, is that the adverse-effect profile of selinexor is challenging when it’s given at 80 mg twice weekly. In particular, significant cytopenias and platelets are problematic. There are also nonhematologic adverse effects that are challenging at that dose and schedule. There are constitutional adverse effects, such as fatigue. There are gastrointestinal adverse effects, such as loss of appetite; nausea, sometimes with vomiting; and diarrhea. We’ve learned as time has gone on that the once-weekly dosing strategy of selinexor—particularly in the combination strategies—has performed very well, not only from an efficacy perspective but from an adverse effect perspective as well.

Selinexor and dexamethasone got its initial accelerated approval for the relapsed/refractory patient population, but the phase 3 BOSTON trial was done in patients with earlier-relapsed myeloma. This was a study looking at bortezomib and dexamethasone with or without selinexor for patients with relapsed multiple myeloma who had 1 to 3 prior lines of therapy. To make a long story short, the addition of selinexor to the regimen decreased the risk of myeloma progression and death by approximately 30%. Importantly, in that particular study, they used selinexor on a once-weekly basis. When you look at the rates of constitutional and gastrointestinal adverse effects in the BOSTON trial in the selinexor arm compared with the selinexor-dexamethasone treatment in the STOMP trial, it’s much better tolerated. These days, a lot of us are using selinexor and dexamethasone with other agents.

Suzanne Lentzsch, MD, PhD: Selinexor is being tested in the STOMP trial in different combinations. The trial has multiple arms. Selinexor is being tested in combination with pomalidomide, ixazomib, daratumumab, inotuzumab, and in quadruplets. This is very promising, because we know that selinexor, as a single agent, has a response rate of around 23%. It has substantial adverse effects. Combining a medication that has an excellent and very interesting mechanism of action, and is potentially very potent, with other drugs, is very promising because it will also allow us to reduce the dose of selinexor and combine it with other drugs that have fewer adverse effects, like elotuzumab and pomalidomide. We found that selinexor used in a lower dose, like 60 mg, and only once a week is much better tolerated than when we use it twice a week or in higher doses, such as 80 mg. We learned that lesson from the initial single-drug study, and we continue to as we use selinexor in a lower frequency and lower concentration in combination with other drugs. The data from the BOSTON trial are especially promising, where selinexor is used in combination with bortezomib, and showed superiority in a randomized trial over bortezomib and dexamethasone.

Transcript Edited for Clarity