Role of Selinexor in Patients with Relapsed/Refractory Multiple Myeloma

Expert oncologist Joshua Richter, MD, defines triple-class refractory multiple myeloma and describes selinexor’s unique mechanism of action.


Joshua Richter, MD: Even though we’ve had several FDA-approved therapies across the last decade, we still have a large unmet need in patients with overall poor prognosis in the heavily refractory setting. We define patients as triple-class refractory when they’ve been exposed to and progressed beyond 3 of our initial classes of therapies, including 1 immunomodulatory drug [IMiD], like lenalidomide; 1 proteasome inhibitor [PI], like bortezomib; and 1 CD38 antibody, like daratumumab. For example, if you were to receive the therapy dara [daratumumab]-RVd [lenalidomide, bortezomib, and dexamethasone], and progress on that therapy, you’re already triple-class refractory. We even go so far as to further define this as being quad-refractory, and penta-refractory. Quad-refractory is 2 IMiDs, or 2 PIs, and a CD38, and penta-refractory is refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab.

To get a better idea of what their prognosis is, we derive a lot of our data from the MAMMOTH study, and some real-world data sets, including the Flatiron [Health] data set, to see what happens when patients progress beyond these major classes. Although for newly diagnosed patients, we expect the majority of them to live well beyond a decade, when patients become triple-class refractory, their overall survival is less than a year. And if you look at penta-refractory patients, the median overall survival is around 5.6 months. So as you become refractory to these initial agents, even though there are further drugs within that class—so refractory to lenalidomide, you can get pomalidomide, refractory to bortezomib, you can get carfilzomib—once you’re refractory to a drug within each class, or refractory to all 5, you must look to novel mechanisms of action to get better outcomes and survival.

Selinexor is what’s known as a SINE, selective inhibitor of nuclear export. The important thing about this MoA [mechanism of action] is that it’s not myeloma specific, it’s cancer specific, and this type of mechanism is applicable to a variety of different malignancies. In fact, selinexor has additional approvals outside of myeloma, specifically at the moment of this recording, in diffuse large B-cell lymphoma, however there are ongoing studies in other malignancies as well. Essentially, when the body produces a cancer cell and recognizes that it’s cancer, it targets it for a programmed cell death, apoptosis.

Intracellularly, there’s a cascade of events that happen—let’s call that 1 through 6—where the cell gets signaled, and inside the nucleus you get 1, 2, 3, 4, 5, 6, and then the cell commits suicide and dies. One of the ways that cancer cells like to survive is to take part of that equation and kick it outside of the nucleus. Let’s take No. 3; let’s kick No. 3 outside of the nucleus through these little holes called exportins, or XP01. So the cell gets signaled for cell death, it gets to 1, 2, but there’s no 3, so the cell can’t complete that cascade and the cell survives, cancer spreads, and it ends up having progressive malignancy.

Selinexor selectively inhibits nuclear export, and it blocks XP01 and traps the cell from trying to kick those elements outside of the nucleus, therefore forcing the cell to undergo cell death, and leads to a better control of malignancies. What’s important about this MoA is that once you have a new mechanism of action in a disease like myeloma, you don’t just get 1 more therapeutic option, you get a multitude of options because you can combine this with other agents or other classes within the field. This is best evaluated in the STOMP study, which combined selinexor with a variety of other drugs, such as immunomodulatory drugs, like lenalidomide and pomalidomide; proteasome inhibitors, like bortezomib and carfilzomib; as well as the CD38 antibodies, like daratumumab.

Transcript edited for clarity.

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