With approximately 20 drugs approved over the last 20 years, the options for patients with myeloma continue to grow. One of these agents that we have had for the last few years is Selinexor, also known as Xpovio®. It is the first in a new class of myeloma drugs called XPO1 inhibitors, sometimes called Selective Inhibitors of Nuclear Export (SINE).
We can consider Selinexor to now be the fourth major class of myeloma drugs after proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. It is very important that we develop new classes of drugs because these drug classes provide unique ways of attacking myeloma. Often, we use the expression “new mechanisms of action” to describe the different ways that we can treat myeloma.
Selinexor presents a novel and significant mechanism of action in targeting myeloma cells for destruction. A hallmark of cancer cells is their ability to grow autonomously, detached from the body's typical cellular coordination. They overcome the body's natural mechanisms that prevent cancer growth.
These natural prevention mechanisms are called “tumor suppressors,” or proteins inside cells, (and often inside the nucleus of the cell). These tumor suppressors keep the cells in check. Cancer wants to “get rid” of these tumor suppressors.
There is a pathway, or a doorway, out of the nucleus called XPO1. The good tumor suppressors can exit the nucleus through this pathway, leaving the cell at risk of becoming cancerous.
In myeloma, we have learned that this XPO1 pathway is overused (or we say, “upregulated”). This pathway forces the tumor suppressors to leave the nucleus at a rapid rate. Selinexor is an XPO1 INHIBITOR, and therefore blocks the pathway. Thereby, it keeps the good tumor suppressors in the nucleus and reduces the risk of the cell being cancerous.
This means we have a new way to attack myeloma.
Selinexor was first introduced in myeloma through the STORM trial. It demonstrated that it could work even in the most heavily treated patients. These patients were penta-refractory – meaning their disease was resistant to bortezomib (Velcade®), carfilzomib (Kyprolis®), lenalidomide (Revlimid®), pomalidomide (Pomalyst®) and daratumumab (Darzalex®). In these patients, Selinexor by itself had a response rate of about 25%. As a result, it was approved in heavily relapsed myeloma to be given twice weekly with dexamethasone alone.
Several studies have now been done with Selinexor earlier in the disease course of myeloma –
as early as second-line therapy. The phase 3 clinical trial BOSTON also showed that it can be used once weekly when combined with Velcade. Since then, Selinexor has been used in multiple clinical trials in combination with other myeloma drugs such as Velcade, Kyprolis, Pomalyst, and Darzalex. As a result, it can be used in all these combinations.
Selinexor is a pill that is taken orally. When first introduced, it caused a lot of GI side effects like nausea and anorexia (a lack of desire to eat). It also caused other effects such as low blood counts, a low sodium level, and fatigue. However, we have learned that if we give the drug once weekly, and with the right supportive care (like antinauseants), it is much better tolerated.
We also use a much lower dose than when it was first introduced. Initially, we would give it at a dose of 80mg twice weekly, but now we typically give it between 40-80mg once weekly. Please watch my other “Myeloma Made Simple” video called “Selinexor Side-Effect Management Made Simple” to learn the details.
So, in summary, Selinexor is the first of a new class of drugs known as XPO1 inhibitors that is highly effective in myeloma when given with dexamethasone alone, or preferably in combination with other myeloma agents. It is much easier to take once weekly and at lower doses.
Lastly, with the introduction of so many T cell therapies like CAR T and bispecific antibodies, we have also learned that Selinexor can be very effective before these therapies are given. This is because Selinexor does not impair the functioning of a patient’s T cells. It is great to have yet another tool in our myeloma toolbox to treat our patients.
