Advancing Survival in Relapsed/Refractory Multiple Myeloma - Episode 6
Paul G. Richardson, MD: I want to move on and discuss future directions. Obviously, with STORM and of course BOSTON under our belts, I want to spend a bit more time asking you to share your experiences from STOMP. Obviously, there are a number of arms in that study—9 in total, in fact. That’s very appropriate as you’re trying to partner and purpose a drug with best partners. It makes complete sense. You’ve had a leadership role in that trial. I would love for you to comment, if you don’t mind, on a couple of things.
First, Christine Chen very kindly presented that at ASH [the American Society of Hematology Annual Meeting] to, I think, a quite appreciative audience. What are your thoughts on the selinexor-pomalidomide-dexamethasone experience, because that’s an all-oral regimen. Obviously, in the era of COVID-19 [coronavirus disease 2019], that’s a relevant point.
Cristina Gasparetto, MD: This is a very important combination. It was clear that the selinexor given twice a week in combination with pomalidomide was too toxic. We had some DLTs [dose-limiting toxicities]. Remember, STOMP was designed to determine the maximum tolerated dose of selinexor in combination with the different drugs and then the recommended phase 2 dose. Each arm of STOMP was initially, in phase 1, the 3+3 design. When recommended for phase 2, there was an extension phase.
With these particular combinations that Christine presented on last year, a couple of dosages were observed. The first was a higher dose of selinexor, given weekly at 80 mg, with pomalidomide at 2 mg. The most interesting, to me, is the lower dose of selinexor in combination with 4 mg of pomalidomide. That is the full dose. Of course, there were not many patients enrolled in this arm. But if you look at the difference, response was actually significant. The response was, like, 83% versus a response of about 50% in the entire population, taking into account the different dosage of the selinexor and pomalidomide. I’m trying to say that we need to explore these dosages because pomalidomide, a full dose—4 mg—with the lower dose of selinexor was performing the best.
Paul G. Richardson, MD: Yes, that’s an excellent point, and I’m so grateful for you bringing that up. That is exactly the group that caught my eye as well. Essentially, you were going low with the selinexor and going high with the pomalidomide, and obviously the 2 drugs together did partner well at that dose level. What you then saw was real efficacy because patients stayed on treatment.
Cristina Gasparetto, MD: Exactly. Decreasing the selinexor but maintaining the pomalidomide means it was good. We were all concerned about the myelosuppression with this combination. There was a little more myelosuppression, a little more neutropenia and thrombocytopenia. But we learned very quickly that aggressive supportive care with a growth factor, including thrombopoietin receptor agonists, means we could use those. Particularly, the heavily pretreated patients entered the trial with suboptimal platelet numbers, anemia. So, it’s a problem. We need to support them aggressively. But we need to pay attention to this combination. It’s oral. After the first few months of loading, achieving a response—the response was incredible—there was a synergy between the proteasome inhibitor and the selinexor that’s probably only additive with the immunomodulatory drugs. Still, it was an incredible response considering that pomalidomide-dexamethasone alone is about 30% response.
Paul G. Richardson, MD: Exactly. I absolutely agree with you. What people fail to appreciate with pomalidomide is that these immunomodulatory effects that are generated through the targeted degradation, through the E3 ligase complex, are very sophisticated in terms of downstream effects. People imagine that it’s all outside the myeloma and it’s immune modulation. It’s much more complex than that. As you know, that E3 ligase complex sits close to the DNA and the nucleus, so what you’re basically doing is optimizing the potency of that intracellular effect of the pomalidomide through the inhibition of XPO1 with its direct apoptotic signal on the myeloma. To me it’s very interesting. I agree with you. I’m very excited for pomalidomide and selinexor going forward, particularly if you then partner it with a proteasome inhibitor. I suspect that will be a really important regimen, and I know studies are underway looking at that very point.
Transcript edited for clarity.