ASH 2025 | STOMP: selinexor, mezigdomide, & dexamethasone in patients with RRMM

The STOMP Phase I results combine the highly active cereblon III ligase modulator, or so-called CELMOD, mezigdomide, as an oral therapy with a very powerful oral agent, selinexor, which is an XPO1 inhibitor, an XPO1 inhibitor. And this agent, obviously, selinexor, is approved for the treatment of relapsed refractory multiple myeloma in combination and indeed as a single agent just combined with dexamethasone and is exquisitely active in highly refractory disease, but sometimes difficult to give because of the tolerability profile of this particular agent. Although I must say that with lower dose and weekly scheduling, as well as supportive care in our experience, selinexor has had a very manageable side effect profile, and it’s particularly active in highly resistant high-risk disease, in particular 17P-deleted multiple myeloma. So to combine it with mezigdomide was, in our view, a very important next step, because not only does selinexor take on high-risk multiple myeloma, but it also appears to be very active in extramedullary disease. Mezigdomide does the same, and there’s a strong rationale for potential synergy preclinically between cereblon III ligase modulation and XPO1 inhibition. Moreover, selinexor has been shown to have T-cell enhancing effects, and so with that in mind, as well as the T-cell enhancing effects of mezigdomide, this was a very logical combination to put together. So this study led by my colleague, Dr Clifton C. Mo, has partnered mezigdomide with selinexor and dexamethasone in highly refractory patients. And what we’ve seen so far is number one, a manageable safety profile. Two, that at low doses of both mezigdomide and selinexor, the selinexor dosing has been between 40 and 60 milligrams once a week. Together with mezigdomide dosed between 0.3 milligrams and one milligram, we’ve seen exquisite activity and a manageable side effect profile. And speaking on behalf of one of my patients, I can share quite a remarkable result as a simple description of a patient journey. This patient, unfortunately, had a very difficult time post-CAR-T, had relapsed with very aggressive disease, triple-class refractory 17P deleted, and he was able to tolerate mezigdomide and selinexor with appropriate dose adjustments and supportive care, and had a remarkable response in the context of a light chain burden that was very high and most importantly extramedullary disease that responded beautifully just to this all oral combination. So the data you’re hearing at this meeting are preliminary but nonetheless very attractive and support the role of this combination going forward and we’re very hopeful that this will provide a particularly important platform for patients in whom cellular therapies and T-cell redirection has unfortunately failed them. And then they can move to this particular platform as a next step. The other opportunity, Tom, is to bring it earlier and to use it in front of these cellular approaches. And another one of my patients who declined to go to CAR-T immediately and who’s reported in Cliff’s abstract was just one of these patients and he did exquisitely well or has done exquisitely well with the combination of mezigdomide and will go to CAR-T for his choice in due course but not now because he’s had such a high-quality response. So we’re very encouraged by it and we are hopeful that this particular all oral combination with a very very manageable safety profile will actually find its way into the therapeutic armamentarium.

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