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COMy 2021 | Targeting XPO1 in myeloma therapy

XPO1 is an export receptor that facilitates the nuclear-cytoplasmic transport of proteins and RNA. Inhibition of XPO1-mediated nuclear export has been investigated as a therapeutic strategy in multiple myeloma following the pre-clinical establishment of XPO1 as a beneficial therapeutic target. Mohamad Mohty, MD, PhD, Saint-Antoine Hospital, Paris, France, discusses the current evidence supporting the use of XPO inhibitors for the treatment of myeloma. Selinexor is the first oral selective inhibitor of nuclear export to be approved in myeloma, based on evidence from the STORM (NCT02336815) and BOSTON (NCT03110562) trials. The progress made to date demonstrates the promise of XPO inhibitors as an effective drug family in myeloma, warranting their further investigation. This interview took place during the 7th World Congress on Controversies in Multiple Myeloma (COMy), 2021.

Transcript (edited for clarity)

During the COMy Congress, COMy 2021, I’ll be talking about the role of a new family in the treatment of multiple myeloma, namely the XPO inhibitors. And obviously this is really a very attractive new family of drugs, and we know that XPO1 facilitates transport of large macromolecules, including RNA and protein, across the nuclear membrane to the cytoplasm. And this would allow to regulate translation and ribosomal biogenesis...

During the COMy Congress, COMy 2021, I’ll be talking about the role of a new family in the treatment of multiple myeloma, namely the XPO inhibitors. And obviously this is really a very attractive new family of drugs, and we know that XPO1 facilitates transport of large macromolecules, including RNA and protein, across the nuclear membrane to the cytoplasm. And this would allow to regulate translation and ribosomal biogenesis.

There are some very nice in vitro and animal data suggesting that XPO1 is a therapeutic target in multiple myeloma. And in addition, these data could show that for instance, we can see synergy with proteasome inhibitors, such as bortezomib. So this served as a background actually for the development of a nice drug, oral selinexor, which is now approved for relapsed/refractory multiple myeloma based on two major trials. The so-called STORM trial where selinexor was combined with dexamethasone and used twice weekly. And interestingly, actually this was a trial which included patients who were penta-refractory or quadra-refractory. So these are really heavily pretreated, highly advanced patient who received all other available drugs. And we could see a median PFS in the study of 3.7 months, a median duration of response of 4.4 months.

When it comes to selinexor in combination, this is about the BOSTON trial, the multicenter, open-label, randomized Phase III trial, combining selinexor, bortezomib, dexamethasone, a new combination compared to, I would say, the classical bortezomib-dexamethasone. And here it’s extremely important because these are patients with one to three prior lines of therapy, so less advanced compared to the patient from the STORM trial. And we do have a median PFS of almost 14 months compared to 9.4 months for the control arm. So selinexor-Vd 14 months versus 9.4 months for Vd. And interestingly, when you look to the patient subsets and efficacy of this combination, one would like to highlight that deletion 17p patients are likely to benefit from this new combination.

So in summary, I believe that these new XPO inhibitors and the approved one is selinexor, represent a new, attractive and effective, rather convenient because this is an oral drug, new family in relapsed/refractory patient. Of course, I would like to highlight the tolerance and safety issues because there have been some important side effects described like fatigue, GI toxicity, hyponatremia, thrombocytopenia, but actually all of these safety issues can be managed in a symptomatic fashion. And most importantly, actually the incidence and severity have significantly decreased when switching to once weekly administration of the drug.

So definitely, this new drug is most welcome, I would say in the field because when it comes to relapsed/refractory myeloma, there’s no such one size fits all and we need to try more and more to personalize the choice of the combination for the patient.

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