Xpovio combo plus mezigdomide to be tested in relapsed-refractory MM

Therapy in arm being added to Phase 1b/2 trial of Xpovio and dexamethasone

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A Phase 1/2 clinical trial will evaluate the safety and efficacy oral mezigdomide, Bristol-Myers Squibb’s investigational treatment, when added to the approved oral combination of Xpovio (selinexor) plus dexamethasone in people with difficult-to-treat multiple myeloma.

Under the terms of a trial collaboration and supply agreement, Karyopharm Therapeutics — which markets Xpovio — will sponsor the study as an additional arm of its ongoing Phase 1b/2 STOMP trial (NCT02343042), which is investigating Xpovio and dexamethasone in a number of combinations.

Set to begin next year, the study will involve people with relapsed or refractory multiple myeloma (RRMM) who have previously received two or more treatment lines, including immunomodulators, proteasome inhibitors, and anti-CD38 therapies.

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Participants also must either be ineligible for or failed to respond to therapies based on immune T-cell responses, including CAR T-cell therapy or bispecific antibody treatments such as Tecvayli and Elrexfio.

“This is an important collaboration with Bristol Myers Squibb to explore this novel and entirely oral combination in patients who have progressed following T-cell engaging therapy,” Richard Paulson, Karyopharm’s president and CEO, said in a company press release.

“Pre-clinical studies with [Xpovio] and mezigdomide post T-cell mediated therapies provide a scientific rationale for this novel combination to potentially … improve outcomes for more of these patients,” Paulson added.

In recent years, approaches for combating myeloma have focused on using immune T-cells’ natural ability to fight cancer cells. Both CAR T-cell therapies and bispecific antibodies, in different ways, help guide T-cells to cancer cells, where they can launch immune attacks against them.

A caveat with these therapies, however, is that T-cells can become exhausted over time and stop working as they should, raising the risk of cancer relapse.

“Despite multiple treatment advances, there is a growing need for new combinations, particularly those that are all-oral, accessible and that have novel mechanisms to help treat patients with relapsed and refractory multiple myeloma,” said Paul Richardson, MD, the study’s senior investigator and a professor at Dana Farber Cancer Institute.

Karyopharm launched the STOMP study to test Xpovio in combination with various other myeloma treatments, across about a dozen trial arms, in RRMM patients and those newly diagnosed with multiple myeloma.

Possibility for an oral combination targeting cancer, stimulating immune system

Xpovio, marketed as Nexpovio in some countries, works by suppressing exportin 1, a protein produced in large amounts by cancer cells to help them escape the body’s natural tumor-suppressing mechanisms.

As a cereblon E3 ligase modulator, mezigdomide works by influencing the activity of cereblon, a component of a E3 ubiquitin ligase complex that regulates protein breakdown.

The experimental therapy has been shown to promote the breakdown of proteins that help myeloma cells survive, making them more vulnerable to T-cell attacks. As such, it is considered to have a direct effect on cancer cells, while also stimulating the immune system.

“Pre-clinical data suggests the combination of a selective inhibitor of nuclear export (SINE), such as [Xpovio], with potent cereblon E3 ligase modulators, such as mezigdomide, may spare T-cell function while showing potential activity against resistant myeloma,” Richardson said.

Mezigdomide also is being tested in other clinical trials involving RRMM patients.

The upcoming STOMP arm into mezigdomide in combination with Xpovio (40 or 60 mg) plus dexamethasone has two main goals. One is to assess treated patients’ objective response rate — the amount of people achieving at least a partial response, or cancer reduction — and the other their clinical benefit rate, meaning the percentage of RRMM patients with a partial response or better, or who remain stable for at least six months.

Key secondary goals include progression-free survival, or the time patients live without signs of disease progression; overall survival; and duration of treatment responses. Changes in T-cell populations and activity during treatment also will be evaluated.

In the U.S., Xpovio is approved in combination with Velcade (bortezomib) and the immunosuppressive treatment dexamethasone for multiple myeloma patients after at least one prior therapy, and in combination with dexamethasone for RRMM patients with at least four prior therapies.