Selinexor combinations boost ORR and PFS

ATLANTA—A truism recognized by both clinicians and patients is that first-line treatment of multiple myeloma is rarely enough to hold the disease at bay, which is why the choice of second-line or add-on therapies is such a crucial decision.

“We’ve made great strides in myeloma, but still more treatment is usually needed,” explained Joseph Mikael, MD, MEd, a professor at the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute (TGen), an affiliate of City of Hope Cancer Center and Chief Medical Officer of the International Myeloma Foundation (IMF). “Patients become chemo-resistant, and we need to look to immunomodulating therapies, monoclonal antibodies to partner with different drugs rather than relying on a single agent,” he said in a phone interview with BreakingMED.

Ravi Vij, MD, professor of medicine, bone marrow transplantation specialist at the Siteman Cancer Center of Washington University in St. Louis School of Medicine, echoed Mikael’s comments, noting that the hunt for new, effective combinations—choosing what agent to add to make a doublet a triplet or a triplet a quad—is “a hot research area today.”

Against that background, Suzanne Lentzsch, MD, professor of medicine at Columbia University, and colleagues, launched a study focusing on multiple myeloma that has become refractory to anti-CD 38 monoclonal antibodies (αCD38 mAB), noting that after myeloma becomes refractory to αCD38 mAB, patients have an “overall response rate of 31%, median progression-free survival [PFS] 3.8 months and overall survival [OS] 9.3 months.”

“Selinexor is a first-in-class, oral, selective inhibitor of nuclear export compound approved for patients with previously treated multiple myeloma as well as diffuse large B-cell lymphoma,” Lentzsch said at her poster presentation at the American Society of Hematology 2021 meeting here. Administered as a doublet with dexamethasone (Xd), it had a 26% overall response rate in patients who were refractory to triple-class therapy (immunomodulatory drug, proteosome inhibitor, and αCD38 mAB) and improved overall survival.

In the STOMP study, a phase Ib/II open label study, Lentzsch and colleagues enrolled 46 multiple myeloma patients and randomized them 1:1 to selinexor plus pomalidomide (XPd) or selinexor plus carfilzomib (Xkd). The median age of participants in the pomalidomide arm was 64, and 57% were women. In the carfilzomib arm the patients were older (median age 70) and fewer of them were women (39%). Across both treatment arms, the “median time from diagnosis was 5 years, and median number of prior regimens 4 (range, 2–10). All patients were previously treated with an immunomodulatory drug, a proteosome inhibitor, an αCD38 mAb; 78% (XPd) and 52% (XKd) had triple refractory multiple myeloma.”

The most common αCD38 mAb administered in prior therapies was daratumumab, she said.

Findings among evaluable patients included:

  • Overall response rate: 57% in the XPd arm.
  • Overall response rate: 65% in the XKd arm.
  • Clinical benefit rate: 76% in the XPd arm.
  • Clinical benefit rate: 74% in the XKd arm.

In the XPd arm, median PFS was 8.7 months (95% CI: 7.6, NE), median duration of response was 7.9 months (95% CI: 3.9, NE), and median OS was 21.8 months (95% CI: 8, NE). In the XKd arm, median PFS was 15 months (95% CI: 12.0, NE), median duration of response was 13.1 months (95% CI: 10.2, NE), and median OS was 33.0 months (95% CI: 20.4, NE), according to the study authors.

Moreover, response to XKd therapy compared favorably to the prior αCD38 mAb-containing regimen used at least one line earlier: “[Overall response rate] ORR 65% versus 52%, [clinical benefit rate] CBR 74% versus 57%, median PFS 15.0 months (95% CI: 12.0, NE) versus 8.5 months (95% CI: 5.9, 17.3).”

The most common hematological treatment emergent adverse events (TEAEs) and most common events grade 3 or higher were “thrombocytopenia (XPd: 35%; 30%; XKd: 78%; 39%), anemia (XPd: 57%; 39%; XKd: 57%; 22%), and neutropenia (XPd: 57%; 48%; XKd: 35%; 4%).”

Lentzsch and colleagues concluded that among patients who have become refractory to αCD38 mAb-containing regimens, treatment with selinexor-containing regimens “demonstrates high response rates and PFS… treatment was safe and well-tolerated and can be continued indefinitely.”

The data, she said, “position treatment with selinexor-based combinations selinexor plus pomalidomide (XPd) or selinexor plus carfilzomib (Xkd) as optimal therapies in the evolving landscape of relapsed MM after αCD38 mAb therapy, including in patients with triple class treated multiple myeloma after 1-2 regimens.”

Vij, who was not involved in the study and who spoke with BreakingMED to offer some context for the findings, did not characterize selinexor as an “optimal therapy” choice, but agreed it is a reasonable choice. He added that in day-to-day clinical practice, oncologists are more likely to add an agent based on what they have observed as its clinical effect, since “the ability to do testing to identify specific targets does not really exist outside of academic settings.”

Mikael, who disclosed that he was involved in studies that led to the development of selinexor but was not involved in the STOMP trial, said he found studies such as this valuable because they provide evidence to bolster a clinical decision. He added that he anticipated that NCCN guidelines would soon be updated to reflect the latest data on triplet therapies.

  1. In the STOMP trial, selinexor-led combinations demonstrated efficacy among patients who were refractory to αCD38 mAB therapy.

  2. Be aware that this activity describes findings reported at a medical meeting. These findings should be regarded with caution until they are published in a peer-reviewed journal.

Peggy Peck, Editor-in-Chief, BreakingMED™

Lentzsch disclosed consultant or research funding agreements with Janssen, AbbVie, Celularity, GSK, Takeda, Karyopharm, Oncopeptide, Sanofi, and Cael Biosciences. She disclosed stock holdings or equity interest in Magenta, Ossium Health and Kadmon.

Mikhael is a consultant for Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda.

Joseph Mikhael, MD, MEd, FRCPC, FACP

Chief Medical Officer, International Myeloma Foundation

Professor, Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), City of Hope Cancer Center

Consultant Hematologist and Director, Myeloma Research, Phase 1 Program, HonorHealth Research Institute

Adjunct Professor, College of Health Solutions, Arizona State University

Cat ID: 332

Topic ID: 78,332,730,332,468,192,925,331