Proteasome inhibitors (e.g., bortezomib and carfilzomib), immunomodulatory drugs (e.g., lenalidomide and pomalidomide), alkylating agents, and monoclonal antibodies (e.g., daratumumab) have significantly increased the treatment options available for patients with multiple myeloma.
Unfortunately, most patients eventually relapse and many develop triple-class refractory disease, which is resistant to all available therapies. The median overall survival for heavily pretreated patients with relapsed/refractory multiple myeloma is just 1.7 to 3.0 months.
In response to the urgent need for additional treatments for these patients, research scientists around the globe are investigating the potential clinical benefits of other agents and combinations of agents, including the first-in-class inhibitor of the nuclear export protein exportin 1 (XPO1) selinexor.
As a selective inhibitor of nuclear export, selinexor induces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA (mRNA) translation.
Preclinical studies have shown that selinexor has antitumor activity against circulating myeloma cells, as well as against solid tumors, either as monotherapy or in combination with dexamethasone, a glucocorticoid used to fight inflammation in several patient populations.
In the open-label, phase IIb STORM clinical trial, researchers evaluated for objective treatment response in patients with triple-class refractory multiple myeloma who received a combined treatment of selinexor and dexamethasone (N Engl J Med 2019;381:727-738).
The 123 patients included in the STORM trial, which was conducted at 60 centers across the U.S. and Europe between May 2015 and March 2018, were heavily pretreated with a median of seven prior lines of therapy, including 10 anti-myeloma agents and at least one monoclonal antibody.
The primary endpoint in the study was the overall response rate, which was defined as a confirmed partial response or better, characterized by 50 percent or greater reduction in the serum level of myeloma protein. Disease response was adjudicated by an independent review committee of four physicians who observed an overall objective treatment response in 26 percent of the study cohort.
Based on the results from the STORM clinical trial, FDA approved selinexor-dexamethasone for heavily pretreated patients with relapsed/refractory multiple myeloma last year.
Maria Gavriatopoulou, MD, PhD, Assistant Professor in the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital in Greece, was the co-lead investigator of the clinical trial at the top recruiting site for the STORM clinical trial in Europe.
In recognition of her work, Gavriatopoulou has been named a winner of an Excellence in Oncology award from the Oncology Times. In an interview following the announcement of the award, she shared additional insights about the landmark study.
What inspired you to investigate this research question?
“Treatment advances including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies have significantly improved the prognosis of patients with multiple myeloma during the last number of years, whereas autologous stem cell transplant remains a standard option for fit patients.
“Novel agents are introduced constantly in the therapeutic armamentarium with anti-BCMA antibodies and bispecific antibodies being the most promising. Nevertheless, the survival curve of patients with relapsed/refractory disease is not flattened, since the vast majority of multiple myeloma patients will eventually become refractory to all available agents.
“For this patient group, the choice is either palliative care or the administration of novel agents with distinct mechanisms of action. In this context, selinexor has been developed to address this unmet therapeutic need and had shown promising activity in preclinical and early-phase clinical studies.”
What were the key findings in your study?
“We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory).
“A partial response or better was observed in 26 percent of patients (95% CI, 19-35), including two stringent complete responses; 39 percent of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months.
“Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73 percent of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in six patients.”
Were there any unexpected findings or surprising outcomes in your research?
“A unique toxicity profile for selinexor-dexamethasone emerged and consisted of nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia.
“The prevention and management of these adverse events can be challenging in the clinical practice. In this context, we have recently also provided a review of 437 patients with multiple myeloma treated with selinexor-based regimens in clinical trials and assessed the kinetics of adverse events and impact of supportive care measures (Leukemia 2020; doi: 10.1038/s41375-020-0756-6).
“Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannabinoids. Loperamide and bismuth subsalicylate ameliorated diarrhea.
“The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids, or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement.”
Is there anything about the results of your research that others might get wrong?
“Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to appropriate supportive care. Continuous patient surveillance is of outmost importance, along with monitoring of other comorbidities, especially for the elderly.”
What are the clinical implications, if any, of your research?
“The combination of selinexor with dexamethasone reinforces the therapeutic armamentarium against multiple myeloma.
“The FDA has already provided its regulatory approval for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
“Selinexor-dexamethasone is jump this particularly important for patients with no other therapeutic choices, including those previously treated with novel cellular treatments.”
What further research needs to be done on this topic?
“The addition of selinexor to other backbone treatments has also shown promising results, whereas the SVd regimen has shown significant clinical activity in a randomized phase III study.
“Patient selection is necessary for determining the optimal selinexor-based combination according to disease status, previous exposure to anti-myeloma agents, and patient characteristics including age and comorbidities.
“Well-designed studies are needed to address the effect of selinexor in subgroups of patients of special interest such as those with ultra-high risk cytogenetics or extramedullary disease or involvement of the central nervous system or plasma cell leukemia.
“Ongoing and future studies will determine the exact position of selinexor-based treatments in the therapeutic continuum of patients with multiple myeloma.”
Is there anything else about your research that you would like to share?
“There has been an unprecedented progress in multiple myeloma therapeutics with the introduction of several novel agents both in the upfront and the relapsed/refractory setting during the last decade.
“The availability of different agents poses two main challenges; the optimal sequence of treatment and the management of heavily pretreated patients. The introduction of novel agents from the bench to the bedside significantly contributes to the improvement of patient outcomes.”
Editor's note: Ioannis Ntanasis-Stathopoulos, MD, MSc, PhD, a sub-investigator of the STORM clinical trial in the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Greece, helped facilitate the interview with Dr. Gavriatopoulou and contributed to this article.
Chuck Holt is a contributing writer.
2020 Excellence in Oncology