Summary
Selinexor, the orally bioavailable first-in-class selective inhibitor of nuclear export (SINE) was initially approved by the FDA in July 2019 in combination with dexamethasone for previously treated patients with relapsed or refractory multiple myeloma. Currently, in the phase III BOSTON trial (NCT03110562), which is a two-arm, randomized, active comparator-controlled, open-label, multicenter study, the use of once weekly selinexor plus bortezomib and dexamethasone (SVd) was compared with twice-weekly bortezomib plus dexamethasone (Vd) in patients with multiple myeloma who had received 1-3 prior therapies.
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Original Article
Initial Results From the Phase III BOSTON Study for Multiple Myeloma
Oncology Times
By Richard Simoneaux
Selinexor, the orally bioavailable first-in-class selective inhibitor of nuclear export (SINE) was initially approved by the FDA in July 2019 in combination with dexamethasone for previously treated patients with relapsed or refractory multiple myeloma. Currently, in the phase III BOSTON trial (NCT03110562), which is a two-arm, randomized, active comparator-controlled, open-label, multicenter study, the use of once weekly selinexor plus bortezomib and dexamethasone (SVd) was compared with twice-weekly bortezomib plus dexamethasone (Vd) in patients with multiple myeloma who had received 1-3 prior therapies.
Two leading clinicians on this study are Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, and Meletios Dimopoulos, MD, Professor and Chairman in the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine. Dimopoulos gave a remote presentation of these initial results as part of the 2020 ASCO Annual Meeting (Abstract 8501).
When asked about the results for this study, Richardson noted, “In these patients, the regimen of once-weekly SVd offered an effective, convenient triplet, requiring approximately 40 percent fewer clinic visits and, additionally, reduced rates of peripheral neuropathy, an important treatment-associated toxicity for bortezomib.”
Selinexor & the STORM Study
The July 2019 approval for selinexor, which was largely based on the results obtained in part 2 of the STORM clinical study (NCT02336815), was for patients who had had at least four previous lines of treatment with disease that displayed resistance to at least two different proteasome inhibitors (e.g., bortezomib, carfilzomib), two different immunomodulatory agents (e.g., lenalidomide, pomalidomide), and a CD38-targeting monoclonal antibody (e.g., daratumumab) (N Engl J Med 2019;381:727-738). This phase IIb, open-label, single-arm study evaluated the use of selinexor plus low-dose dexamethasone (Sd) in patients with both tetra- and penta-refractory multiple myeloma.
Regarding the results for the STORM study, Richardson noted “A partial response or better was observed in 26 percent of patients, including two stringent complete responses, while 39 percent of patients had a minimal response or better. The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months in this otherwise heavily treated population with very poor prognosis.
“One of the most frequently observed toxicities was thrombocytopenia, which is partly due selinexor’s inhibition of thrombopoietin signaling; this was reversible and was typically managed with dose interruptions and thrombopoietin-receptor agonists,” he added.
STOMP Study
In the phase I/II STOMP study (NCT02343042), the use of selinexor in combination with different anti-myeloma therapies was evaluated in patients with relapsed/refractory and newly diagnosed multiple myeloma (Blood 2018;132(24):2546-2554). In preclinical studies, synergistic anti-myeloma activity was noted between selinexor and proteasome inhibitors (Oncotarget 2016;7(48):78883-78895). This activity was via the suppression of nuclear factor kappa-B (NF-κB) signaling and retention of tumor suppressor proteins in the nucleus.
“The primary objectives of the STOMP study were to determine the safety profile, the overall response rate (ORR), and importantly, a recommended phase II dose (RP2D) for the SVd regimen,” Richardson noted.
In this study, patients had a median of 3 prior lines of therapy (range 1-11 therapies); additionally, half had disease refractory to proteasome inhibitor therapy. Grade 3 or 4 treatment-related adverse events that were observed in 10 percent or more patients included thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). The frequency of peripheral neuropathy was low and generally not severe (grade 2 or less).
The maximum-tolerated dose was not reached and the RP2D was selinexor—100 mg once a week, bortezomib—1.3 mg/m2 subcutaneously once a week, and dexamethasone—40 mg orally a week (2 x 20 mg). Treatment of patients with relapsed or refractory disease with the SVd regimen produced high response rates in patients, even in those with bortezomib-refractory disease; importantly, there were no unexpected side effects.
BOSTON Study
The study’s primary endpoint was progression-free survival (PFS), while key secondary endpoints included objective response rate (ORR), patients achieving a very good partial response or greater (≥VGPR), and the prevalence of grade 2 or higher peripheral neuropathy. Other secondary outcomes were overall survival (OS), duration of response (DoR), time to next treatment, and safety measures.
Among the inclusion criteria were the following: adult (18 years of age or older); 1-3 prior anti-myeloma therapies (plus at least a partial response to proteasome inhibitor therapy if that was one of the therapies); an ECOG performance status score of 0-2; and proper renal, hepatic and hematopoietic functioning. Some of the exclusion criteria were prior treatment with a SINE (including selinexor), a prior malignancy that required treatment/had evidence of recurrence, a concurrent medical condition such as a disease and/or an active infection, active plasma cell leukemia, and central nervous system-based multiple myeloma.
For the BOSTON clinical trial, patients in the SVd arm received the following dosing regimen: selinexor—100 mg orally on days 1, 8, 15, 22, and 29 of each 35-day cycle; bortezomib—1.3 mg/m2 subcutaneously on days 1, 8, 15, and 22 of each 35-day cycle; dexamethasone—20 mg orally on days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle.
In contrast, those patients in the Vd arm received the following regimen: bortezomib—1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 of each 21-day cycle for cycles 1-8, and then on days 1, 8, 15, and 22 of each 35-day cycle for cycles 9 and higher; dexamethasone—20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for cycles 1 to 8, and on days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle for cycles 9 and higher.
Study Results
A total of 402 patients were enrolled in this study, with 195 and 207 being randomized to the SVd and Vd arms, respectively. The median PFS values were 13.93 and 9.46 months for those in the SVd and Vd arms accordingly, providing a hazard ratio (HR) of 0.70 (p = 0.0075).
“Importantly, this benefit in PFS was noted for the SVd arm across different subgroups (e.g., prior lenalidomide or proteasome inhibitor therapies, age, frailty, high-risk cytogenetics, etc.),” Richardson observed. “There was an association of significantly higher ORR for the SVd arm overall and across all subgroups.”
In the SVd arm, a significantly higher rate of deep response (i.e., VGPR or greater) was noted (44.6%) compared to the Vd arm (32.4%), affording an odds ratio of 1.66 (95% CI: 1.1-2.5; P=0.0082).
One major treatment-associated toxicity for bortezomib is peripheral neuropathy. Indeed, in this study, peripheral neuropathy was the most common treatment-related adverse event (AE), resulting in treatment discontinuation. This was the case for 4.6 percent and 7.4 percent of the patients in the SVd and Vd arms, respectively. Additionally, rates for peripheral neuropathy were statistically significantly lower in the SVd arm relative to the Vd arm (32.3% vs. 47.1%, p=0.0010).
Conclusion
When asked his observations with regards to the study’s primary endpoint, Richardson noted, “Once-weekly SVd significantly prolongs PFS relative to Vd, with a median PFS improvement of 47 percent. SVd was superior to Vd across all efficacy endpoints, that is, PFS, ORR, ≥VGPR, TTNT, and DoR; these results included those patients having prior lenalidomide exposure or those with disease having unfavorable cytogenetic features such as del[17p]. While the median OS for the Vd arm was 25 months, the median value had not been reached for the SVd arm.”
“The once-weekly dosing used in the SVd arm was associated with significantly lower rates of bortezomib-related peripheral neuropathy compared with twice-weekly Vd,” Richardson said. The most frequently encountered hematological and non-hematological AEs were cytopenia, infections, gastrointestinal issues, decreased weight, fatigue, and cataracts.
“However, the AEs associated with SVd administration were both manageable and reversible and, consequently, the discontinuation rate due to adverse events were relatively low in both study arms, 17 percent and 11 percent in the SVd and Vd arms, respectively,” Richardson explained.
“For patients with multiple myeloma who have received 1-3 prior therapies, including prior lenalidomide or proteasome inhibitor therapy, the once-weekly SVd regimen offers an effective, convenient triplet, which requires roughly 40 percent fewer clinic visits and simultaneously tends to be associated with lower rates of bortezomib-related peripheral neuropathy, as well as otherwise manageable toxicity, and particular activity in high risk disease,” Richardson noted.
In addition to the remarkably promising results in myeloma, selinexor has recently won accelerated approval in diffuse large B-cell lymphoma. Most recently, selinexor has also galvanized interest in the fight against COVID -19, which in turn disproportionately affects myeloma patients, with an estimated mortality of 20-30 percent in hospitalized multiple myeloma patients affected by the disease.
COVID-19 Study
With the lack of available vaccines or approved therapies for COVID-19, a number of therapeutic options are being considered. One such potential option are SINEs such as selinexor, which have been implicated as having the potential to interfere with key host protein interactions in several viruses (e.g., influenza, respiratory syncytial virus, SARS-CoV-2, among others) (Nature 2020; https://doi.org/10.1038/s41586-020-2286-9).
In addition, exportin 1 (XPO1, also known as CRM1) was identified as a host protein having several functional connections with SARS-CoV-based proteins (Cell Discovery. 2020;614). SINEs such as selinexor have displayed potent anti-inflammatory activity which is mediated via inhibition of NF-kB, which then results in decreases in cytokines such as interleukin 6 (IL6), IL1, interferon-gamma (IFNg), and others in preclinical models (Biochem Biophys Res Commun 2018; 503(3):1773-1779). Such activity may be of clinical utility for patients who are hospitalized with COVID-19 or other serious viral infections.
XPORT-CoV-1001 (NCT04349098) is a randomized, multi-center, placebo-controlled phase II study assessing low-dose selinexor for activity and safety. In the study, 20 mg selinexor was dosed orally TIW for 2 weeks. Those patients experiencing clinical benefit and tolerant to therapy may be eligible for treatment continuation for an additional 2 weeks at the discretion of the treating physician.
The study’s primary endpoint is time to clinical improvement, based on improvement in the ordinal scale (which is consistent with the COVID-19 trial recommendations of both the World Health Organization and the FDA). Additional secondary endpoints in the study include overall death rate at day 28, rate of mechanical ventilation, and time to mechanical ventilation.
Richard Simoneaux is a contributing writer.