Optimal Supportive Care With Selinexor Improves Outcomes in Patients With Relapsed/Refractory Multiple Myeloma

Abstract

Multiple myeloma treatments, including selinexor, exacerbate symptoms of the disease and induce additional adverse effects. Supportive care is therefore essential. Using post hoc analysis we tested the effect of earlier aggressive supportive care on selinexor's efficacy. Star ting suppor tive care administration from the first days of treatment and using multiple agents to mitigate specific adverse effects, increases selinexor tolerability and efficacy. Background: Supportive care improves outcomes in many cancers. In the pivotal STORM study selinexor, a first-inclass, oral, selective exportin 1 inhibitor, and low-dose dexamethasone proved to be an effective treatment for patients with triple-class refractory myeloma. We conducted a post-hoc analysis to test the hypothesis that increased utilization of supportive care measures in a sub-cohort of the STORM study prolonged treatment duration with-and improved efficacy of-selinexor. Materials and Methods: The STORM protocol included specific recommendations for dose modifications and supportive care to mitigate selinexor most common adverse events (AEs) including nausea, fatigue, and thrombocytopenia. The Tisch Cancer Center at Mount Sinai School of Medicine (MSSM) incorporated additional supportive care strategies within the framework of the STORM protocol. Results: Of 123 patients enrolled in STORM, 28 were enrolled at MSSM. The overall response rate was 26.2% in the overall STORM population and 53.6% in the MSSM cohort. Moreover, duration of response, progression free survival, and overall survival were longer in the MSSM cohort. AEs and dose modification events were similar in the 2 groups. The MSSM cohort had more dose reductions (67.9% vs. 50.5%), and higher use of multiple antiemetic agents (71.4% vs. 50.1%) and romiplostim (32.1% vs. 6.3%), but less discontinuations due to treatment-related AEs (3.6% vs. 25.3%). Conclusion: These results suggests that in addition to more frequent dose reductions, prompter and more aggressive supportive care may have contributed to the low discontinuation rate, longer duration therapy, and greater efficacy rates observed in the MSSM cohort. (ClinicalTrials.gov NCT02336815).

Chemotherapy-induced nausea and vomiting: can we do better?

“…In the first group, prophylaxis based on a triple combination should be proposed, although there is a lack of data on the mode of administration. This is the case, for example, with a treatment such as Selinexor, which is used to treat multiple myeloma, considered to be at equivalent risk of emesis to carboplatin [16]. In other situations, oral anticancer treatment is administered on a daily basis, which again raises the question of regular administration of steroids, NK1-RA or 5HT3-RA depending on their tolerability, safety and potential drug-drug interactions.…”

Selinexor: Targeting a novel pathway in multiple myeloma

“…Lower rates of common gastrointestinal adverse events (AEs), haematological AEs, fatigue and other common AEs such as infections and hyponatremia are seen with once-weekly dosing, and initial toxicity management guidelines for twice-weekly selinexor-dexamethasone [96,98,99] have been more recently revised to reflect the safety profile of the less intensive weekly regimen (Table 6) [97]; in this context, it should also be recognised that early-phase studies such as STORM were conducted in a more heavily pre-treated population than BOSTON, which may also have contributed to the differing safety profiles. Nevertheless, as detailed in the management guidelines [96][97][98][99] and in the US and EU labels for selinexor [49,50], common toxicitiesnotably gastrointestinal toxicities-remain important considerations for treatment associated with both regimens, and these are generally manageable through optimal supportive care (Table 6) and, where required, dose reductions. Indeed, in an analysis of the BOSTON trial, not only did dose reductions result in substantially lower rates of key AEs but also they enabled patients to remain on selinexor-Vd treatment for a prolonged period of time (compared to those who did not have dose reductions), and this translated into improved therapeutic outcomes with the regimen [100].…”

“…Some studies have suggested that nausea and vomiting with selinexor‐based therapy is possibly an effect mediated by the central nervous system (CNS) and resulting from selinexor crossing the blood–brain barrier [98]. Another common grade 3/4 toxicity with selinexor‐based regimens is hyponatremia, which was reported in 22% of patients in part 2 of STORM; as with the other common AEs, this is manageable with supportive care (Table 6) [96, 97, 99]. Importantly, given its approval in combination with Vd, selinexor does not appear to be associated with an increased risk of peripheral sensory neuropathy, a key dose‐limiting toxicity of bortezomib; indeed, in the BOSTON trial, the rate of any‐grade peripheral neuropathy was lower with selinexor‐Vd versus Vd (32% vs. 47%) [61], presumably due to the use of once‐weekly versus twice‐weekly bortezomib during the first 24 weeks of treatment.…”

“…The safety profile and rates of toxicities are distinct between selinexor regimens that utilise twice‐weekly dosing, such as with selinexor‐dexamethasone in the STORM study [53, 54], and those employing a once‐weekly dosing schedule, such as used with selinexor‐Vd in BOSTON [61]. Lower rates of common gastrointestinal adverse events (AEs), haematological AEs, fatigue and other common AEs such as infections and hyponatremia are seen with once‐weekly dosing, and initial toxicity management guidelines for twice‐weekly selinexor‐dexamethasone [96, 98, 99] have been more recently revised to reflect the safety profile of the less intensive weekly regimen (Table 6) [97]; in this context, it should also be recognised that early‐phase studies such as STORM were conducted in a more heavily pre‐treated population than BOSTON, which may also have contributed to the differing safety profiles. Nevertheless, as detailed in the management guidelines [96–99] and in the US and EU labels for selinexor [49, 50], common toxicities—notably gastrointestinal toxicities—remain important considerations for treatment associated with both regimens, and these are generally manageable through optimal supportive care (Table 6) and, where required, dose reductions.…”

“…Expert recommendations (for once-weekly selinexor) [97] Patient • Selinexor-Vd: patients who have received ≥1 prior therapy • Selinexor-dex: patients who have received ≥4 prior therapies; disease refractory to ≥2 PIs, ≥2 immunomodulatory drugs, an anti-CD38 mAb • Weekly selinexor-based regimen with a PI or an immunomodulatory drug in patients progressing on an anti-CD38 mAb [97] • US: selinexor-Vd, selinexor-dara-dex, selinexor-Kd following 1-3 prior therapies; selinexor-pom-dex following 2 prior therapies including a PI and immunomodulatory drug (and refractory to last prior therapy) [9] Baseline evaluations / actions 6) [96,97,99]. Importantly, given its approval in combination with Vd, selinexor does not appear to be associated with an increased risk of peripheral sensory neuropathy, a key dose-limiting toxicity of bortezomib; indeed, in the BOSTON trial, the rate of any-grade peripheral neuropathy was lower with selinexor-Vd versus Vd (32% vs. 47%) [61], presumably due to the use showing a greater increase in the 'sensory' scale of the instrument [103]; in contrast, the 'autonomic' scale of the QLQ-CIPN20 showed a larger increase with selinexor-Vd.…”