Response seen in 1 in 4 patients in difficult to treat population

Health-related quality of life is an important clinical outcome for most patients. This article, originally published Oct. 14, 2021, takes a look at the STORM trial, which showed that multiple myeloma patients treated with selinexor did not see a decline in HRQOL. We include it as part of our year-end review. Click here to view the original article and obtain CME/CE credit.

For patients with penta-exposed relapsed/refractory multiple myeloma (RRMM), health-related quality of life (HRQoL) did not decline during treatment with selinexor, an analysis of the secondary endpoint of the STORM (Selinexor Treatment of Refractory Myeloma) trial found.

“A key finding of the analysis is that, generally, the combined proportions of patients who experienced no change in HRQoL or improvements were higher compared to those who experienced declines in the early cycles of treatment with selinexor and dexamethasone according to minimal clinically important differences,” wrote Gabriel Tremblay, MBA, of Purple Squirrel Economics, Montreal, Quebec, and the STORM investigators. “In addition, the difference analysis identified that treatment responders had less HRQoL decline than nonresponders.”

The analysis was published in BMC Cancer.

Selinexor was approved by the FDA in 2019 in combination with dexamethasone for the treatment of patients with RRMM “who 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.”

The results of this HRQoL analysis were also presented at ASCO 2020 by Sundar Jagannath, MD, a professor of medicine at Mount Sinai in New York, and other co-authors, including Tremblay.

The patient-reported outcomes were assessed using the Functional Assessment of Cancer Therapy—Multiple Myeloma (FACT-MM), which combines the general version of FACT ( 27 items) with an MM subscale of 14 items looking at symptomatic burden and disease-specific well-being.

The phase IIb, open-label study included 122 patients, 83 of whom had penta-refractory myeloma, “i.e. refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab,” Tremblay and colleagues wrote. The trial showed the safety and efficacy of selinexor combined with low-dose dexamtheasone, and the trial’s primary endpoint of overall response (partial response or better) was seen in “26% of patients (95% CI, 19-35%). Among all responders, the median duration of response was 4.4 months. In the modified intent-to-treat (mITT) population, the median overall survival was 8.6 months. The most common adverse events were thrombocytopenia, nausea, fatigue, anemia, decreased appetite, and decreased weight, which were managed with supportive care and dose modifications.”

Looking at the secondary endpoint (HRQoL), of the 122 patients in the STORM modified intent-to-treat (mITT) population, 80 (66%) completed the FACT-MM at baseline as well as at one or more follow-up points in the treatment cycle or at the end of treatment. The data were collected at baseline and day 1 of each 4-week treatment cycle, as well as at the end of treatment.

“Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models,” Tremblay and colleagues wrote. “Two approaches for evaluating minimal clinically important differences [MCID]were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to [end of treatment] EOT for treatment responders and non-responders.”

The 80 patients included in the QoL analysis were divided into responders and non-responders. The majority of the patient population was male, had a mean age of 63, and most were White. Looking at ECOG performance status, 31% were classified as ECOG 0, 56% were ECOG 1, 9% were ECOG 2, and 4% were missing an ECOG score. The mean number of prior therapies was 7.9 with a mean duration of myeloma of 7.6 years.

Twenty-one patients with a partial response or better were in the responder group and 59 were in the the non-responder group.

“Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second),” Tremblay and colleagues wrote. “Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores.”

Notably, the researchers pointed out that the number of patients declined in each cycle, “reflecting the highly advanced nature of disease and the proportion of patients who remained well-enough to continue treatment.”

HRQoL and response to treatment is not a novel association, as it has been seen in other randomized clinical trials, Tremblay and colleagues pointed out.

“A significant improvement in HRQoL was observed in patients with partial or complete response with bortezomib in the SUMMIT phase 2 trial, while deterioration in HRQoL was observed among patients who did not respond and had progressive disease based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30),” the researchers wrote. “In the carfilzomib, lenalidomide, and dexamethasone arm of the phase 3 RCT ASPIRE, patients achieving a partial response or better had significantly higher HRQoL over 18 cycles of treatment compared with patients who did not respond to treatment, according to the Global Health Status scale of the EORTC QLQ-C30.”

The finding that HRQoL is not greatly impacted by treatment, particularly in responders, “suggests a favorable benefit-risk profile of selinexor, given its demonstrated efficacy and tolerability among patients with penta-refractory MM, and considering the unmet therapeutic need in this patient population.”

Limitations of the study include the single-arm design of the STORM trial; the small sample size of patients with HRQoL data after baseline; and the fact that treatment responders were not randomized and thus significant differences between responders and non-responders could not be determined.

On Dec. 18, 2020, the FDA approved selinexor in combination with bortezomib and dexamethasone for the treatment of multiple myeloma patients who had at least one prior therapy. This approval was based on results from the BOSTON trial.

“The main efficacy outcome measure was progression free survival (PFS) assessed by an independent review committee using International Myeloma Working Group response criteria. The estimated median PFS was 13.9 months (95% CI: 11.7, Not Estimable) for the SVd arm and 9.5 months (95% CI: 7.6, 10.8) for the Vd arm (estimated hazard ratio 0.70; 95% CI: 0.53, 0.93),” the FDA wrote in its approval.

Candace Hoffmann, Managing Editor, BreakingMED™

Tremblay and two co-authors are employees of Purple Squirrel Economics, and received funding from Karyopharm Therapeutics Inc to conduct the analysis. Four other co-authors are employees of Karyopharm Therapeutics. The rest of the authors were investigators in the STORM trial.

Cat ID: 468

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