Selinexor Plus Dexamethasone Studied in Triple-Class Refractory Multiple Myeloma

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In a phase IIb study (STORM Part 2) reported in The New England Journal of Medicine, Ajai Chari, MD, of Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, and colleagues found that oral selinexor and dexamethasone were active in some patients with multiple myeloma refractory to prior treatment with an alkylating agent, immunomodulatory agent, and the CD38-directed antibody daratumumab.1

Ajai Chari, MD

Ajai Chari, MD

Selinexor is a nuclear export inhibitor that blocks exportin 1. It induces nuclear accumulation and activation of tumor-suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation.

Study Details

In the study, 123 patients (122 in the modified intent-to-treat primary efficacy analysis) from 60 sites in the United States and Europe were enrolled between May 2015 and March 2018. They were treated with selinexor at 80 mg and dexamethasone at 20 mg twice weekly until disease progression or discontinuation. Eligible patients had measurable myeloma according to International Myeloma Working Group (IMWG) criteria. Patients had to have previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. All patients were required to receive 8 mg of ondansetron, or equivalent, prior to the first dose of the study drug and two or three times daily as needed; other antiemetics could be used if ondansetron was not tolerated or for persistent nausea. Supportive measures were used at investigator discretion and could include intravenous fluids, hematopoietic growth factors, transfusions, and appetite stimulants.

The primary endpoint was overall response, defined as a confirmed partial response or better (≥ 50% reduction in serum level of myeloma protein) on IMWG criteria, as assessed by an independent review committee. Clinical benefit was defined as confirmed minimal response (≥ 25% to < 50% reduction in serum level of myeloma protein) or better.

The median age of study patients was 65 years (15% aged > 75 years); 58% were men; an Eastern Cooperative Oncology Group performance status was 0 for 30%, 1 for 58%, and 2 for 9%; high-risk chromosomal abnormalities were present in 53%, including gain of 1q in 33%, del(17p)/p53 in 26%, t(4;14) in 14%, and t(14;16) in 4%; median time since initial diagnosis was 6.6 years; median number of previous treatment regimens was 7 (range = 3–18); and percentage of patients refractory to treatment regimens were 96% for carfilzomib, pomalidomide, and daratumumab (triple–class refractory disease), and 68% for bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (penta-refractory disease).

Oral Selinexor Plus Dexamethasone

  • Partial response or better was observed in 26% of patients with triple-class refractory multiple myeloma and minimal response or better in 39% of patients treated with oral selinexor and dexamethasone.
  • Median overall survival was 8.6 months among all patients and 15.6 months among those with minimal response or better.

Response Rates and Survival

Confirmed partial response or better was observed in 32 patients (26%), including stringent complete response in 2, very good partial response in 6, and partial response in 24. Confirmed minimal response or better was observed in 48 patients (39%). Stable disease was observed in 48 patients (39%), and 26 (21%) had progressive disease or disease that could not be evaluated for response.

Partial response or better was observed in 18% of patients with high-risk cytogenetic abnormalities, with minimal response or better in 37%. Partial response or better was observed in 21% of patients with penta-refractory disease, with minimal response or better in 37%.

For other subgroups, rates of partial response or better and minimal response or better were 26% and 38% for disease refractory to carfilzomib, pomalidomide, and daratumumab; 35% and 50% among 20 patients with International Staging System stage I disease; 27% and 41% among 78 patients with stage II disease; 17% and 26% among 23 patients with stage III disease; 43% and 54% among 35 patents with free light chains; and 20% and 33% among 87 without free light chains.

Median time to partial response or better was 4.1 weeks (range = 1–14 weeks). Median duration of response was 4.4 months (95% confidence interval [CI] = 3.7–10.8 months), median progression-free survival was 3.7 months (95% CI = 3.0–5.3 months), and median overall survival was 8.6 months (95% CI = 6.2–11.3 months). Median overall survival was 15.6 months (95% CI = 15.6 months to not evaluable) in patients with partial response or better, 15.6 months (95% CI = 12.9 months to not evaluable) in patients with minimal response or better, 5.9 months (95% CI = 4.3–10.4 months) in patients with best response of stable disease, and 1.7 months (1.2 months to not evaluable) among patients with best response of progressive disease/not evaluable.

Biomarker Analysis of Response

Analysis of 35 pretreatment samples, including 16 from responders and 19 from nonresponders, identified a 4-protein classifier (IRF3, ARL2BP, ZBTB17, and ATRX) that was predictive of response to treatment, with a receiver operating characteristic AUC value of 0.862 (95% CI = 0.741–0.982). Additional blinded analysis of samples from 12 patients yielded an AUC value of 0.770 (95% CI = 0.456–1.000); the classifier correctly identified outcome in four of five responders and six of seven nonresponders, for a predictive accuracy of 83%.

Adverse Events

The most common nonhematologic adverse events of any grade were fatigue (73%), nausea (72%), decreased appetite (56%), decreased weight (50%), diarrhea (46%), vomiting (38%), hyponatremia (37%), upper respiratory tract infection (23%), constipation (22%), and dyspnea (22%). The most common grade ≥ 3 nonhematologic adverse events were fatigue (25%), hyponatremia (21%), nausea (10%), and pneumonia (8%). The most common grade ≥ 3 hematologic adverse events were thrombocytopenia (58%), anemia (44%), and neutropenia (21%).

“Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies.”
— Ajai Chari, MD, and colleagues

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Adverse events led to dose modification or interruption in 80% of patients, with the most common events being thrombocytopenia (43%), fatigue (16%), and neutropenia (11%). According to the investigators, intensity or duration of adverse events was generally reduced with supportive care, including granulocyte colony-stimulating factor, thrombopoietin receptor agonists, appropriate fluid and caloric intake, appetite stimulants, psychostimulants, and additional antinausea medications. Treatment was discontinued due to adverse events in 18% of patients, with the most common causes being nausea (6%), fatigue (5%), decreased weight (4%), and asthenia (4%). Serious adverse events occurred in 63% of patients, with the most common being pneumonia (11%) and sepsis (9%). Adverse events led to death in 12 patients, with death considered related to treatment in two deaths (one due to pneumonia with concurrent disease progression and one due to sepsis).

The investigators concluded: “Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies.” 

DISCLOSURE: The study was funded by Karyopharm Therapeutics. Dr. Chari has served as a consultant or advisor to Adaptive Biotechnologies, Amgen, Array Biopharma, Bayer, Bristol-Myers Squibb, Celgene, Janssen Oncology, Karyopharm, Millennium, Novartis, OncoPeptides, Sanofi Genzyme, and Seattle Genetics; has received institutional funding from Acetylon Pharmaceuticals, Biotest, and Bristol-Myers Squibb; has received personal funding from Amgen, Array BioPharma, Celgene, Janssen, Millennium, Novartis, Onyx, Pharmacyclics, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Bristol-Myers Squibb, Celgene, Janssen Oncology, Karyopharm, Novartis, Sanofi Genzyme, and Takeda.


1. Chari A, Vogl DT, Gavriatopoulou M, et al: Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med 381:727-738, 2019.


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