Selinexor Shows Synergy in Combination with Pomalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma
Bibliographic record
Abstract
Abstract Introduction - The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; NF-kB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In murine MM models, the combination of selinexor with IMIDs shows synergistic anti-MM activity with good tolerability. Methods - This phase 1b/2 dose escalation study (NCT02343042) using the standard 3+3 design, is designed to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and preliminary efficacy of selinexor in combination with pomalidomide and dexamethasone (SdP). Patients (pts) with relapsed/refractory MM who received ≥ 2 prior therapies including lenalidomide and a proteasome inhibitor (PI) were enrolled. Selinexor is dose escalated once-weekly (QW, starting at 80 mg) or twice-weekly (BIW, starting at 60 mg), pomalidomide 4 mg PO daily, days 1 -21 and dexamethasone (dex) 40 mg PO weekly in a 28 day cycle. Results - As of 25-Jul-2016, 11 pts (7 male / 4 female) have been enrolled. The median age is 58 years (range, 43 - 76), with a median of 5 (range, 2 - 9) prior treatment regimens. Eight pts had MM refractory to lenalidomide and 7 pts to bortezomib; including 5 pts with MM refractory to both. For the once-weekly selinexor cohort, the 80 mg dose level has been cleared and the 100 mg dose level is on going. For the twice-weekly cohort, the 60 mg dose level has been cleared and 80 mg dose level is on going. Common related grade 1/2 adverse events (AEs) include: nausea 7pts (64%), altered taste 5pts (45%), anorexia 3pts (27%), and diarrhea 3pts (27%). Grade 3/4 AEs include: neutropenia 8pts (73%), thrombocytopenia 4pts (36%), and leukopenia 3pts (27%). There was no febrile neutropenia or bleeding reported to date. No dose limiting toxicities have been observed and MTD has not been reached. Ten pts were evaluable for response including, 1 complete response (CR), 5 partial responses (PR), 3 minor responses (MR), and 1 stable disease (SD). The overall response rate (ORR) is 60% with a clinical benefit rate of 90% (ORR + MR). Responses are rapid in onset, with at least MR achieved by cycle 2 day 1. In lenalidomide and bortezomib refractory patients the ORR was 50%. One pt was deemed not evaluable due to non-compliance with study procedures. Eight pts are still on study, (range <1 - 7+ months) including 4 pts maintaining their response for > 3 months. Conclusions - The all oral combination of selinexor, pomalidomide and low dose dex (SdP) has significant clinical activity (ORR 60%) in pts with heavily pretreated MM. Responses are rapid in onset even with the lower dose cohorts tested thus far, CR can be achieved. No additive toxicities over monotherapy of either pomalidomide or selinexor have been observed. This novel treatment regimen therefore holds promise in addressing the urgent need to induce meaningful and durable responses in patients with IMiD and PI relapsed/refractory MM. Disclosures Chen: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Research Funding. Sebag:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Kouroukis:Karyopharm: Research Funding; Amgen: Research Funding; Janssen: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Acetylon: Research Funding; Bayer: Research Funding; Takeda: Honoraria, Research Funding. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Bahlis:BMS: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".