Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure
Bibliographic record
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 cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM) with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of 3.6 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability. We present the results of a phase I dose escalation study of selinexor in combination with pom and dex (SPd) in RRMM. Methods - The primary objective of this phase 1b/2 study (NCT02343042) is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of SPd. Patients (pts) with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60; 80 mg) or twice-weekly (BIW, 60; 80 mg), with pomalidomide (pom) 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW. Results - As of 15-Jul-2017, 29 pts (14 male / 15 female) have been enrolled. The median age is 61 years, with a median of 4 (range, 2 - 9) prior treatment regimens. Twenty-five patients were IMiD refractory (15 len, 2 pom, 8 pom/len). Three dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (60 mg BIW, pom 3 mg) and 4 missed doses in Cycle 1 (100 mg QW, pom 4 mg). Common treatment related Grade 1/2 adverse events (AEs) include: nausea (55%), fatigue (48%), anorexia (48%) and diarrhea (24%). Grade 3/4 AEs include: neutropenia (48%), thrombocytopenia (31%), and anemia (28%). Doses of 60 mg QW and 80 mg QW are being evaluted to determine RP2D. Twenty-four pts were evaluable for response. Responses rates can be seen in Table 1. Median PFS is 11.6 months with a median follow up of 7.7 months. Eight pts are still on study, (range 1 - 16+ months). Conclusions - Once weekly selinexor can be safely combined with Pd. This all oral combination of selinexor, pom and dex (SPd) has significant clinical activity with an ORR 54% in pts with heavily pretreated MM compared to previously published data of 30% ORR. No additional toxicities over monotherapy with selinexor or the Pd combination were observed. The novel all oral combination of SPd is a well-tolerated regimen and supports further clinical development in RRMM. Disclosures Chen: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sebag: Celgene, Janssen: Consultancy. Bensinger: Bayer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding. Gasparetto: Celgene: Research Funding; Janssen, BMS, Celgene: Consultancy; Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed. Lentzsch: Caelum Biosciences: Other: leadership position and stock; Amgen: Consultancy; BMS: Consultancy. Schiller: Celator/Jazz: Research Funding. Kauffman: Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Shacham: Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Jeha: Karyopharm Therapeutics: Employment. Saint-Martin: Karyopharm Therapeutics: Employment. Shah: Karyopharm Therapeutics: Employment. Bahlis: Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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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".