Anti Tumor Activity Of Selinexor (KPT-330), A First-In-Class Oral Selective Inhibitor Of Nuclear Export (SINE) XPO1/CRM1 Antagonist In Patients (pts) With Relapsed / Refractory Multiple Myeloma (MM) Or Waldenstrom’s Macroglobulinemia (WM)
Bibliographic record
Abstract
Background Exportin 1 (XPO1/CRM1) is overexpressed in MM and was identified as an essential protein for MM cell growth. The majority of Tumor Suppressor Proteins (TSP) are transported out of the nucleus exclusively by XPO1, leading to their inactivation. Selinexor (KPT-330) is a potent, selective oral inhibitor of XPO1 and shows potent anti myeloma activity in preclinical models. Methods Patients (pts) with advanced, relapsed/refractory MM or WM were dosed with oral Selinexor (8-10 doses / 4-week cycle) as part of a broad Phase 1 program (NCT 01607892) in advanced hematological malignancies. Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and tumor biopsies on selected patients were performed. Response evaluation was performed every cycle. All pts in this study had documented progressive disease on study entry and were relapsed/refractory to at least one proteasome inhibitor and one immunomodulating agent. Results 17 MM and 2 WM pts with median age 67yrs (range 50-75); ECOG PS 0/1: 6/13; median number of prior regimens: 5 [range 1-13], received Selinexor across 6 dose levels (3 to 30 mg/m2). Five patients experienced drug-related grade 3/4 Adverse Events (AEs), including thrombocytopenia without bleeding (n=4), neutropenia (n=4), impaired renal function (n=1), decreased WBC (n=1) and febrile neutropenia (n=1). The most common grade 1/2 toxicities are gastrointestinal (GI) including nausea (16/19; 84%), anorexia (11/19pts; 58%), vomiting (8/19; 42%), diarrhea (7/19pts; 37%), weight loss (4/19; 21%) and dysgeusia (4/19; 21%). Grade 1/2 study drug related fatigue was also observed in 10/19 or 53% of the patients. No grade ≥3 GI related AEs were observed. These side effects were well managed with supportive care. No clinically significant cumulative drug toxicities have been noted and patients have remained on therapy for >8 months (median duration on therapy 50 days, range 8-274 days). Two pts died during the study, one due to E.coli sepsis and the other due to renal dysfunction, both events deemed by treating investigators to be unrelated to study drug. PK analysis demonstrated total exposure increased with increasing dose, with no accumulation and without affecting half-life (5-7 hrs) or clearance of KPT-330. At 23 mg/m2, exposure (Cmax 289 ng/mL and AUC0-inf 2219 ng*h/mL) was comparable to anti tumor exposure observed in mice and dogs. Significant increases (2-20x) in leukocyte XPO1 mRNA levels (PDn marker) were observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA. Response was evaluable in 15 MM pts: Partial response (PR) in 1 pt (6.7%) at 35mg/m2, Minimal Response (MR) in 6 pts (40%) at doses of 16.8 to 30mg/m2, Stable Disease (SD) in 5 pts (33%) and Progressive Disease (PD) in 3 pts (20%). One MR and 1 SD were observed in the 2 WM pts. Evaluation of serial bone marrow samples from one patient confirms Selinexor-induced nuclear localization of multiple TSPs as well as reduction in CD138+ MM cells. Dose escalation is ongoing at 35 mg/m2 twice weekly. Conclusions Oral Selinexor treatment is generally well tolerated, with favorable PK and PDn properties. Prolonged disease control and responses are observed in heavily pretreated patients with progressive MM whose disease is relapsed or refractory to available agents. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Experimental use of Selinexor, a drug not yet approved. Baz: Celgene, Millennium, BMS, Novartis, Karyopharm, Sanofi: Research Funding. Reece: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; BMS: Research Funding; Otsuka: Honoraria, Research Funding; Onyx: Consultancy. Siegel: Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau. Kuruvilla: Seattle Genetics : Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Research Funding. Shacham: Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Rashal: Karyopharm Therapeutics Inc.: Employment, Equity Ownership. McCauley: Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin: Karyopharm Therapeutics Inc.: Employment, Equity Ownership. McCartney: Karyopharm Therapeutics Inc.: Employment, Equity Ownership. Landesman: Karyopharm Therapeutics: Employment, Equity Ownership, Patents & Royalties. Klebanov: Karyopharm Therapeutics: Employment, Equity Ownership. Pond: Osmozis : Consultancy. Kauffman: Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Mirza: Karyopharm Therapeutics Inc.: Consultancy, Equity Ownership.
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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".