Peripheral neuropathy symptoms, pain, and functioning in previously treated multiple myeloma patients treated with selinexor, bortezomib, and dexamethasone

With over 34 000 new cases and ~12 400 deaths from multiple myeloma (MM) anticipated in 2021 the United States1 about twice as many Europe, there is an unmet medical need for therapies patients with previously treated MM that have progressed on available agents. Currently, are few agents mechanisms of action approved early-line treatment. Selinexor (XPOVIO, Karyopharm Therapeutics Inc.) a potent, oral, first-in-class, selective inhibitor nuclear export specifically blocks exportin 1 (XPO1).2 The impact patient's health-related quality life (HRQoL) well established,3 deterioration physical function, increased fatigue, pain, dyspnea, anxiety depression cited most common symptoms. Peripheral neuropathy (PN), which can be associated itself4 and/or certain treatments, includes sensory, motor and, to lesser extent, autonomic neuropathy. Sensory symptoms frequent characterized varying terms sensation (e.g., numbness, tingling, burning) type shooting, chronic, electric-shock), lead problems ambulation even require use wheelchair.4 Without proper management, PN subsequent limitations due become permanent, constraining future treatments.5 BOSTON trial (NCT03110562) was Phase 3 comparing novel triplet regimen once weekly oral selinexor bortezomib low dose dexamethasone (XVd) versus standard plus moderate (Vd) adult who received one three prior anti-MM regimens. This first bortezomib-based therapy (i.e., XVd) showed lower rates overall Grade ? 2 compared doublet Vd while conferring longer progression free survival (PFS), required 37% fewer clinic visits than Vd.2 Recently, assessment patient-reported outcomes (PROs) has important component clinical trials they provide information disease treatment perspective.6 To this end, analyses PROs were included evaluate patterns therapy-induced symptoms, function.2 Patient-reported assessed using European Organization Research Treatment Cancer (EORTC) Quality Life Questionnaire Chemotherapy-induced Neuropathy (QLQ-CIPN20) validated instrument (secondary HRQoL endpoint). In addition, EORTC Cancer-30 item (QLQ-C30) between randomized XVd arm vs (exploratory At Baseline Day each cycle, both QLQ-CIPN20 QLQ-C30 questionnaires (Figure S1). For study, focused functioning, role pain subscales pre-specified domains interest QLQ-C30. Mixed effects models repeated measures (MMRM) fit longitudinal data estimate differences time. Assessment ordinal model. All cycles 35 days long arm; had eight 21-day before switching 35-day cycles.2 only visit two arms at 106 (XVd cycle 4, Cycle 6). Adjusted MMRM model treatment, time (categorical: 22, 36, 43, 64, 71, 85, 106, etc), baseline PRO score, PI therapy, number regimens, revised international staging system (R-ISS) stage MM, exposure. Meaningful change thresholds (MCTs) derived anchor-based distribution-based methods or estimated literature used identify experienced meaningful worsening functioning (Supplementary Material Time definitive (TDD) defined measured by scales, declined identified clinically MCT (time randomization occurrence not followed improvement) S2 S3). TDD conducted symptom Global Health/Quality (QoL) scale. Cox proportional hazard adjusted questionnaire stratification factors (prior R-ISS MM) A total 402 enrolled trial; 388 completed (191 197 arm). Age, sex, race balanced (Table When examining mean scores time, domain (worsened) arm, remained unchanged several cycles. Specifically, 5.34 points less (95% confidence interval [CI]: ?8.39, ?2.29, p value = 0.006). Additionally, Pain worsened but improved ? 6.58 difference observed favor CI: ?11.36, ?1.80; 0.007). pronounced Motor scores, smaller non-significant (?1.81, 95% ?4.72, 1.10, 0.223). Autonomic similar increase arms, later increasing more (Day 106: 4.99, 0.73, 9.25, 0.022). Ultimately, trends persisted throughout study across all 1; Figures sensory greater (86 patients, 45.7%) 51 (27.7%) S4). median approximately 8 months (20.7 [95% 15.4, estimable] 12.5 7.8, 18.8]), corresponding ratio (HR) 0.53 0.38, 0.75; < 0.001). also (83 43.9%) (65 35.3%). 16.2 15.1 (HR: 0.72, 0.52, 1.00, 0.052). Roughly half (54.6% 48.4%, Vd, respectively) no significant (HR 1.14, 0.373). While statistically significant, deteriorations function extended deterioration. PFS underlying hypothesis first-in-class provides equivalent (or better) when arm. QLQ-CIPN20, reported higher scores. classifying according whether their meaningfully baseline, rapid rate trend XVd. may related superior control. One limitation misaligned timepoints impacted ability direct time-on-treatment assessments. Each analysis considered timing, however, was, times, limited conduct some complexity modeling. As improving, minimize cumulative side such becomes improve QoL. reduction PN-related setting PFS, next patient-preferred administration supports potentially patient experience decreased health care burden long-term morbidity. Jamie Mertoian Emily Calderbank, writers supported funding Therapeutics, Inc., provided drafts editorial assistance authors during preparation manuscript. Additional support Dr. Maria Victoria Mateos, Gavriatopoulo, Halyna Pylypenko, Vadim Doronin, Tuphan Kanti Dolai, Nuriet Khuazheva, Philippe Moreau, Ashraf Z. Badros, Polina Kaplan. funded Inc. Xavier Leleu reports honoraria AbbVie, Amgen, Bristol-Myers Squibb, Carsgen Ltd, Celgene, Gilead Sciences, Janssen-Cilag, Merck, Mundipharma, Novartis, Oncopeptides, Pierre Fabre, Roche, Sanofi, Takeda non-financial Takeda. Jennifer L Beaumont, Hailin Yu, Stacie Hudgens employees Clinical Outcomes Solutions analytic planning execution activities research. Holger W. Auner advisory Karyopharm; grant Amgen; speaker's bureau Janssen. Hang Quach grants board Karyopharm, GlaxoSmithKline; research drug supply Sanofi; Janssen Cilag Specialized Therapeutics. Sosana Delimpasi Janssen, Takeda, Celgene. Ivan Špi?ka personal fees Sanofi Aventis, Novartis; Colgene, BMS, Amgen. Iryna Kriachok consulting role, MSD; travel MSD, Roman Hájek consultant relationship PharmaMar, Takeda; Christopher Venner BMS/Celgene, GSK, Mamta Krishnan Garg attending conferences Jansen, Celgene; Sundar Jagannath services Pharmaceuticals, Merck involvement Principal Investigator Intas Dr Reddy's Laboratories. Moshe Levy receiving lecture Seattle Genetics, Jazz Spectrum Larry D. Anderson Jr. activity following: Oncopeptides. Nizar Jacques Bahlis Abbvie, GSK Karyopharm. Thierry Facon Oncopeptides; Celgene/BMS, Yi Chai, Xiwen Ma, Shijie Tang, Hoyee Leong, Michael Kauffman stockholders Jatin Shah being employed owning stock Celbene/BMS, Sharon Shacham holding patents (8 999 996, 9 079 865, 714 226, PCT/US12/048319, I574957) hydrazide-containing transport modulators uses, pending (PCT/US12/048319, 499/2012, PI20102724, 012 928) uses. Paul Richardson other declare conflict interest. original data, please contact [email protected] Appendix S1. Supporting Information Please note: publisher responsible content functionality any supporting supplied authors. Any queries (other missing content) should directed author article.