selinexor and Hematologic-Diseases

Cellular homeostasis requires the proper nuclear-cytoplasmic partitioning of large molecules, which is often deregulated in cancer. XPO1 is an export receptor responsible for the nuclear-cytoplasmic transport of hundreds of proteins and multiple RNA species. XPO1 is frequently overexpressed and/or mutated in human cancers and functions as an oncogenic driver. Suppression of XPO1-mediated nuclear export, therefore, presents a unique therapeutic strategy. In this review, we summarize the physiological functions of XPO1 as well as the development of various XPO1 inhibitors and provide an update on the recent clinical trials of the SINE compounds. We also discuss potential future research directions on the molecular function of XPO1 and the clinical application of XPO1 inhibitors.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Exportin 1 Protein; Forecasting; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydrazines; Karyopherins; Molecular Targeted Therapy; Neoplasm Proteins; Receptors, Cytoplasmic and Nuclear; RNA, Neoplasm; Triazoles

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Idarubicin; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Progression-Free Survival; Recurrence; Salvage Therapy; Triazoles

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase III as Topic; Dexamethasone; Drug Administration Schedule; Female; Frailty; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydrazines; Kaplan-Meier Estimate; Male; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Peripheral Nervous System Diseases; Progression-Free Survival; Randomized Controlled Trials as Topic; Retrospective Studies; Severity of Illness Index; Triazoles