ABSTRACT
BACKGROUND: The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. OBJECTIVE: The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. PATIENTS AND METHODS: Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. RESULTS: Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥ 10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). CONCLUSIONS: Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.
ABSTRACT
BACKGROUND: Translocation t(4;14) has traditionally been classified as a high-risk cytogenetic feature in patients with multiple myeloma with shortened progression-free (PFS) and overall survival (OS) despite initial response to treatment. Recent data have shown an improved long-term survival in these patients treated with novel agents, such as bortezomib. PATIENTS AND METHODS: We conducted a retrospective study on our patients with t(4;14) multiple myeloma treated with bortezomib-based induction between July 1, 2006 and June 30, 2014 to assess the real-world outcomes of these patients in a tertiary center. RESULTS: Among the 75 patients analyzed, the median PFS was 33.5 months, and the median OS was 69.6 months after a median follow-up of 41 months. Even in the era of novel agents, patients who received frontline autologous stem cell transplant had a better PFS than those who received chemotherapy alone (median PFS, 24.2 months vs. 41.5 months; P = .01). Hypercalcemia at the time of presentation was found to be a significant predictor of progression (hazard ratio [HR], 10.1; 95% confidence interval [CI], 4.0-26.0) and death (HR, 9.4; 95% CI, 3.2-27.8), and co-harboring of del(17p) by fluorescent in situ hybridization with t(4;14) was associated with a significantly inferior OS (HR, 4.0; 95% CI, 1.4-11.4). CONCLUSION: Even in the era of novel agents, t(4;14) remains a negative prognostic marker. Frontline autologous stem cell transplant remains as an essential tool when treating these high-risk patients, but further prospective randomized studies are needed to determine the most effective strategy for this patient group.
