Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma

Abstract

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://ichgcp.net/clinical-trials-registry/NCT03110562 .

Keywords: Exportin-1; Multiple myeloma; SINE compound; Selinexor.

Conflict of interest statement

M-VM has served as member of advisory boards or received honoraria from Janssen, BMS-Celgene, Takeda, Amgen, Sanofi, Oncopeptides, GSK, Adaptive, Pfizer, Regeneron, Roche and Sea-Gen. MG reports (Maria Gavriatopoulou) receiving honoraria from Amgen, Karyopharm Therapeutics, Takeda, Genesis Pharma, and Janssen-Cilag. TF reports an advisory board role for Karyopharm, Amgen, Roche and Oncopeptides; an advisory board role and a speaker bureau role for Janssen, Celgene/BMS, and Takeda. HWA reports an advisory role for Takeda and Karyopharm; grant from Amgen; and a speaker’s bureau role for Janssen. NB reports grants and personal fees from Celgene; personal fees from Janssen, Amgen, Takeda, Abbvie, GSK and Karyopharm. RH has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. IS reports personal fees from Janssen-Cilag, Takeda, Sanofi Aventis and Novartis; personal fees and non-financial support from Colgene, BMS and Amgen. IK reports a consulting role, an advisory role, and a speaker’s bureau role for Takeda, Janssen, Roche, Abbvie and MSD; Travel support by Takeda, MSD, Roche, Abbvie and Janssen. CPV has received honoraria from BMS/Celgene, Janssen, Sanofi, Amgen, GSK, and Takeda. MG (Mamta Garg) reports support for attending conferences from Takeda; an advisory role for Amgen, Takeda, Jansen, Novartis and Celgene; and a speaker’s bureau role for Janssen. HQ reports grants from and an advisory board role for Amgen, Celgene, Karyopharm, GlaxoSmithKline; non-financial support and research drug supply from Sanofi; an advisory board role for Janssen Cilag and Specialized therapeutics. SJ reports consulting services for AbbVie, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck & Co. PM reports personal fees from Celgene, Amgen, Takeda, Janssen and Abbvie. ML reports receiving consulting fees and lecture fees from Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals, and Janssen. NJB reports grants and personal fees from Celgene; personal fees from Janssen, Amgen, Takeda, Abbvie, GSK and Karyopharm.YC, JJ, MA, JS and MGK are employees of and stockholders of Karyopharm. SS reports being employed by and owning stock in Karyopharm Therapeutics, holding patents (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide-containing nuclear transport modulators and uses, and holding pending patents (PCT/US12/048319, 499/2012, PI20102724, and 2012000928) on hydrazide-containing nuclear transport modulators and uses. PGR reports receiving grant support and honoraria from Oncopeptides, Celgene, and Takeda, grant support from Bristol-Myers Squibb, and honoraria from Amgen, Janssen, and Karyopharm Therapeutics. All other authors declare no competing interests.

Figures

Fig. 1

Depth of response by subgroup and treatment arm. The distribution of response pattern in subgroups based on number of prior lines, lenalidomide (LEN) or proteasome inhibitor (PI) treatment, IMiD refractoriness, and autologous stem cell transplant (ASCT). Bort bortezomib, CR complete response, IMiD immunomodulatory drug, NS not significant, PR partial response, sCR stringent complete response, VGPR very good partial response. Odds ratio and P value shown. *P < 0.05; **P < 0.01, ***P < 0.001