Efficacy and tolerability of once‐weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice‐weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study

Patients with hematological malignancies, particularly multiple myeloma (MM), typically have a high prevalence of renal impairment (RI). When combined with the nephrotoxic risk of anticancer drugs, especially with an older patient population like that frequently observed in MM, optimizing treatment regimens that are both safe and efficacious is difficult.1 Taken together, there is a need to identify effective therapeutic options that can be used in patients with RI and do not pose or induce additional renal toxicity in patients with MM. Selinexor is an oral selective inhibitor of nuclear export (SINE) compound, which specifically blocks exportin 1 (XPO1). By inhibiting XPO1, SINE compounds force the nuclear retention of tumor suppressor proteins (TSPs), leading to their functional activation, which is followed by induction of apoptosis in myeloma and other cancer cells, while largely sparing normal cells.2 Selinexor has good oral bioavailability, and is metabolized primarily by multiple hepatic routes without significant renal metabolism.3 In addition, it does not directly affect creatinine clearance (CrCl), though it can be associated with asymptomatic hyponatremia, which may be due to increased sodium loss from the kidney.2 Selinexor is approved by the United States Food and Drug Administration for patients with MM after at least one prior therapy based on the BOSTON study,4 with no contraindications based on renal dysfunction. The combination of selinexor, bortezomib, and dexamethasone (XVd) conferred a significant improvement in progression-free survival (PFS), overall response rate (ORR), and time to next therapy (TTNT), and showed a trend toward improved overall survival (OS),5 while rates of peripheral neuropathy (PN) were lower in the XVd than the Vd arm.4 Here, we present data on the efficacy and safety of selinexor in MM patients with and without RI (additional details in Supplemental Methods). The BOSTON study enrolled a total of 402 patients, of which 195 were randomized to XVd and 207 were assigned to Vd. Among these, 56 patients in the XVd arm and 70 in the Vd arm had RI (CrCl < 40 or 40–60 mL/min), while 139 and 137 had normal renal function, respectively. Baseline patient characteristics are shown in Table S1. The median PFS of patients with CrCl 40–60 mL/min was significantly improved with XVd compared to Vd (16.62 vs 7.26 months) (p = .028) (Figure S1A, Table 1). A similar significant improvement was observed in patients with normal kidney function: 13.24 months with XVd and 9.66 months with Vd (p = .019). In patients with CrCl < 40 mL/min, the median PFS was 7.62 months with XVd and 4.30 months with Vd (p = .129). Patients with RI treated with XVd had a significantly higher ORR than patients who received Vd (< 40 mL/min, 81.0% vs. 53.8%, respectively, p = .027; and 40–60 mL/min 80.0% vs. 59.1%, respectively, p = .024). Rates of very good partial response (VGPR) or better were higher with XVd in patients with 40–60 mL/min (48.6% XVd vs. 27.3% Vd, p = .026). In patients with normal renal function, the ORR was also significantly higher with XVd (p = .037) (Table 1). OS in patients with RI trended in favor of XVd (median not reached in both < 40 mL/min and 40–60 mL/min) versus Vd (median, < 40 mL/min 19.06 months and 40–60 mL/min 21.22 months) (< 40 mL/min HR, 0.74 [95% CI, 0.29–1.88], p = .263; 40–60 mL/min HR, 0.55 [95% CI, 0.23–1.29], p = .080) (Figure S1B, Table 1). The median TTNT was significantly improved in patients with CrCl 40–60 mL/min with XVd compared to Vd (p = .040). Patients with normal renal function also showed significantly improved TNNT with XVd compared to Vd (p = .007) (Table 1). Treatment-emergent adverse events (TEAEs) were similar between patients with CrCl > 60 mL/min with XVd (99.3%) and Vd (97.1%), and patients with RI (< 40 mL/min 100.0% XVd, 96.0% Vd; 40–60 mL/min 100.0% XVd, 97.6% Vd). Despite the higher rate of thrombocytopenia on the XVd arm, there was no difference in the rate of clinically significant (Grade ≥ 3) bleeding on the XVd arm, even in patients with RI, with a single case of clinically significant bleeding in each arm. Serious AEs (SAEs) were similar between treatment arms and subgroups (< 40 mL/min XVd 66.7% vs. Vd 40.0%; 40–60 mL/min XVd 42.9% vs. Vd 47.6%; > 60 mL/min XVd 51.8% vs. Vd 34.3%). The percentage of patients with dose reductions was numerically higher with XVd than Vd, regardless of CrCl levels. Treatment discontinuation due to AEs was similar in both arms for patients with CrCl 40–60 and >60 mL/min. Although a smaller number, those in the <40 mL/min group trended toward a lower rate of discontinuation with XVd (Table S2). Overall, grade 2 or greater AEs related to PN in patients with RI (< 40) was lower in the XVd arm compared to the Vd arm (< 40: XVd 4.8% vs. Vd 36.0%) and similar in the 40–60 subgroup (40–60: XVd 34.3% vs. Vd 35.7%). A trend of lower grade 2 or greater PN AEs were observed in patients with CrCl > 60 mL/min (XVd 20.1% vs. Vd 33.6%) (Table S2). The BOSTON study in patients with previously treated MM evaluated the standard twice-weekly Vd regimen versus the once-weekly XVd regimen, which utilizes 40% less bortezomib and 25% less dexamethasone in the first 24 weeks, compared with Vd. The study showed that XVd was superior to Vd on the primary endpoint of PFS, and several secondary endpoints, with adequate tolerability.4 Here we have assessed the impact of baseline calculated CrCl as an indicator of RI on efficacy and tolerability between the two regimens. Patients with RI in the BOSTON study that were treated with XVd had a 44% improvement in median PFS compared to the Vd arm. KM-curves of PFS (Figure S1) demonstrated that despite the median age being 73 years and 53.6% having high-risk cytogenetics, this patient population had early and sustained separation of XVd from Vd treatment arms, similar to the entire intention-to-treat (ITT) population. Among patients with RI, and specifically those with CrCl 40–60 mL/min, however, there appeared to be more pronounced improvements in ORR, deep (≥ VGPR) responses, and a trend toward improved OS for XVd versus Vd, as compared with patients with normal renal function. Thus, there was a significant increase in ORR in patients with RI treated with XVd, as compared to those treated with Vd, with significantly more ≥VGPR with XVd. In patients who had normal renal function (defined as CrCl > 60 mL/min), similar, but often less marked, differences were observed. Overall, these results demonstrate that the simple, once-weekly XVd regimen clearly benefited patients with baseline RI, with no dose adjustments required for renal function levels. The increased risk of toxic side effects and fatalities in patients with RI can require a dose reduction, or administration of a less effective treatment, which reduces efficacy and can cause a failure in therapy, andultimately reduce survival time.6 Many aggressive therapeutics, such as those in second or third or more lines of therapy, require a minimum kidney function threshold, which leaves a population of patients who cannot benefit from a more aggressive treatment.6 Lenalidomide, which is renally excreted, demonstrated a median PFS of 7.8 months and a 50% ORR in phase 3 studies in patients who had severe RI (CrCl of < 30 mL/min).7 Although about 2% of pomalidomide is excreted in the kidneys,8 treatment with pomalidomide plus dexamethasone demonstrated an ORR under 40% (39.4% in moderate RI, 32.4% in severe RI, and 14.3% in severe RI that requires hemodialysis) in heavily pre-treated patients.9 While we cannot make a direct comparison, the ORR of 80.4% overall observed in patients with RI treated with XVd, and the PFS of 16.62 months in patients with CrCl 40–60 mL/min, demonstrates a robust and durable potential option for MM patients with RI. The incidence of AEs was comparable between groups within treatment arms, notably grade 3 PN in the XVd arm versus the Vd arm (normal: 3.6% vs 5.8%; RI: 5.4% vs 14.9%), which is improved over other MM treatments. For example, our results are significantly improved compared to results of the OPTMIUM phase 3 study with thalidomide as a monotherapy, which demonstrated an incidence of grade 2 or more PN that increased with dosage 12%–22%.10 Taken together, these results present a case for the ability to more safely treat a larger population of patients, even those with RI and aggressive disease that have limited options, with better safety and efficacy, placing less importance on renal function and more importance on patient needs. Renal insufficiency is common in patients with MM and limits the opportunity to be treated with optimally effective therapeutics. Our data demonstrates that the once-weekly XVd regimen conferred improved clinical outcomes and good tolerability in patients with MM who have RI, as compared with standard twice-weekly Vd. The XVd regimen induced deep and durable responses in patients with RI, despite the fact that these patients were older and had more high-risk cytogenetics than those with normal renal function. In conclusion, the use of selinexor may provide improved, durable outcomes, and reduced incidence of PN in patients with previously treated MM and RI. This study was supported by research funding from Karyopharm Therapeutics, Inc. JetPub Scientific Communications LLC, supported by Karyopharm Therapeutics, Inc., assisted in the preparation of this manuscript, in accordance with Good Publication Practice (GPP3) guidelines. SD has received honoraria from Janssen, Takeda, Amgen, and Celgene. MVM 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. 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. HWA reports an advisory role for Takeda and Karyopharm; grant from Amgen; and a speaker's bureau role for Janssen. MG reports (Maria Gavriatopoulou) receiving honoraria from Amgen, Karyopharm Therapeutics, Takeda, Genesis Pharma, and Janssen-Cilag. 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. 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. PM reports honoraria from Celgene/BMS, Amgen, Janssen, Sanofi, 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. 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 2 012 000 928) 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. Karyopharm Therapeutics agrees to share individual participant data that underlie the results reported in this article (after deidentification), including the study protocol and statistical analysis plan. Data availability will begin 9 months after publication and will be available 36 months after publication. To gain access, data requestors should submit a proposal to [email protected] Proposals will be reviewed by an independent review committee identified for this purpose. Appendix S1 Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.