Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk

Abstract In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1–3 prior regimens were randomized to once‐weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib‐dexamethasone (XVd) or twice‐weekly bortezomib‐dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression‐free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high‐risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n = 70; Vd, n = 71), and 261 (64.9%) exhibited standard‐risk cytogenetics (XVd, n = 125; Vd, n = 136). Among patients with high‐risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p = 0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p = 0.004). In the standard‐risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p = 0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p = 0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.


| INTRODUCTION
Front-line treatment of multiple myeloma (MM) includes immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and/or proteasome inhibitors (PI), with or without high dose alkylating agents followed by stem cell transplantation. Despite these highly active agents, essentially all patients will relapse and require subsequent therapies. Multiple myeloma cytogenetics have been shown to influence disease outcomes, with high-risk anomalies such as del(17p), t(4;14), t (14;16), and amp1q21 1-3 associated with shorter progression-free survival (PFS) and overall survival (OS) relative to those with standard-risk cytogenetics. 4,5 Given that patients with high-risk cytogenetics have inferior outcomes, there is a need to evaluate whether novel treatment regimens can overcome the negative impact of these cytogenetic alterations in patients with previously treated MM.
Exportin 1 (XPO1), an oncoprotein overexpressed in various hematologic and solid tumor malignancies including MM, 6,7 transports certain proteins and RNAs from the nucleus to the cytoplasm. 8,9 In addition to correlating with more aggressive MM, elevated levels of XPO1 have been shown to correlate with resistance to proteasome inhibitors [8][9][10][11] and to IMiDs. 12 In cancer cells, overexpression of XPO1 leads to the nuclear export of tumor suppressor proteins (TSP) and the glucocorticoid receptor, culminating in their functional inactivation. High XPO1 also facilitates the nuclear export and translation of several oncoprotein mRNAs (e.g., cyclin D1, c-myc) leading to elevated oncoprotein levels. 8,9,13 Selinexor is a potent, oral, selective inhibitor of nuclear export (SINE) compound that binds reversibly and selectively to Cys528 in the cargo-binding pocket of XPO1. 14 XPO1 inhibition forces the nuclear localization and functional inactivation of TSP, trapping IκBα in the nucleus leading to suppression of nuclear factor κB (NF-κB) activity, enhanced glucocorticoid receptor function and reduction in oncoprotein mRNA translation. 10,15 These actions induce the apoptosis of tumor cells, while largely sparing normal cells. 10,16 In preclinical studies, selinexor increased p53 localization in the nucleus and synergized with PIs to induce significant cytotoxicity in PI-resistant MM cells 10 and in a MM xenograft mouse model. 17 The phase 1b/2 STOMP study confirmed these data, with XVd demonstrating on ORR of 84% in patients with bortezomib non-refractory MM and 43% for patients with disease refractory to a PI in a previous line of therapy. 18 This was particularly compelling, as the XVd regimen utilized only once weekly bortezomib rather than the standard twice weekly bortezomib dosing, along with 25% less dexamethasone than standard Vd. Of note, two of the four patients with high-risk cytogenetics at screening responded to treatment with a CR in a patient with t(4;14) for 16.7 months and a VGPR in a patient with del(17p) for 32.9 months. Rates of peripheral neuropathy were low, consistent with the weekly bortezomib.
Selinexor is approved in the United States for the treatment of patients with previously treated MM 19 and diffuse large B-cell lymphoma. 20 The approval for MM was based on efficacy and safety in a prespecified subgroup analysis of 83 patients in Part 2 of the STORM study (NCT02336815), in which twice weekly sel-dex was administered to patients whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. The ORR was 25.3% with one stringent complete response (CR), four very good partial responses, and 16 partial responses. 7 In the phase 3 BOSTON study, treatment with the once weekly selinexor plus once weekly bortezomib and low dose (40 mg) dexamethasone (XVd) was compared with standard twice-weekly bortezomib and moderate dose (80 mg) dexamethasone (Vd) in patients with previously treated MM. 19

| Treatment
Patients in each participating country were randomized (1:1) to either XVd or Vd, with randomization stratified by prior PI treatment (yes vs.

| Outcomes
The primary endpoint was PFS (time from randomization to disease progression or death, whichever occurred first), as assessed by an independent review committee (IRC based on IMWG Criteria 21 ). Sec- In pre-specified analyses, the primary and secondary endpoints were evaluated in the subgroups of patients with high-risk and standard-risk cytogenetic features. Fluorescent in situ hybridization (FISH) was performed centrally on CD138-positive cells isolated from bone marrow aspirates collected at screening. The high-risk group included patients with at least one of the following cytogenetic abnormalities: del(17p), t(4;14), t(14;16), or amplification (≥4 copies) of 1q21 in at least 10% of screened plasma cells. Prognostic values of poor outcomes determined by FISH include cell positivity levels of 10%-20% for t(4;14) and t(14:16), 22,23 50% for del(17p), 24 and 20% for amp1q21. 24,25 The standard-risk group consisted of all other patients with known or unknown baseline cytogenetics.

| Statistics
All efficacy analyses were performed on the intent-to-treat (ITT) population (all randomized patients). The safety population (all patients who received ≥1 dose of study treatment) was used for the safety analyses. PFS, OS, DOR, and TTNT were evaluated using the Kaplan-Meier method. The hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were estimated via T A B L E 1 Baseline characteristics by cytogenetic risk status and treatment

| Efficacy
Median PFS in the high-risk group was longer for patients who  (Figure 1(B)).

| Safety
In the high-risk and standard-risk subgroups, one and two patients,  (Table 3). In both cytogenetic risk subgroups, thrombocytopenia and nausea were the most common AEs and were more frequently reported in XVd-versus Vdtreated patients.
The most common grade ≥3 AE was thrombocytopenia, which was more common in XVd-treated than Vd-treated patients in both the high-risk (54.3% vs. 20.0%) and standard-risk (32.0% vs. 16.4%) subgroups (Table 3). Of note, despite the higher rates of thrombocytopenia with XVd versus Vd, the occurrence of clinically significant (Grade ≥3) bleeding was similar and low (i.e., only one in XVd and two in Vd). In the high-risk subgroup, the rate of grade ≥2 peripheral neuropathy was less common in XVd-treated than in Vd-treated patients (25.7% vs. 35.7%). Similarly, in the standard-risk subgroup, the rate of grade ≥2 peripheral neuropathy was lower with XVd than Vd (18.4% vs. 33.6%). The most common non-hematologic grade ≥3 AE was pneumonia, which occurred at similar frequencies across treatments arms in the high-risk (12.9%-15.7%) and standard-risk (9.7%-8.8%) subgroups.
The proportion of patients who discontinued treatment due to an AE was greater among XVd-treated than Vd-treated patients in the high-risk subgroup (15.7% vs. 8.6%) and in the standard-risk subgroup (24.0% vs. 19.4%). Five and 17 patients in the high-risk (XVd, n = 2; Vd, n = 3) and standard-risk (XVd, n = 10; Vd, n = 7) subgroups, respectively, died due to an AE.

| DISCUSSION
The as high-risk cytogenetic abnormalities. 27 The present analysis of BOS-TON also included amplification of 1q21, which is notable as the presence of ≥3 copies of 1q21 has been demonstrated to be negatively prognostic of response to bortezomib-based treatment and may confer resistance to bortezomib. 28 Here, we focused our analyses on the more conservative definition of ≥4 copies of 1q21 as high risk. 29 Of particular note, overall rates of PN on DVd were 49% and 55% in standard-and high-risk patients, respectively, substantially higher than the rates on the Vd arm in that study. 27 In OPTIMISMM, patients with relapsed or refractory MM who had received 1-3 previous regimens (including two or more cycles of lenalidomide) and had progressive disease were randomly assigned 1:1 to pomalidomide, twice weekly bortezomib, and dexamethasone (PVd) or Vd. 30  The safety profiles of XVd and Vd in the high-risk and standardrisk subgroups were similar to each other and consistent with those observed in the overall study population. 19 As in the primary analysis of BOSTON, 19 the most common grade ≥3 AE reported in the highrisk and standard-risk subgroups was thrombocytopenia. Importantly, rates of PN were lower in all XVd cohorts as compared with the Vd cohorts. While discontinuation rates were higher with XVd due to AEs, a significantly prolonged TTNT was observed suggesting that these patients were responding well and did not require immediate salvage therapy in contrast to patients who discontinued. Furthermore, improved supportive care as a result of physician experience is anticipated to further enhance the activity of XVd, and lead to a reduction in the number of patients discontinuing therapy due to AEs.
Preclinically, the combination of selinexor with a PI shows remarkable synergy. 17 Changes in gene expression that support cell proliferation and tumorigenesis have been observed in MM with any of the four highrisk cytogenetics analyzed in this study. Given the novel mechanism of action against a single target that impacts most TSP pathways, we hypothesize that these high-risk associated changes would still be inhibited by selinexor. For example, del(17p) results in loss of the TSP p53 expression, 34 but the loss of p53 by (using siRNA knockdown) did not reduce sensitivity to selinexor. 35 Translocation of t(4:14) upregulates fibroblast growth factor receptor 3 (FGFR3), 36 which activates mitogenic pathways including AKT, MAP mTOR and NFκBall inhibited by selinexor. 37 The t(4;14) and t(14:16) translocation may lead to the overexpression of the c-MAF protooncogene that upregulates IL-4 and IL-10 cytokine expression, 38 and selinexor may negate such transactivation through the inhibition of the NFKB signaling. 39 Lastly, the amp1q21 may result in the overexpression of CKS1B, upregulating cyclins and CDK activity, overcoming normal cell-cycle checkpoints that are activated by the inhibition of XPO1 with selinexor. 37,40 Taken together, despite the relatively small sample size for each cytogenetic abnormality, our results show significant differences based on high-risk cytogenetic profiles that also align with the potential mechanism of action.
BOSTON enrolled one of the greatest numbers of clinical trial participants with high-risk cytogenetics as compared to the other large bortezomib-based randomized studies. 27,30 However, even though the analyses in this subpopulation were pre-specified, a major limitation of the present analysis is the fact that BOSTON was not powered statistically to compare outcomes between patients with high-risk and standard-risk cytogenetics. While XVd improved outcomes compared to Vd in high-risk patients, the confidence intervals over suggest that standard-risk patients may have had more significant improvements. In addition, no adjustment was made for multiplicity testing, and the cytogenetic risk status was unknown for 10.0% of patients. Despite the plethora of additional therapies available to patients following progression on BOSTON, and allowing crossover from Vd to a selinexor-based regimen on objective progression, a trend towards improved OS for XVd over Vd was also observed, suggesting that treatment with selinexor may have modified the biology of the MM. However, given the limitations noted above, these results should be considered hypothesis-generating.
In conclusion, these data suggest that the oral XPO1 inhibitor selinexor, with its novel mechanism of action, can be used to treat patients with previously treated MM with either high-risk or standard-risk cytogenetics. XVd provided a non-IMiD-based regimen with superior benefits over Vd in a number of clinical outcomes across both the high-risk and standard-risk populations. Given that most patients now receive lenalidomide-based therapy in the frontline setting, a non-IMiD based, simple triplet regimen with reduced long-term toxicity (e.g., peripheral neuropathy) and without the need for intravenous or prolonged subcutaneous infusions makes it a viable option in the treatment of patients with MM after at least one prior regimen, whether they have high risk or standard risk disease.

ACKNOWLEDGMENTS
This study was supported by research funding from Karyopharm Therapeutics, Inc. JetPub Scientific Communications LLC, supported by