Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma

Abstract We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty‐four patients (median prior therapies, 3 [range, 2‐10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose‐limiting toxicities (DLTs) were reported in the selinexor 60 mg twice‐weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment‐related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression‐free survival 12.5 months in daratumumab‐naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI‐ and IMiD‐free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.

Exportin 1 (XPO1) is one of eight nuclear export proteins. It facilitates the transport of tumor suppressor proteins (TSPs), the glucocorticoid receptor and oncoprotein messenger RNAs (mRNAs) from the nucleus to the cytoplasm [12]. XPO1 is frequently overexpressed in MM and is associated with reduced survival and increased bone lesions [13,14]. Selinexor is an oral selective inhibitor of nuclear export (SINE) compound that binds covalently to and inactivates XPO1, leading to the accumulation of TSPs in the nucleus, reducing translation of oncoproteins, enhancing glucocorticoid receptor signaling, and inducing cell cycle arrest, ultimately resulting in death of MM (and other malignant) cells but not in normal cells [15][16][17][18][19]. In the Phase 2b STORM study in patients with triple class (PI, IMID, and daratumumab) refractory MM, selinexor plus dexamethasone showed an overall response rate (ORR) of 26.2%, supporting the approval of selinexor in the United States [20,21]. Selinexor continues to be evaluated in earlier lines of therapy with once-or twice-weekly administration and in combination regimens. Preclinical data have shown that selinexor exhibits synergy with various anti-MM agents [17,22,25]. The combination of once weekly (QW) selinexor with QW bortezomib plus low-dose dexamethasone showed superior progression-free survival (PFS) and ORR, a trend to reduced mortality, and significantly less peripheral neuropathy as compared with standard twice weekly (BIW) bortezomib in the Phase 3 BOSTON trial (NCT03110562) [26].
Daratumumab is a humanized IgG-kappa monoclonal antibody that targets the CD38 glycoprotein on the surface of MM cells and induces specific cell cytotoxicity through antibody-dependent binding [27]. The ORRs for daratumumab (∼29%) and selinexor (∼26%) are similar, and the associated median PFS was 3.7 months in patients with RRMM who previously received both PIs and IMiDs [3,20]. As selinexor was shown to sensitize MM cells from newly diagnosed patients to daratumumab (Turner et al, 2017 unpublished results), we hypothesized that selinexor plus daratumumab with low-dose dexamethasone (SDd regimen) would induce high ORR and prolonged PFS in patients with PIand IMiD-refractory MM.
The objectives of the current study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, and preliminary efficacy of SDd in patients with RRMM previously treated with a PI and an IMiD. ing Group (IMWG) guidelines as lack of response while on therapy or disease progression within 2 months of completing therapy [28]. A full list of inclusion/exclusion criteria have been published previously [29].

Study design and oversight
Briefly, adults (age ≥18 years) with symptomatic, histologically confirmed, measurable MM with evidence of disease progression based on IMWG guidelines [28], an Eastern Cooperative Oncology Group (ECOG) [30] Performance Status of ≤2, and adequate hepatic, renal, and hematopoietic function were eligible for enrollment.
The study protocol was approved by the institutional review board or an independent ethics committee at each participating center and was in accordance with the Declaration of Helsinki, the International Conference on Harmonization-Good Clinical Practice, and local laws.
All patients provided written informed consent prior to enrollment. All authors reviewed the data for accuracy and collaborated in the preparation of the manuscript.

Treatments
In the dose-escalation phase, patients were enrolled in two dosing cohorts using a 3 + 3 design in which patients were enrolled in blocks of three, sequentially. After three patients were enrolled in the once-

Study assessments
Safety was monitored throughout the study, and severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03. All patients who received at least one dose of therapy were considered evaluable for safety. Efficacy was assessed using modified IMWG guidelines [28].

Statistics
The sample size for the dose escalation phase of the study was based on the standard 3 + 3 dose escalation scheme. The expansion phase was designed to test the null hypothesis that the true ORR was ≤0.30 against a one-sided alternative that the true ORR was ≥0.6 (i.e., ≥60%) and required a sample size of 25 patients. The modified intent-to-treat (mITT) population (patients who received ≥1 dose of study drug) was subjected for analysis, where the first 10 patients treated at the RP2D were considered the first stage of the two-stage design. If ≤3 patients responded in Stage 1, the expansion phase would be terminated.
If more than patients responded, an additional 15 patients were to be enrolled to include a total of 25 patients at the RP2D. If the total number of patients responding was ≥45%, the treatment was accepted as promising for further study. This design achieved 80% power at a 1-sided 0.10 significance level. both. An independent committee approved the inclusion of this patient in the study. Two patients, both enrolled into the escalation phase, had disease refractory to daratumumab. Patient demographics and disease characteristics at baseline are shown in Table 2.

Patients and Treatment
As of the cut-off date, six (18%) patients were still receiving treatment, 17 (50%) patients discontinued due to progressive disease, five (15%) discontinued due to AEs (one each of daratumumab IRR, hyponatremia and depression, and two patients due to fatigue), five (15%) patients withdrew consent for unknown reasons, and one (3%) patient discontinued to undergo autologous hematopoietic stem cell transplantation. The patient who underwent stem cell transplantation after SDd had received two prior lines of therapy consisting of bortezomib + lenalidomide + dexamethasone (VRd) and carfilzomib + lenalidomide + dexamethasone (KRd) without any responses to these combinations but achieved a partial response with SDd.

Efficacy
Response was evaluated in 32 patients during the dose-escalation and expansion phases. Two patients were excluded for response evaluation because of early withdrawals due to (a) an IRR to daratumumab that occurred on day 1 of cycle 1, and (b) depression related to dexamethasone that was reported in week 3 of cycle 1. The ORR  The median follow-up duration for this efficacy-evaluable population (n = 32) was 12.5 months.

F I G U R E 3
Depth of response to SDd in patients with relapse or refractory multiple myeloma (efficacy evaluable patients, n = 32). Waterfall plot depicts the best % changes in the primary myeloma marker (serum M-protein, urine M-protein, IgA, or serum free light chain) from baseline. The dotted line at −25%, −50%, and −90% correspond the level of reduction for a minimal response, partial response, and very good partial response, respectively Two patients had MM refractory to daratumumab. One patient, who provided consent to enroll in this study immediately after progressing within the first 4 weeks of daratumumab, pomalidomide, and dexamethasone therapy, had progressed ∼1 month after the first dose of SDd; this was the only case of immediate PD. The other patient, who received daratumumab and dexamethasone 10.9 months before enrolling in this study as the last prior therapy, achieved SD with a maximal M protein reduction of 20.6%, but withdrew consent during cycle 2.
Duration of treatment is presented in Figure 1. Among responding patients, DOR was estimated as 11.4 months (95% CI: 9.7, NE).

DISCUSSION
The present study was designed to determine the RP2D and assess the safety, tolerability, and preliminary efficacy of selinexor plus   [34]. Rates of grade ≥3 neutropenia on SDd were considerably lower than those on daratumumab-IMiD combinations, and febrile neutropenia was not observed. Common nonhematological treatment-related AEs were nausea, fatigue, dys-geusia, diarrhea, and anorexia, which were also similar to those observed with Sd [20]. More than one-third of patients experienced these treatment-related nonhematological AEs, most of which were grade 1 or 2, reversible and also managed or prevented with supportive care and dose modifications. For nausea and anorexia, use of prophylactic 5HT3 receptor antagonists (e.g., ondansetron) was mandated; addition of low-dose olanzapine (or an NK1 antagonist) in cases of breakthrough nausea and/or vomiting were effective in mitigating these AEs. Moreover, low-dose olanzapine (e.g., 2.5-5.0 mg po qhs) is also recommended prophylactically in patients at risk of nausea or anorexia [34]. Olanzapine was also prescribed for anorexia and to prevent weight loss related to selinexor [35][36][37]. Five patients (15%) discontinued treatment because of AEs: one each due to daratumumab IRR, hyponatremia, and depression, and two patients due to fatigue.
In conclusion, the QW combination of oral selinexor 100 mg, dexamethasone 40 mg, and IV daratumumab 16 mg/kg provided deep and durable responses in patients with heavily pretreated RRMM, 74% of whom had MM refractory to PIs and IMIDs. Therefore, further investigation into this combination for patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.

ACKNOWLEDGMENTS
We thank the patients who participated in this trial, their families and caregivers, the investigators and study staff at each of the clinical sites.
Medical writing support was provided by Osnat Ben-Shahar, PhD of Karyopharm Therapeutics, Inc. This study was sponsored Karyopharm Therapeutics Inc.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from Karyopharm Therapeutics. To gain access, data requestors should submit a proposal to medicalinformation@karyopharm.com. The data are not publicly available due to privacy or ethical restrictions. consulting or advisory role-Caelum Bioscience, Sorrento, Janssen, and