Multiple myeloma (MM) is a bone marrow-based malignant plasma-cell disorder that is characterized by production of monoclonal immunoglobulin (M protein), osteolytic bone lesions, hypercalcemia, anemia and associated organ dysfunction (Palumbo and Anderson, 2011). Over the past 2 decades, survival of patients with multiple myeloma has significantly improved as a result of the introduction of autologous stem cell transplantation (ASCT) and several novel classes of drugs, including proteasome inhibitors (PIs) (bortezomib, carfilzomib and ixazomib), immunomodulatory agents (IMiDs) (thalidomide, lenalidomide and pomalidomide), monoclonal antibodies targeting CD38 (daratumumab, isatuximab) and SLAMF7 (elotuzumab), and HDAC inhibitors (panobinostat) (Miguel et al., 2013; Dimopoulos et al., 2015; Lonial et al., 2015; Dimopoulos et al., 2016; San-Miguel et al., 2016; Chim et al., 2018; Goldschmidt et al., 2019; Kumar et al., 2019). However, none of these agents are curative, despite these additions to the MM armamentarium, most patients will relapse and develop refractory disease to all available therapies (Kumar et al., 2019; Kumar et al., 2012; Gandhi et al., 2019). Therefore, it remains a high priority to develop novel, more efficacious and less toxic treatment strategies for patients with relapsed/refractory MM.

Exportin 1 (XPO1), the only known nuclear export protein for most tumor suppressor proteins, cell-cycle regulators, the glucocorticoid receptor, and several eIF4A-bound oncoprotein mRNAs for key oncoproteins, including c-MYC, BCL-2 and Cyclin D (Gaubatz et al., 2001; Culjkovic-Kraljacic et al., 2012; Gravina et al., 2014). XPO1 is overexpressed in multiple myeloma and correlates with increased bone disease and shorter survival (Tiedemann et al., 2012; Tai et al., 2014), a genome-wide RNA interference screen identified XPO1 as an essential gene required for myeloma cell survival and proliferation (Schmidt et al., 2013). Furthermore, elevated levels of XPO1 is associated with the development of resistance to proteasome inhibitors (including bortezomib) (Chanukuppa et al., 2019) and immunomodulatory agents (Bhutani et al., 2017).

Selinexor (SEL) is an orally bioavailable, highly-selective, and slowly-reversible small molecule that binds to the Cys528 residue in the cargo-binding pocket of XPO1 (Gravina et al., 2014). Treatment of cancer cells with selinexor induced nuclear retention of tumor suppressor proteins (TSPs) and blocked the export of eIF4E-bound oncoprotein mRNAs, leading apoptosis, reduced levels of proto-oncoproteins and impaired osteoclastogenesis (Gravina et al., 2014; Tan et al., 2014). Preclinical studies have shown that selective inhibitor of nuclear export compounds showed noticeable anti-myeloma activity largely independent of genotype, as well as synergistic activity with glucocorticoids, proteasome inhibitors, and immunomodulatory drugs (Tai et al., 2014; Turner et al., 2014; Turner et al., 2016a). The combination of selinexor (80 mg, twice per week) and dexamethasone (DEX) has been approved in the United States for patients with penta-refractory multiple myeloma in July 2019 based on the STORM clinical trial. There are several prospective clinical trials having been conducted to investigate the safety and efficacy of selinexor-based treatment in patients with MM. However, a quantitative and comprehensive meta-analysis focus on the safety and efficacy of selinexor-based treatment is still scarce. In this study, we analyzed the comprehensive safety and efficacy of selinexor-based treatments in patients with relapsed or/and refractory MM, and overcome the limitations of individual studies, such as small sample size and lack of statistical power. Besides, we also used subgroup analysis to compare the efficacy and safety of different combination therapies (SEL + DEX + PIs vs SEL + DEX). These findings lead to the evaluation of XPO1 inhibitors for the treatment of MM.

Multiple myeloma (MM) is a bone marrow-based malignant plasma-cell disorder without curative treatment, most patients will face the risk of relapse and develop refractory disease (Kumar et al., 2012; Gandhi et al., 2019; Kumar et al., 2019). It’s very meaningful to find more efficacious and less toxic treatment strategies for patients with relapsed/refractory multiple myeloma. Selinexor is an orally bioavailable, highly-selective, and slowly-reversible small molecule that binds to the Cys528 residue in the cargo-binding pocket of XPO1(12). We performed this meta-analysis to investigate the efficacy and safety of selinexor based treatments for multiple myeloma patients.

We included six studies, four studies were combined selinexor with dexamethasone and proteasome inhibitors regimens and two studies were combined selinexor with dexamethasone regimens. This review included a total of 276 MM patients treated with SEL + DEX + PIs treatment and 201 patients with SEL + DEX treatment. A random effects model was used when significant heterogeneity was observed in the analysis of efficacy and safety. Galbraith plots provides a visual impression of the amount of heterogeneity and indicates potential sources of heterogeneity. The results showed that one study (Grosicki et al., 2020) contributed mostly to publication bias in the pooled efficacy, and the reason for this phenomenon may be that this study provided the maximum number of enrolled patients. We also performed prespecified exploratory subgroup analyses by different treatments.

Our meta-analysis revealed that selinexor-based regimens could offer reasonable efficacy in patients with multiple myeloma. It worth noting that Selinexor exhibited a higher efficacy against MM resistant to previous therapies. The prior lines of therapy patients received ranged from 1 to 18, including iMiDs (lenalidomide, pomalidomide, thalidomide), PIs (bortezomib, Carfilzomib, Ixazomib), anti-CD38 monoclonal antibody (Daratumumab), Panobinostat, Alkylating Agent, antigen receptor-modified T cell therapy (CART), and ASCT. Patients with RRMM are heterogeneous, despite new treatment regimens improving outcomes, the prognosis remains particularly poor for heavily pretreated and/or multiple treatment-refractory patients (Usmani et al., 2016). Excessive nuclear export is an important factor in both the initiation and progression of cancer and is associated with resistance to chemotherapy (El-Tanani et al., 2016). Data from many preclinical studies confirm that selinexor effectively overcome different drug resistance, including bortezomib (Muz et al., 2017; Chanukuppa et al., 2019), anthracycline (Turner et al., 2013; Turner et al., 2016b), and so on. The results of subanalysis showed that SEL + DEX + PIs treatment could improve ORR, CBR, sCR, and VGPR compared to SEL + DEX treatment, while SEL + DEX treatment was associated with higher PDR (rate of progressive disease) and SDR (rate of stable disease) compared to SEL + DEX + PIs treatment. However, there was no difference in PR and MR between SEL + DEX + PIs treatment and SEL + DEX treatment. The combination of SEL and DEX has been approved by the FDA for patients with penta-refractory multiple myeloma. Due to the novel mechanism of action compared with other agents for MM, combining selinexor with other therapies is regarded as a promising therapeutic strategy. Our analysis revealed that the efficacy of SEL + DEX treatments could be enhanced by combinating with PIs. Furthermore, the pooled ORR (43%) in our analysis of SEL-based treatments was higher than that (39.1%) reported in a meta-analysis of bortezomib-based retreatment in relapsed/refractory myeloma (Knopf et al., 2014), revealing that the efficacy of SEL-based treatments was higher than bortezomib-based retreatment. Although the subgroup analysis of CR was not performed, in the RCT we included (Grosicki et al., 2020), the CR (7%) in the SEL + DEX + BTZ group was higher than the CR (4%) in the BTZ + DEX group. Considering that, selinexor-based regimen would be a good option for patients with R/R MM.

Although the recent approval of therapies, including next-generation PIs and immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs) and other new drug with novel mechanisms of action, has provided novel treatment options, MM remains an incurable disease, most patients will relapse and develop refractory disease to all available therapies (Kumar et al., 2012; Lonial et al., 2015; Kumar et al., 2019). Agents capable of harnessing the power of cellular immunity have long been sought, however, ASCT has remained the only proven therapy capable of long-term disease eradication through a graft-vs-myeloma effect (Nathwani et al., 2016). However, ASCT have a high treatment and transplant-related mortality rate (Giralt et al., 2015). It’s encouraging that the OS of patients with MM after ASCT has improved over time along with the introduction of new drugs for the treatment of MM (Shimazu et al., 2021). The development of other innovative immunotherapy approaches including monoclonal antibodies, chimeric antigen receptor T-cell therapy, checkpoint blockade, and novel vaccine therapies has led to a new era of immunotherapy in multiple myeloma (Nathwani et al., 2016). In addition to the combination with existing standard-of-care therapies like bortezomib, to explore the option of organically combining cellular immunotherapy with selinexor and transplantation for providing better treatment to multiple myeloma patients. Given the heterogeneity of RRMM, it’s critical to selected treatment plan more properly. Using the predictors of survival in patients such as early platelet engraftment and the administration of a CD34 ⁺ HPC count would be a rational choice (Aladağ Karakulak et al., 2020).

In our analysis, the most common AEs in all grade were thrombocytopenia, anemia, fatigue, nausea and decreased appetite. Besides, the most common AEs in grade≥3 were thrombocytopenia, anemia, neutropenia, and fatigue. Notably, hematological toxicities were the most frequent severe AEs. The pooled incidence of thrombocytopenia in all grade was 68%, 95%CI (60%,76%), and 54%, 95%CI (44%,65%) in grade≥3. The subanalysis showed no difference in the incidence of thrombocytopenia between SEL + DEX treatment and SEL + DEX + PIs treatment. Thrombocytopenia occurred in more than half of the patients, which was partly caused by selinexor because of its inhibition of thrombopoietin signaling in the differentiation of stem cells into megakaryocytes (Machlus et al., 2017). As thrombocytopenia was reversible and could be managed with dose interruptions, transfusion of blood products and thrombopoietin-receptor agonists, these patients rarely experienced severe thrombocytopenia (Machlus et al., 2017). Clinicians need to pay attention to the patients’ platelet status and adjust the medication regimen flexibly according to the patient’s platelet reduction. Bortezomib combined with dexamethasone was approved as a standard treatment in the United States for relapsed or refractory multiple myeloma. Peripheral neuropathy is the main dose-limiting toxicity caused by the standard treatment (Delforge et al., 2010; Cavaletti and Jakubowiak, 2010), In our included six studies, only two studies mentioned the incidence of peripheral neuropathy (Bahlis et al., 2018; Grosicki et al., 2020), other studies didn’t mention it because the incidence is too low. Both of the two studies used the selinexor + bortezomib + dexamethasone. However, the only one RCT study suggested that the triplet combination (SEL + DEX + PIs) was well tolerated with much lower rates of peripheral neuropathy compared to bortezomib + dexamethasone treatment in all grade (32 vs 47%) and grade≥3 (5 vs 9%) (Grosicki et al., 2020). Therefore, it seemed that the combination with selinexor was associated with lower rates and severity of bortezomib-induced peripheral neuropathy. The selinexor-based treatments have an improved side effect profile, while the SEL + DEX + PIs treatment has reduced levels of peripheral neuropathy. All patients involved in the meta-analysis received prophylactic use of antiemetics to mitigate gastrointestinal events. However, the all-oral Sid (selinexor, ixazomib, and low-dose dexamethasone) combination therapy for heavily pretreated patients (the patients had a median of five prior lines of therapy, ranged from 1 to 11 lines) with R/R MM resulted in frequent treatment delays and dose reductions owing to thrombocytopenia and gastrointestinal related toxicities, which lead to progression of disease (Salcedo et al., 2020). It suggested that heavily pretreated patients with R/R MM required careful consideration of using the combination therapy.

The subgroup analysis results suggested that SEL + DEX + PIs treatment was more effective and tolerated than SEL + DEX treatment for patients with MM. Preclinical data suggested that combining selinexor with proteasome inhibitors and dexamethasone had a mechanistic rationale (Turner et al., 2016a; Kashyap et al., 2016), as XPO1 is overexpressed in multiple myeloma and correlates with increased bone disease and shorter survival (Tai et al., 2014; Tiedemann et al., 2012), a genome-wide RNA interference screen identified XPO1 as an essential gene required for myeloma cell survival and proliferation (Schmidt et al., 2013). Furthermore, elevated levels of XPO1 is associated with the development of resistance to proteasome inhibitors (including bortezomib) (Chanukuppa et al., 2019) and immunomodulatory agents (Bhutani et al., 2017). Therefore, selinexor could inhibit the XPO1 and improve the resistance to PIs in R/R MM. Considering the relapsed/refractory status of the patient population enrolled in the meta-analysis, the efficacy of patients treated with selinexor-based treatments was satisfactory with tolerable AEs.

There are several inevitable limitations in our analysis. Firstly, most of the involved studies were single-armed studies without double-blinded randomized controlled trials. In addition, the dose of the drugs was different between individual trials, and some AEs were dose dependent. Finally, although the patients were all in advanced stages, the degree of multiple myeloma was dispersive, which might have aroused bias to the final analysis. No survival benefit was confirmed in our study due to the small sample size, the varied length of follow-up time and loss of data in some studies.

In conclusion, our meta-analysis further demonstrated that selinexor-based regimen was a novel and potent treatment option for patients with R/R multiple myeloma. The combination of selinexor with proteasome inhibitors and dexamethasone contributed to improve the efficacy and reduce the incidence of AEs than SEL + DEX treatment. Further studies are needed to explore the feasibility and efficacy of treatment for heavily pretreated patients with R/R MM. Combining XPO1 inhibitors with other effective antimyeloma agents and cellular immunotherapy was expected to be complementary to existing therapies for multiple myeloma, as well as for other neoplasms. Additionally, it is also important to focus on improving patients’ compliance, whether investigating new XPO1 inhibitors or new forms of combination.