Selinexor‐based regimens for the treatment of myeloma refractory to chimeric antigen receptor T cell therapy

Abstract

Recent reports indicate that chimeric antigen receptor T cell (CAR-T) therapy can induce deep and durable responses for many patients with heavily-pretreated multiple myeloma (MM), with median progression-free or event-free survival ranging between 7 and 12 months (Zhao et al., 2018; Cho et al., 2018; Raje et al., 2019; Xu et al., 2019). Relapse post CAR-T, however, is common, and treatment options for these patients are limited. Currently, there is minimal published data and no consensus on subsequent therapies after progression on CAR-T. Most strategies, including CAR-T retreatment, have proven largely ineffective, establishing a major unmet medical need for this patient population. Selinexor is an oral, small-molecule inhibitor of the nuclear export protein exportin 1 (XPO1) that induces accumulation of tumour suppressor proteins in the nucleus, reductions in oncoproteins, cell cycle arrest and apoptosis of cancer cells (Abdul Razak et al., 2016; Chen et al., 2017; Vogl et al., 2018). XPO1 is overexpressed in many cancers, including MM, and elevated levels are correlated with poor prognosis, increased bone lytic lesions and resistance to therapy (Tai et al., 2014). In patients with penta-exposed, triple-class refractory MM, selinexor plus low-dose dexamethasone (Sd) produced an overall response rate of 26·2% and clinical benefit rate (≥ minimal response) of 39·3%, which translated into a survival benefit for responding patients (Chari et al., 2019). The activity of selinexor was preserved regardless of prior therapy, as expected from a drug with a novel mechanism of action; however, the efficacy after CAR-T therapy has not been specifically described. Here, we report on observations of the activity of Sd alone or administered as a triplet in combination with bortezomib (SVd) or carfilzomib (SKd) in patients with MM whose disease has progressed after CAR-T therapy. We identified seven patients across selinexor trials who received lymphodepleting conditioning with fludarabine and/or cyclophosphamide followed by an effective dose of CAR-T cell therapy [>108 CAR-positive cells targeting B-cell maturation antigen (BCMA)] for their MM prior to being enrolled in a trial using a selinexor-containing regimen. One patient was treated on the STORM study (NCT02336815) with selinexor (80 mg twice-weekly, days 1 and 3) plus dexamethasone (20 mg twice-weekly, days 1 and 3); one patient was treated with selinexor (100 mg once-weekly) plus bortezomib (1·3 mg/m2 once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly) in the compassionate use program; and five patients were treated with selinexor (100 mg once-weekly) plus carfilzomib (20/56 or 20/70 mg/m2) and dexamethasone (40 mg once-weekly or 20 mg twice-weekly) in the NCT02199665 trial. Response was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Baseline characteristics for the seven patients are summarized in Table 1. All patients were heavily pretreated (median 10 prior therapeutic regimens; range: 5–15) and had high-risk cytogenetics; six patients had rapidly progressing disease as evidenced by the percent increase in paraprotein from screening to cycle 1, day 1 (C1D1) (range: 17–91%). Four patients had MM that was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide and daratumumab in a prior regimen (penta-refractory), and all patients had progressed after autologous stem cell transplantation, alkylating agents, as well as CAR-T therapy. The median time to progression on CAR-T therapy was 4 months (1–7 months). All patients received a selinexor combination immediately after progression on CAR-T (with the exception of one patient who received two additional lines of therapy prior to receiving Sd). As of the date of data cutoff, the median time on a selinexor-based regimen was 6·0 months (range: 3·7–8·3 months); four patients’ disease had progressed, one patient had withdrawn consent, and two patients were still responding and on therapy. Response assessments for each patient are outlined in Fig. 1A,B, and included one stringent complete response, three very good partial responses, two partial responses and one minimal response. Responses (≥ partial response) occurred within the first cycle of treatment for four patients; a noteworthy observation, given the rapidly progressing paraprotein levels at baseline. Interestingly, despite meeting IMWG criteria for having disease progression (>25% increase from nadir) after 6·5 months, Patient 1 continued treatment with Sd for an additional 1·5 months and derived clinical benefit before ending study with paraprotein levels nearly 50% below C1D1. The anti-myeloma activity seen in patients with disease that was refractory to bortezomib, carfilzomib and/or dexamethasone in a prior line of therapy validates reported data showing that selinexor overcomes resistance to proteasome inhibitors (PIs). Preclinical studies have demonstrated that selinexor synergizes with PIs and glucocorticoids through enhanced suppression of the NF-κB signaling pathway and potentiation of glucocorticoid receptor transcriptional activity in the presence of dexamethasone, respectively (Kashyap et al., 2016; Argueta et al., 2018). These results are supported with clinical findings from the STOMP (NCT02343042) and NCT02199665 trials, which have demonstrated efficacy of Sd in combination with bortezomib or carfilzomib in patients with MM refractory to PIs (Bahlis et al., 2018; Jakubowiak et al., 2019). Consistent with other studies testing Sd, SVd or SKd in heavily pretreated patients with MM, the most common adverse events among the patients described here were nausea, fatigue, thrombocytopenia, neutropenia and anaemia (Chen et al., 2017; Bahlis et al., 2018; Vogl et al., 2018; Jakubowiak et al., 2019). Most patients required a dose interruption or reduction in selinexor during the course of treatment. The seven patients presented here were managed for nausea with prophylactic 5-HT3 antagonists, and additional supportive care agents including rolapitant, omeprazole, lorazepam or olanzapine. In addition, thrombocytopenia was managed and reversible with dose reductions or interruptions combined with weekly doses of romiplostim, a thrombopoietin agonist (typically starting at 1 ug/kg and increasing, if needed, to 10 ug/kg), to stimulate platelet production. This is the first data set demonstrating anti-myeloma activity of selinexor-based regimens in patients who have progressed after CAR-T therapy. The activity was observed regardless of prior treatment history, with no cross resistance. Though the findings reported here are based on a small group of patients, the responses are intriguing and warrant further investigation. Currently, the available therapeutic options for patients described here include intensive multi-agent chemotherapy, recycling various combinations or entry onto an investigational trial. As CAR-T therapy moves into earlier lines of MM treatment and more patients develop resitance to this approach, selinexor-based regimens may offer important therapeutic benefit, underpinned by a novel mechanism of action which is key in the setting of relapsed and refractory disease, and should be considered (Richardson & Blade, 2014). The authors would like to thank the patients who participated in these trials and their families, as well as the coinvestigators, nurses and study coordinators at each of the sites. In particular, Bernadette Libao at the University of Chicago, and Nicole Devito, Alexandra Dardac and Amishi Dhadwal at the Icahn School of Medicine at Mount Sinai are thanked for their support in data collection. A.C.: honoraria from Amgen, Antengene, Celgene, Janssen, Karyopharm, Millennium/Takeda, Novartis Pharmaceuticals, Oncopeptides, Sanofi; research funding from Amgen, Celgene, Janssen, Millennium/Takeda, Novartis Pharmaceuticals, Pharmacyclics. D.T.V.: consulting or advisory role at Celgene, Amgen, Karyopharm Therapeutics, Teva, Janssen Pharmaceuticals; research funding from Millennium (Inst), Acetylon Pharmaceuticals (Inst), GlaxoSmithKline (Inst), Calithera Biosciences (Inst), Constellation Pharmaceuticals (Inst). S. J.: Advisory board fees and consulting fees from Celgene, Bristol-Myers Squibb, Janssen Pharmaceuticals and Merck. J. J.: no relevant conflicts of interest. T.J.U and A.D.: employee and stockholder of Karyopharm Therapeutics. J.S. and M. K.: executive and stockholder of Karyopharm Therapeutics. S.S.: president, executive and stockholder of Karyopharm Therapeutics. A.J.: honoraria, consulting, and advisory role at Amgen, Karyopharm Therapeutics, Abbvie, Celgene, Janssen Pharmaceuticals, Takeda, Sanofi, SkylineDx. A.C., D.T.V., S.J., J.J. and A.J.: enrolled patients, analysed and interpreted data, wrote and reviewed the manuscript. T.J.U. and A.D.: collected, analysed and interpreted the data; wrote and reviewed the manuscript. J.S., M.K. and S.S.: contributed to the design of the study, analysed and interpreted the data, wrote and reviewed the manuscript.

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