Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

Abstract

Summary Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non‐clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose‐escalation trial of twice‐weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib‐refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP2D of twice‐weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment‐emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual‐class refractory (PI and immunomodulatory drug)/quad‐exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression‐free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re‐established disease control in RRMM patients, including carfilzomib‐refractory patients. Registered at ClinicalTrials.gov (NCT02199665)

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

“…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 , ; Bahlis et al , ; Vogl et al , ; Jakubowiak et al , ). Most patients required a dose interruption or reduction in selinexor during the course of treatment.…”

“…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 , ; Argueta et al , ). 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 , ; Jakubowiak et al , ).…”

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…467 In regard to relapsed MM, recommended therapies usually involve PIs and immunomodulatory drugs (IMiDs; e.g., lenalidomide, pomalidomide) in doublet or triplet combinations with corticosteroids or other systemic therapies including the anti-CD38 monoclonal antibody daratumumab and the immunoglobulin G1 (IgG1) monoclonal antibody isatuximab for the CD38 receptor. [468][469][470] For patients with MCL and diffuse large B-cell lymphoma, combination treatment of PIs and chemotherapies or histone deacetylase inhibitors also yields benefits, 471,472 which may also overcome the impact of gain-of-function p53 mutations in solid tumors. 473 In the clinic, with regard to bortezomibresistant tumors, the combination treatments of bortezomib with chemotherapy drugs such as doxorubicin, plerixafor and daratumumab have shown improved clinical outcomes, suggesting that conventional chemotherapy could increase the sensitivity of bortezomib to malignancies.…”

Targeting nuclear import and export in hematological malignancies

“…A different study evaluates selinexor–carfilzomib and dexamethasone, with ORR of 48% in heavily pretreated patients. Interestingly, a very good partial response of 15% is reported for patients who are refractory to carfilzomib in the last line of treatment [ 69 ]. Selinexor is also being studied in combination with melphalan before stem cell transplant (NCT02780609).…”