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.

The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology

“…Specifically, high-risk MM is characterized by the presence of gain of chromosome 1q, deletion of chromosome 17p (del(17p)), t(4;14), t(14;16), t(14;20) or p53 mutations [ 9 , 12 ]. Despite therapeutic advances including the introduction of ImmunoModulatory Drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies and most recently selinexor, a Selective Inhibitor of Nuclear Export (SINE) that binds and inactivates exportin-1 (XPO1) [ 13 ], the B Cell Maturation Antigen (BCMA) targeting antibody-drug-conjugate (ADC) belantamab-mafodotin [ 14 ], and BCMA-directed CAR-T cells [ 9 ], the management of MM remains challenging, mainly due to the development of drug resistance. Therefore, the identification of novel therapeutic targets and the development of derived anti-MM treatment strategies are urgently needed.…”

Immunotherapy with Antibodies in Multiple Myeloma: Monoclonals, Bispecifics, and Immunoconjugates

“…These triple-class refractory patients benefit from newly approved drugs with novel mechanism of action such as selinexor, which inhibits XPO-1-mediated nuclear export [55], or the immunoconjugate belantamab mafodotin (see next section) [56]. One study with 34 patients (median of three prior lines of therapy) showed that selinexor can also be effectively combined with daratumumab and dexamethasone [57]. Common adverse events with this IMiD-and PI-free regimen included thrombocytopenia, nausea, and fatigue.…”

Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor

“…Selinexor, in combination with daratumumab and dexamethasone, has been evaluated, within the STOMP trial (NCT02343042), in 34 RRMM patients who had received three or more prior lines of therapy, including a PI and an IMiD, or whose MM was refractory to a PI and an IMiD ( 75 ). The median number of prior therapies was 3 (range: 2–10).…”

“…Selinexor (once weekly: 100 mg; twice weekly: 60 mg) in 28-day cycles; Daratumumab (16 mg/kg weekly for weeks 1-8, every 2 weeks for weeks 9-24, then every 4 weeks for weeks ≥25); Dexamethasone (40 mg once weekly) RP2D: Selinexor (100 mg once weekly), Daratumumab (16 mg/kg weekly for weeks 1-8, every 2 weeks for weeks 9-24, then every 4 weeks for weeks ≥25), Dexamethasone (40 mg once weekly) whose MM was refractory to a PI and an IMiD (75). The median number of prior therapies was 3 (range: 2-10).…”