Selinexor, Venetoclax, and Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma (SELVEDge Study)

Background and Significance: Patients with multiple myeloma (MM) harboring translocation t(11;14) have been shown to benefit from the apoptosis-inducing drug venetoclax; however, the drug lacks FDA approval for the treatment of multiple myeloma thus far. Selinexor is an inhibitor of nuclear export that is FDA-approved for patients with multiple myeloma refractory to multiple lines of therapy. We recently reported that in four patients with multiple myeloma with t(11;14), the concomitant administration of venetoclax and selinexor was safe and associated with disease response (Nguyen et al. Nature Precision Oncology 2022). Moreover, the combination was synergistic in t(11;14) multiple myeloma cell lines and caused decreased levels of Cyclin D1 (which is overexpressed due to the CCND1-IGH fusion) when given in combination as compared to single agents ( Figure 1). These data suggested that the combination of venetoclax and selinexor is effective and t(11;14) may serve as a therapeutic marker for response and target for future clinical trials. We have therefore developed an investigator-initiated study of selinexor and venetoclax in patients with relapsed, refractory multiple myeloma harboring translocation t(11;14)- the SELVEDge study. Methods and Study Design:This is an investigator-initiated, Phase 2 clinical study (NCT05530421) that is being conducted at the Sylvester Comprehensive Cancer Center at the University of Miami of adult (≥18 years) patients with relapsed refractory MM (RRMM) harboring t(11;14) in which approximately 24 patients will be treated with selinexor, venetoclax, and dexamethasone (SELVEDge) to determine the primary objective of response rate (ORR). Therapy will be given in 28-day cycles. Patients will receive venetoclax orally for cycle 1 only at a dosage of 400 mg daily for the first 7 days followed by 800 mg daily for the remainder of the cycle with oral dexamethasone given weekly. From cycle 2 and beyond, patients will receive oral selinexor 80 mg weekly; venetoclax daily, and dexamethasone weekly. Using a Simon Optimal 2-stage design, in the first stage, 9 patients will be enrolled and if ≥2 clinical responses occur (≥PR), the study will continue to the second stage to enroll a total of 24 patients. Early termination for excessive toxicity has been incorporated. Patients will undergo BM biopsy prior to cycle 2 and between cycle 3-4 and/or at CR and/or PD. PET/CT imaging will be performed at the same time points as bone marrow biopsie