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 biopsies. MM serum markers for response will be performed at baseline and the start of every cycle. Exploratory corollary research will be performed on research samples collected at clinical timepoints including BCL2/MCL1 biomarkers. The study design is shown in Figure 2.

The primary objective of the study is to determine the overall response rate (ORR) of SELVEDge in t(11;14)-positive RRMM with secondary objectives of durability of response (DoR), measurable residual disease (MRD) negative remission rate, progression-free and overall survival, and safety and tolerability. For patients to be included in the study they must have documented evidence of receiving two prior lines of therapy and be refractory to, not a candidate for (ineligible), or intolerant of at least one immunomodulatory (IMiD), one proteasome inhibitor, and one anti-CD38 monoclonal antibody-based treatments. Patients with prior therapy with selinexor or another specific inhibitor of nuclear exporter (SINE) compound are excluded.

Statistical Hypothesis: Historically, in patients who have RRMM and have progressed after receiving IMiD, PI, and anti-CD38 -based regimens, approved experimental agents have been associated with an ORR of ~25%. It would be desirable to demonstrate that XVenD has a substantially higher response rate with a clinically meaningful ORR of 50%. As such, the study would rule out an unacceptably low ORR of 25% (p0=0.25) in favor of an improved response rate of 50% (p1=0.50), with a one sided alpha = 0.05 (probability of accepting a poor treatment=0.05) and beta = 0.20 (probability of rejecting a good treatment=0.20).

Current Status: This clinical trial is currently open to enrollment at the Sylvester Myeloma Institute, University of Miami and to date 5 patients have been thus far enrolled and treatment initiated.