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

Background: BCL2 inhibition with venetoclax (Ven) has been shown to benefit patients with relapsed/refractory multiple myeloma (RRMM) harboring t(11;14). Selinexor (X), an XPO1 inhibitor, with dexamethasone (D) is FDA-approved for RRMM. Case reports suggest the XVenD combination in t(11;14)-RRMM is safe and active (Nguyen et al. Nat Prec Onc 2022). Preclinically, XVenD is synergistic in t(11;14) RRMM cell lines, decreasing levels of Cyclin D1 when administered in combination compared to alone. These (pre)-clinical findings motivated us to develop an investigator-initiated study of XVenD in patients with RRMM harboring t(11;14), the SELVEDge study; herein, the interim Stage 1 results are presented.

Methods:This is a single-center Simon 2-stage Phase 2 trial (NCT05530421) in up to 24 patients with t(11;14)-RRMM who have exhausted >2 prior regimens, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies. The primary objective is to determine the activity (overall response rate (ORR)) with key secondary endpoints of safety/tolerability, response duration (DoR), minimal residual disease (MRD) negativity, progression-free (PFS) and overall (OS) survival. For cycle 1 (28-day cycles), patients receive oral Ven 400 mg daily for 7 days followed by 800 mg daily for the remainder of the cycle with weekly oral D 40 mg. From cycle ≥2, patients receive oral X 80 mg weekly, Ven 800 mg daily, and D 40 mg (20 mg cycle ≥5) weekly. All patients received combination antiemetic prophylaxis starting with the addition of X consisting of ondansetron and olanzapine with alternatives allowed based on drug interactions or patient comorbidities.

The Simon Optimal 2-stage design stipulates treatment of 9 patients in the first stage and if ≥2 partial responses occur (≥PR), the study continues to the second stage to enroll a total of 24 patients where XVenD will be deemed successful if ≥10 of the 24 patients achieve a ≥PR. Patients remain on treatment until progressive disease (PD) or intolerability.

Stage 1 Interim Results: As of 1/18/2024, 9 patients with a median age of 65 years (Range: 59-78) started treatment with XVenD of which 33% were female, 22% Black, 56% Hispanic and had an ECOG PS: 0 (67%); 1 (33%). Other characteristics include: isotype: IgG-lambda (33%), kappa light chain (56%), lambda light chain (11%); t(11;14): 100%; high-risk cytogenetics: 33% (unknown, 22%); prior lines of therapy: median, 2 (range: 2-11); prior BCL2 inhibitor (11%). As of the 7/2/2024 data cut-off, the median number of treatment cycles is 6 (range: 1-15) and 33% remain on treatment; off treatment reasons include PD in 4, toxicity in 1, and investigator decision in 1 patient.

The ORR, ≥very good PR (VGPR), and ≥complete response (CR) rates are 55.6% (95%Confidence Interval (CI): 21.0-86.0%), 55.6% (95%CI: 21.0-86.0%), and 22.2% (95%CI: 2.8-60.0%), respectively; responses included (n): MRD negative (1), stringent CR (2), VGPR (3), minimal response (1), and stable disease (3). Of the 9 patients, 78% had any grade adverse drug reaction (ADR) (44% hematologic (heme); 78% non-heme). ADRs occurring >1 patient included (n): nausea (5), diarrhea (4), fatigue (3), insomnia (3), anorexia (2), dysgeusia (2), neutropenia (2), thrombocytopenia (2), and urinary tract infection (2); 3 and 7 patients had infection of any type and gastrointestinal toxicity, respectively. Grade 3-4 ADRs occurred in 56% (33% heme; 33% non-heme) of patients including 1 Serious ADR (sepsis/febrile neutropenia) and no deaths; Grade 3-4 thrombocytopenia occurred in 2 patients and diarrhea, fatigue, febrile neutropenia, hyperkalemia, insomnia, neutropenia, and sepsis each in 1 patient.

Conclusion: XVenD in t(11;14)+ RRMM appears to be an active combination with an ORR of 55.6% for the Stage 1 part of this 2-Stage study. The prespecified Simon 2-Stage threshold of ≥2 PRs has been met and enrollment to the 2^nd Stage is ongoing. Observed ADRs appear to be in line with known toxicities of the individual agents with no new toxicity observed. Moreover, given the rate of dose reductions in this study and in light of recent data from the CANOVA study, the study was modified to lower the dose of venetoclax to 400 mg daily and selinexor to 60 mg weekly. The XVenD regimen will be further characterized once the 2^nd Stage of the study is enrolled but based on our early study results, appears to be both an active, manageable, and all oral drug combination in t(11;14)-RRMM.

Kazandjian:Magnolia: Honoraria; Alphasights: Consultancy; MJH Life Sciences: Honoraria; Dedham Group: Consultancy; BMS: Honoraria; Aptitude Health: Honoraria; NCI/NIH, FDA, MMRF, DoD-PROMETHEUS (Murtha Cancer Center Research Program), Amgen, BMS/Celgene, Janssen,: Research Funding; Arcellx: Honoraria, Other: served on independent data monitoring committees (IDMC); Aperture Medical Technologies: Honoraria, Other: served on independent data monitoring committees (IDMC); Curio Science: Honoraria; Bridger Consulting Group: Consultancy; MJH Life Sciences: Honoraria; Plexus: Honoraria; Karyopharm Therapeutics: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria. Kowalski:Pfizer: Consultancy. Kuker:ADCT: Research Funding. Thoren:the Binding Site and Sebia: Research Funding, Speakers Bureau. Maura:Sanofi: Consultancy, Honoraria; Medidata: Consultancy, Honoraria. Landgren:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees..

Although drugs are FDA approved, the combination is considered off-label