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3363 Phase II Clinical Trial: Ex Vivo Drug Sensitivity Testing in Parallel with Physician Selected Selinexor-Based Therapy for Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Assays, Clinical Research, Treatment Considerations, Technology and Procedures
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Zachary J. Walker, BS, MS*, Deng Wang*, Sarah E. Parzych, BA*, Lauren T. Reiman, BSc*, Jacob Joram*, Meghan Straubel*, Alfonso Roque*, Kaylynn Imsande*, Katie Zhou*, Peter A. Forsberg, MD and Daniel W. Sherbenou, MD, PhD

Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO

Introduction: Selinexor (KPT-330, XPOVIO), an oral selective inhibitor of XPO1, has shown promise for use in patients with relapsed/refractory multiple myeloma (MM) who have received 4 or more prior lines of therapy. Selinexor partners well with several drugs, creating an opportunity to personalize drug combination choices. Myeloma Drug Sensitivity Testing (My-DST) is a novel ex vivo drug screening platform that can be utilized to determine drug response from patient-donated bone marrow aspirates. With the goal to validate My-DST utility in guiding combination selection, we opened a single institution, open-label phase II clinical trial (NCT04925193) at University of Colorado with 3 treatment arms based on a selinexor/dexamethasone backbone. Patients were treated with the physician’s choice of a third drug between pomalidomide (SPd), carfilzomib (SKd), or daratumumab (SDd). The clinical outcomes were compared prospectively to results from My-DST at screening. At this time, enrollment has been completed and all patients have had response evaluation and correlation of ex vivo and clinical results.

Methods: Patients were eligible if they were ≥ 18 years of age with relapsed or refractory MM, having received 1 or more prior lines of therapy. Trial patients were enrolled in 28-day cycles containing 3 drug therapies assigned by their physician. Considerations such as prior therapeutic exposures, comorbid conditions, and toxicity risk were utilized to assign treatment. Patients continued therapy until progression or unacceptable toxicity. The primary objective was to evaluate the overall response rate (ORR). Secondary objectives included minimal residual disease (MRD) and progression-free survival (PFS). Exploratory objectives included feasibility of My-DST to inform treatment choice and related predictors of response. For My-DST, mononuclear cells containing primary MM cells were isolated from patient bone marrow aspirates and incubated with single agent drugs from each arm of the study. The change in myeloma cell viability was measured at 48 hours via high-throughput flow cytometry.

Results: Accrual for the trial was 18 patients with relapsed MM. Median age was 66 (range, 51-79) with 8 males and 8 females, and median years since diagnosis was 4 (<1-14). The median number of previous lines of therapy was 3 (range, 1-6). High risk cytogenetics were present in 39% of patients. Enrollment on study arms was 9 (50%) on SKd, 3 (17%) on SPd, and 6 (33%) on SDd. At a median follow-up time of 6 months the ORR was 67% with 3 complete responses (CR), 1 achieving MRD negativity, 3 very good partial responses (VGPR), 6 partial responses (PR), 5 with stable disease (SD), and 2 with progressive disease (PD). Median PFS was 7.8 months. Toxicity and tolerability were consistent with previous selinexor trials and generally manageable, with 11% of patients discontinuing treatment early due to adverse events. My-DST results were available for 13 of 18 patients, excluding 2 tests with undetectable MM via flow, 2 inaspirable bone marrow biopsies and 1 censored patient due to coming off trial for COVID early in cycle 1. Using a cutoff of 20% reduction of viable MM cells ex vivo, 62% of patients were sensitive to selinexor, 62% to carfilzomib, 53% to pomalidomide and 69% to daratumumab. Additive drug combination effect was calculated for each patient based on treatment arm and compared to clinical M-protein or free light chain (FLC) response. My-DST identified 9 true responders, 2 true non-responders, 1 false responder, and 1 false non-responder. Thus, the assay was 90% sensitive and 67% specific for clinical response. In 2/13 patients (15%), My-DST results indicated an alternative drug combo could have resulted in deeper clinical response. Overall, additive drug combination effect correlated with patient outcome when utilizing FLC results (r = 0.67, p = 0.01).

Conclusions: Selinexor/dexamethasone-based triplet drug regimens were associated with high response rates in a diverse relapsed MM population. Clinical response to selinexor therapy was correlated with ex vivo drug sensitivity testing via My-DST. The test provided the capability to screen several drugs at once, informing which combination could produce the best possible clinical response. My-DST provides the potential for clinicians to make precision medicine decisions regarding what class of drug to prescribe in combination for individual MM patients.

Disclosures: Forsberg: University of Colorado: Ended employment in the past 24 months; Karyopharm: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Colorado Blood Cancer Institute: Current Employment; Johnson and Johnson, BMS: Membership on an entity's Board of Directors or advisory committees. Sherbenou: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH