Real-World Comparative Outcomes of Anti-CD38 Monoclonal Antibody Retreatment Versus Selinexor-Based Triplets in Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction/Background/Significance: Monoclonal antibodies targeting CD38 (α-CD38), in combination with agents like bortezomib, carfilzomib, and lenalidomide, are a standard therapy for both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients; however, disease relapse inevitably occurs in most. Despite recommendations to switch antigen targets upon progression, the practice of treatment recycling is still prevalent. Selinexor, a first-in-class selective inhibitor of nuclear export (targeting exportin 1), is recommended in triplet combination with multiple agents for patients with RRMM. This study presents a real-world comparative analysis of retreatment with α-CD38 therapy versus selinexor triplet therapy in patients with RRMM previously treated with α-CD38 regimens in the immediate prior line.

Materials and Methods/Case Presentation/Objective: Electronic medical records were reviewed from the OneOncology network of community hematology practices in the United States. The primary and secondary endpoints included disease response, time to treatment discontinuation (TTD), and overall survival (OS). Data on patient demographics, disease characteristics, prior therapies, and performance status (PS) at treatment initiation were collected. Kaplan-Meier and multivariate modeling analyses were used to evaluate the endpoints. Propensity score weighting was applied to control for patient demographic and clinical characteristics.

Results/Description/Main Outcome Measures: The final sample included 74 patients who were retreated with an α-CD38 regimen, and 23 patients treated with a selinexor triplet immediately following an α-CD38 regimen. Baseline characteristics were well balanced between groups in terms of median age, myeloma subtype, prior treatments, and index line of therapy (3L). However, a higher proportion of patients in the selinexor group had light chain disease (17.4%, n=4/23 vs. 12.2%, n=9/74) and a PS ≥ 2 (43.5%, 10/23 vs. 18.9%, n=14/74). The selinexor triplet group had significantly higher likelihood of disease response rates (≥Partial Response = 52.2% vs 28.4%; OR = 3.97; 95% CI: 1.31–12.0). No difference in OS was observed at 12 months; α-CD38 mAb = 71% (95%CI = 58.6-80.3) vs selinexor = 69.4% (95% CI = 46.4-84.1). The median TTD was longer in the α-CD38 group (7.8 vs. 3.9 months) with approximately 55.4% of the α-CD38 retreated patients and 43.4% of selinexor-treated patients receiving subsequent therapy.

Conclusions: Selinexor triplet therapy offers improved response rates compared to α-CD38 retreatment in patients with RRMM. These real-world findings support prioritizing a mechanistically distinct regimen immediately post-α-CD38 exposure and align with the current prospective investigations such as the EMN29 randomized trial (NCT05028348) evaluating selinexor-pomalidomide-dexamethasone vs elotuzumab-pomalidomide-dexamethasone in patients with RRMM immediately following an α-CD38 treatment.