Efficacy and Safety of T-Cell Engagers Compared to Standard of Care for Relapsed/Refractory Multiple Myeloma Treatment: A Real-World RCT Mimicking Analyses

Background: Recently, immunotherapeutic T-cell engagers (ITCEs) have emerged as a promising class of immunotherapies designed to harness the T cell-based immune system to target and destroy cancer cells for patients with relapsed/refractory MM (RRMM) who have previously received standard therapies. In this study, clinical outcomes of ITCEs in patients with RRMM were evaluated by comparing to propensity score-matched synthetic control cohort consists of patients receiving standard of care (SOC chemotherapy) based on observational analysis using multicenter registry database. We also compared the outcome among different ITCEs by adjusting for risk factors. By employing real world data (RWD) to create a synthetic control, this study aims to provide a comprehensive perspective on the effectiveness and safety of T-cell engagers in routine clinical practice.

Methods: From the database, we identified 474 consecutive cases of RRMM who were treated with third line or more between January 2021 and October 2023. Case cohort included patients treated with ITCEs. Subsequently, we established a preliminary control cohort consisting of the remaining 393 cases. Of these, 138 cases had sequential data for both third line and fourth line treatment. For these patients, we used only the data from their last line of therapy (LoT). Consequently, the final control cohort comprised 255 patients who were treated with standard of care (SOC) regimens, which were covered by Korean public health insurance system and recommended by NCCN guideline. Among the patients in the control cohort, a 1:1 propensity score-matched control cohort was created based on index age, sex, number of prior LoT, International staging system at diagnosis, and baseline biochemical characteristics including hemoglobin count and absolute neutrophil count. To ensure at least a 3-months follow-up period, data were observed in February 2024. In the end, 77 patients in case cohort (ITCE group) vs 77 patients in matched control cohort (SOC group) were selected.

Results: In the case cohort, 34 patients (44.2%) received BCMA-targeted ITCEs, 31 patients (40.3%) were treated with non-BCMA-targeted ITCEs, and 12 patients (15.6%) administered a combination of BCMA- and non-BCMA-targeted therapies.

The case cohort showed significantly better progression-free survival (19.2 months vs. 5.4 months, HR = 0.5 [95% CI, 0.33-0.78], p < 0.01) and a favorable trend in overall survival (OS) (both not reached, HR = 0.65 [95% CI, 0.38-1.13], p = 0.13) compared to the control cohort. Interestingly, among the case group, non-BCMA cohort showed improved OS rate comparing to BCMA cohort in 6-months (97% vs. 66%; P=0.03) and 1-year (87% vs. 48%; P=0.04), with a HR of 0.25 (95% CI; 0.10-0.65) and p-value of 0.01.

Safety profiles indicated cytokine release syndrome in 56% of patients in the case cohort, primarily grade 1, with rare occurrences of neurotoxicity. Subgroup analysis revealed that non-BCMA-targeted ITCEs provided significantly superior OS compared to BCMA-targeted ITCEs (HR = 0.25 [95% CI, 0.10- 0.65], p < 0.01).

Quantitative bias analysis and sensitivity analyses confirmed the robustness of these results. To quantify the sensitivity of the adjusted worst-case HR from multiple imputation of 0.51 (95% CI, 0.33-0.78) to residual confounding, we computed the strength of associations of a hypothetical unmeasured confounder with mortality and treatment that would be required to nullify or reverse the observed beneficial effect of ITCE. The E-value corresponding to HR of 0.51 (approximate risk ratio [RR], 0.62) was 2.58, representing confounder-mortality and confounder treatment correlations needing to be simultaneously greater than 2.58 on the RR scale to move the HR point estimate to 1 and reverse our conclusions. At the 95% CI limit of 0.78, the E-value was 1.65, representing the strength of residual confounding required to move the 95% CI to be intersecting with 1, and rendering results nonsignificant.

Conclusion: In conclusion, this study demonstrates that ITCEs offer a significant improvement in survival patients for real-world RRMM patients compared to SOCs, while maintaining acceptable safety profiles. These findings support the integration of ITCEs into treatment protocols for RRMM.