Extended treatment-free hospitalization-free time and quality of life benefits with CAR T-cell therapy in subgroups of patients with relapsed/refractory MM: Insights from the KarMMa-3 trial

Abstract Introduction: Many treatments for relapsed/refractory multiple myeloma (RRMM) require treat-to-progression, which can result in cumulative toxicities from repeated dosing. In contrast, chimeric antigen receptor (CAR) T-cell therapies offer the potential for a treatment-free interval following a one-time infusion. Utilizing KarMMa-3 trial (NCT03651128) data, this research investigated treatment-free hospitalization-free time (TFT) and compared quality of life (QoL)-adjusted event-free survival (EFS) in different patient subgroups (age, tumor burden, prior regimen number, refractory disease status) receiving idecabtagene vicleucel (ide-cel) vs standard regimens; hospitalizations due to infusion, serious adverse events, and other factors were taken into account. Methods: KarMMa-3 is an open-label, phase 3 trial where adults with RRMM who had received 2-4 previous regimens with disease refractory to last regimen were randomized (2:1) to ide-cel or a standard of care regimen. EFS (defined as the duration from randomization to disease progression, subsequent anti-myeloma therapy, or death) observed in the trial was categorized into 4 health states based on study treatment and hospitalization status. A patient may have multiple episodes of the same health state. Time spent in each health state was summarized using the restricted mean survival time (RMST). The average QoL in each health state was determined using the EQ-5D index (1=perfect health and 0=perceived as no better than death). QoL-adjusted EFS was calculated as the sum of RMST in each state weighted by mean EQ-5D index in that state. Significance of EFS and QoL-adjusted EFS were tested via t-test or Mann Whitney U test (depending on data normality). Data for EFS, TFT, and QoL-adjusted EFS are presented as median values; EQ-5D index are mean values. Results: In the age subgroups (≥70 yr, n=73; <70 yr, n=275), ide-cel-treated vs standard regimen-treated patients exhibited longer EFS (17.9 mo vs 9.5 mo; 18.4 mo vs 8.7 mo), longer TFT (15.8 mo vs 0.2 mo; 16.1 mo vs 0.2 mo) with higher EQ-5D index (0.83 vs 0.69; 0.80 vs 0.62), and longer QoL-adjusted EFS (14.7 mo vs 7.1 mo; 14.4 mo vs 6.5 mo,P<0.0001). In the tumor burden subgroups (high, n=88; low, n=246), ide-cel vs standard treatment led to longer EFS (18.1 mo vs 8.4 mo; 18.4 mo vs 9.4 mo), longer TFT (15.7 mo vs 0.1 mo; 15.9 mo vs 0.2 mo) with higher EQ-5D index (0.77 vs 0.66; 0.81 vs NA), and longer QoL-adjusted EFS (13.8 mo vs 6.7 mo; 14.6 mo vs 7.0 mo,P<0.0001). When subgroups were analyzed by number of prior regimens (3-4 regimens, n=239; 2 regimens, n=109), compared with standard treatment, ide-cel resulted in longer EFS (17.5 mo vs 7.8 mo; 18.5 mo vs 10.9 mo), longer TFT (15.2 mo vs 0.2 mo; 16.3 mo vs 0.1 mo) with a higher EQ-5D index (0.81 vs 0.69; 0.80 vs 0.62), and longer QoL-adjusted EFS (13.9 mo vs 5.8 mo;14.6 vs 8.4,P<0.0001). Among patients with (n=222) or without triple-class refractory disease (n=126), those treated with ide-cel vs standard treatment had longer EFS (16.6 mo vs 5.9 mo; 21.2 mo vs 15.5 mo), longer TFT (14.2 mo vs 0.2 mo; 18.5 mo vs 0.1 mo) with higher EQ-5D index (0.80 vs 0.62; 0.81 vs 0.69), and longer QoL-adjusted EFS (12.8 mo vs 4.5 mo; 16.9 mo vs 11.6 mo,P<0.0001). Conclusion: Regardless of age, tumor burden, number of prior regimens, and triple-class refractoriness, patients receiving ide-cel demonstrated significantly longer EFS and QoL-adjusted EFS. This improvement was primarily due to extended periods free from treatment and hospitalization, during which patients' QoL was comparable to that of the general population of the same age. These results enhance our understanding of the survival and QoL benefits associated with a single infusion of ide-cel compared with the standard treat-to-progression regimen, particularly for patient populations who would benefit from reduced hospital visits and more time off therapy.