## 4 Discussion  
In this real-world study of patients with transplant-ineligible NDMM in Japan, those who received 1L DRd showed a trend toward an improvement in OS from the time of MM diagnosis by approximately 34% compared with 2L DRd (inverse HR of 0.658; 95% CI: 0.278, 1.563). Furthermore, by using 1L DRd, rather than delaying its administration until 2L treatment, a trend toward prolongation of TTNT from the first DRd administration by approximately 25% was observed (inverse HR of 0.746; 95% CI: 0.481, 1.149). These findings were confirmed in analyses of potential prognostic factors for OS and TTNT, in which a numerically higher risk for worse OS and shorter median TTNT with 2L and \(\geq\)3L versus 1L DRd treatment was observed. Overall, these results suggest that DRd is more effective when used in earlier treatment lines. These findings are consistent with the improved PFS outcomes observed in clinical studies of DRd when used as 1L in the MAIA study [15] or 2L in the POLLUX study [20]. POLLUX evaluated the efficacy of DRd used as 2L or later and showed that PFS was prolonged with fewer lines of therapy [20], an outcome that, along with our findings, may support the hypothesis that early treatment with a regimen that provides longer TTNT translates into better OS outcomes for patients with MM. In cases where CD38 mAb therapy is not utilized until 2L, its application in later lines remains valuable. POLLUX demonstrated superior PFS with DRd regardless of prior lines of therapy [20]. In addition, the Cox regression analysis in our study demonstrated that the effect of treatment line (1L vs. 2L) on outcomes was consistent even after adjusting for factors associated with OS and TTNT. The findings of our Japanese real-world study are consistent with those from the previous simulation study of clinical and real-world US data from patients with transplant-ineligible NDMM and real-world Singapore data [21; 27]. In the simulation study, 1L DRd (followed by 2L pomalidomide- or carfilzomib-based regimens) prolonged the median OS by 1.0-2.7 years compared with 1L Vrd (followed by a 2L daratumumab-based regimen) and by 2.3-3.8 years compared with the 1L Rd (followed by a 2L daratumumab-based regimen) [21]. Although there are concerns that the results of such simulation studies may not be directly applicable to clinical practice, in part because attrition rates may not be reflective of those in clinical practice, the trends observed in our study do substantiate the simulation study findings, in that 1L DRd was associated with survival benefits. This was despite differences in study methodology and patient populations (i.e., in our study, the 2L and \(\geq\)3L groups only included patients able to receive later lines of therapy who were of a younger age). In the MAIA study, 17.9% of the study participants in the DRd arm (1L treatment) were aged \(\geq\)80 years [28], while in the POLLUX study, 10.1% of the patients in the DRd arm (2L or later treatment) were aged \(\geq\)75 years [16]. In the current study, patients receiving 1L DRd were older (median age of 76 years) than those receiving 2L or \(\geq\)3L DRd (75 and 73 years, respectively). This indicates that, in clinical practice, DRd is used in patients older than those participating in clinical studies [29]. Despite the older age of patients in our study, a trend toward improved OS and TTNT with 1L versus 2L DRd was demonstrated, suggesting that there is a benefit of early treatment with DRd in clinical practice irrespective of patient age. This is consistent with the findings from the POLLUX and MAIA studies, which also found survival benefits in older age groups (\(\geq\)65 years [19] and \(\geq\)75 years [15]). Furthermore, a sub-analysis of the MAIA study conducted to assess the effects of treatment in groups of patients defined by a frailty status (i.e., fit, intermediate, or frail) found that DRd was effective regardless of the frailty status [28].