Real-world experience with first-line regimens in transplant-ineligible patients with multiple myeloma

Abstract Introduction Regimens based on bortezomib and lenalidomide have been a mainstay of treatment for transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM) patients (pts). Recently, the phase 3 MAIA trial established DRd as the new standard of care (SoC), with a median progression-free survival (PFS) of 61.9 months compared to 34.4 months with Rd and a significant benefit in overall survival (OS). In Canada, DRd was funded via the public healthcare system for first-line NDMM TI patients in 2022. The aim of this retrospective study was to evaluate the initial real-world outcomes of this regimen in the context of treatments used prior to the introduction of anti-CD38 antibodies in frontline therapy. Methods We performed a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG-DB), a prospectively maintained disease-specific database with >10,000 pts enrolled in 21 centres across Canada. All NDMM TI pts >18 years treated with CyBorD, Rd, RVd, or DRd as first-line treatment between 01/01/2018 – 30/11/2024 were included. Pts were excluded if they were treated on a clinical trial, did not receive any treatment within 1 year of diagnosis, underwent stem cell transplant ≤1 year of diagnosis, or had amyloidosis, POEMS, or plasma cell leukemia. The primary objective of the study was to determine the following outcomes observed with these first-line regimens: early mortality rate (at 6 months and 1 year), overall response rate (ORR), best response, PFS, and OS. Secondary objectives included assessing the pattern of usage of these different regimens between 01/2018 -11/2024, and identification of variables affecting 1-year early mortality, ORR, and PFS by regimen. Descriptive analysis was used to report demographics, disease characteristics and treatment responses by regimen. Baseline characteristics were summarized by mean, standard deviation, median and ranges as appropriate. Time to event analyses were used to assess PFS and OS. Survival curves were constructed according to the Kaplan-Meier method and impact of covariates of interest were assessed using the log rank test. Results A total of 1,085 pts were eligible. Regimens included: CyBorD in 382 (35.2%), Rd in 292 (26.9%), RVd in 178 (16.4%) and DRd in 233 (21.5%). The median follow-up in months (95% CI) in these 4 cohorts was 41.0 (35.2, 44.7), 50.2 (45.4, 54.5), 29.7 (24.4, 34.4) and 9.3 (7.6, 11.3), respectively. The 6-month and 1-year mortality rates were 6.5% (95% CI 4.3-9.5) and 11.8% (95% CI 8.6-15.4) for CyBorD, 7.9% (95% CI 5.1-11.6) and 14.7% (95% CI 10.9-19.3) for Rd, 4.5% (95% CI 2.0-8.7) and 7.9% (95% CI 4.4-12.8) for RVd and 4.3% (95% CI 2.1-7.8) and 5.6% (95% CI 3.0-9.4) for DRd. The ORR/≥VGPR by regimen included: 95.9%/72.3% with RVd, 94.5%/71.9% with DRd, 89.2%/58.9% with CyBorD and 79.1%/45.3% with Rd. Median PFS was 41.4 months in RVd pts, 28.6 months in Rd pts and 20.2 months in CyBorD pts; an accurate median PFS was not yet available in DRd pts due to short follow-up. However, CyBorD pts had a statistically significant shorter median PFS, while there was no difference between the other regimens to date. Median OS was not yet reached for DRd, 62.2 months for RVd, 60 months for CyBorD, and 55.5 months for Rd (p=0.061). Of the 1,085 pts, 432 (39.8%) have received a 2nd line of therapy. The use of DRd in Canada significantly increased from 1.1% in 2020 to 30.3% in 2022, and was the most common regimen in 2023 (77.5%) and 2024 (78.4%). Conclusion In this real-world retrospective study, we demonstrate that, after public funding, DRd rapidly became the most frequently utilized first-line treatment in Canadian patients with TI NDMM. Early mortality rates at 6 months and 1 year were very low with DRd. Response rates with DRd and RVd were the highest and each produced an ORR of approximately 95% and ≥VGPR of 72%. CyBorD patients had a significantly shorter PFS. However, an accurate evaluation of DRd's PFS efficacy is premature due to its recent introduction into the Canadian treatment algorithm and short follow-up period (9.3 months vs 29+ months in other cohorts). More mature results of DRd, in addition to analyses of potential variables correlated with outcomes, will be assessed in the future. Nevertheless, our findings suggest that both RVd and DRd are highly effective options for treatment of TI NDMM.Financial support: CMRG received financial support from Janssen Inc. for the conduct of this study.