A simulation modeling that incorporated clinically representative sequences for patients with transplant-ineligible NDMM and included attrition rates supports using the D-Rd regimen in the first-line setting instead of reserving it for later lines of therapy.
Simulation modeling can serve as a valuable tool to explore clinical scenarios that were not possible to test in the original trials.1 A simulation modeling analysis sought to understand optimal treatment sequencing in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM). It specifically examined different clinical scenarios to explore the overall survival (OS) benefit of using daratumumab-based regimens in the first line or saving it for subsequent lines of therapy. Results of this analysis were reported at the 2021 ASH Annual Meeting and summarized here.
The study incorporated 3 potential clinically representative treatment sequences or health state clinical simulations to estimate survival outcomes in patients with transplant-ineligible NDMM. The 3 health states were: first-line (time on treatment plus any subsequent treatment-free interval), second-line (time on second-line plus any subsequent line of therapy), and death. Treatment sequences were per clinical guidelines: first-line daratumumab-lenalidomide/dexamethasone (D-Rd), followed by second-line pomalidomide- or carfilzomib-based regimens; first-line bortezomib/lenalidomide/dexamethasone (VRd) or lenalidomide/dexamethasone (Rd) followed by second-line daratumumab-based regimens.
Assumptions were based on MAIA and PEGASUS data: patient characteristics were similar to those in the MAIA study; time spent in the first-line health state with D-Rd and Rd was based on time to next first-line or death curves from MAIA; time to next first-line or death curves with VRd were derived by applying progression-free survival hazard ratios estimated in the PEGASUS study. The attrition rate for the base-case analysis was 58.8% per MAIA data, while the sensitivity analysis used an attrition rate of 27.2% excluding censored patients. Real-world OS data from the nationwide electronic health record–derived deidentified Flatiron Health database were used to derive time spent in the second-line health state with daratumumab-based and pomalidomide- or carfilzomib-based regimens.
In the first-line setting, the modeling found that using the D-Rd regimen improved median OS by 2.5 years compared with delaying daratumumab-based regimens until second-line after failure of VRd (median OS, 7.6 years vs 5.1 years, respectively) or improved by 3.5 years compared with delaying daratumumab-based regimens until second-line after Rd (median OS, 7.6 years vs 4.1 years, respectively). There was a higher probability of being alive at 5 and 10 years with using first-line D-Rd compared with using first-line VRd or Rd. Compared with VRd or Rd, the 5-year OS (VRd, 62.6% vs 51.0%, respectively; Rd, 62.6% vs 44.1%, respectively) and 10-year OS (VRd, 41.8% vs 29.6%, respectively; Rd, 41.8% vs 22.8%, respectively) rates were higher with D-Rd. Sensitivity analysis showed that, while changes in attrition rates impacted the expected median OS, the absolute difference in median OS was maintained, with an incremental OS benefit of >2 years.
The simulation analysis that incorporated clinically representative sequences for patients with NDMM and included attrition rates suggests that using the D-Rd regimen in the first-line setting may result in better patient outcomes compared with reserving it for later lines of therapy.
Source: Fonseca R, Facon T, Hashim M, et al. First-line use of daratumumab, lenalidomide, and dexamethasone confers survival benefit compared with second-line use of daratumumab-based regimens in transplant-ineligible patients with multiple myeloma: analysis of different clinical scenarios. Blood. 2021;138(suppl 1):118.
Reference
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