Comparison of Ixazomib, Lenalidomide Plus Dexamethasone (IRd) and Bortezomib, Lenalidomide Plus Dexamethasone (VRd) in Newly Diagnosed Multiple Myeloma in China

Background: Ixazomib plus lenalidomide and dexamethasone (IRd), an all-oral regimen, has been demonstrated in several trials to have promising efficacy and tolerable side effects in the frail population for newly diagnosed multiple myeloma(NDMM). Bortezomib plus lenalidomide and dexamethasone (VRd) has been the mainstay of frontline therapy for many years in newly diagnosed multiple myeloma (NDMM). However, the VRD regimen has been poorly tolerated in frail populations due to peripheral neuropathy and hematologic toxicity. There was scarce direct comparison between these two triplet regimens among MM patients(pts). This study aims to assess the difference in efficacy and safety profiles of IRd and VRd triplets among an unselected, real-world population.

Methods: This retrospective analysis included pts in six Chinese clinical centers, and enrolled NDMM patients over 18 with evaluable treatment information. We compared the characteristics and outcomes of NDMM pts treated with two individual regimens (IRd Vs VRd), diagnosed between January 2017 and March 2023. Patients received induction therapy at 3- to 4-week intervals and were given regular follow-up. The primary endpoint was progression-free survival(PFS). The response rate (RR) and safety profiles were recorded through pts’ electronic health records.

Results: A total of 86 pts received IRd regimen, and 107 received VRd. The median age was 64.5 (range 27-77) and 64 (range 32-85) in the IRd and VRd groups. Pts received a median of 9 (range,2-37) cycles of induction therapy in the IRd group and a median of 9 (range, 2-14) in the VRd group. Both groups had comparable distribution of International Staging System(ISS)/Revised ISS(R-ISS) stages, disease-related symptoms, and extramedullary disease at baseline. Pts also had similar positive rates of high-risk cytogenetic abnormalities(CAs) (including del17p, 1q21gain/amplification, t(4;14), and t(14;16)). There were 55(64.0%) pts in the IRd group turning to maintenance therapy, while 49(45.8%) pts received maintenance in the VRd group (P=0.018). Thirty-one (36.1%) pts in the IRd group were under inferior performance status with an Eastern Cooperative Oncology Group(ECOG) ≥2, while 33 (30.8%) pts in VRd had ECOG≥2 (P=0.542). With a median follow-up of 26.4±4.3 months in the IRd group and 34.6±0.8 months in the VRd group, pts had a median PFS of 45.0±11.2 months and 38.0±3.9 months, respectively (log-rank P=0.719). A median overall survival(OS) was 53.5±1.4months in the IRd group, while a median OS was not reached in the VRd group (log-rank P=0.085). However, pts with double/triple-hit high-risk CAs tended to have favorable PFS results from IRd regimen (P=0.068). The best overall RR (ORR) and complete response(CR) rates were 93.0% and 39.5% in the IRd group, while it was 93.5% and 49.5% in the VRd group (P>0.05). For the safety profile, the most frequent hematologic adverse event(AE) was lymphopenia(26.7%) in the IRd group. The first two most frequent non-hematologic AEs were hypokalemia(18.6%) and diarrhea(16.3%). Grade 3/4 hematologic AEs happened at 6(7.0%) pts and 8(9.3%) pts occurred grade 3/4(G3/4) non-hematologic AEs from IRd treatment. Meanwhile, the most frequent AE was peripheral neuropathy(34.0%) in the VRd group. The incidences of G3/4 hematologic and non-hematologic events were 17.9% and 15.9% in the VRd regimen (P=0.023 and 0.176, compared to IRd).

Conclusion: In real-world analysis, IRd resulted in similar outcomes to the VRd regimen for NDMM, with a trend to a favorable PFS in pts with double/triple-hit high-risk CAs. Meanwhile, pts received IRd experienced fewer G3/4 AEs and peripheral neuropathy events than those had VRd. As an all-oral regimen, IRd can be a selection for frontline therapy in MM during the post-pandemic era.