Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US

Abstract

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum’s deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

Outcomes of daratumumab in the treatment of multiple myeloma: A retrospective cohort study from the Canadian Myeloma Research Group Database

“…While clinical trials demonstrate impressive benefit of darabased therapies, possible discordance with real-world practice might exist, as many patients in the real world are known to be ineligible for clinical trials. 22,23 A few small real-world multicentre studies specifically focusing on dara have been published, confirming the promising activity noted in clinical trials [23][24][25][26][27] [28][29][30][31] There remains a paucity of studies evaluating the outcomes of dara-containing regimens in larger realworld cohorts. Our study aimed to evaluate the impact of these regimens and to benchmark outcomes that may identify gaps that can be targeted for future optimization.…”

“…Comparing our results to other real‐world studies in this field is challenging given the paucity of data among real‐world patients utilizing dara‐containing regimens. Other such studies have recently been published, almost exclusively in the relapse setting, and the number of patients included were most often less than 100 23‐27 (Atrash et al, 2021; Harvanová et al, 2021; Maouche et al, 2021; Szabo et al, 2021). Additionally, many of these studies focused on patients receiving dara monotherapy 24‐27 (Atrash et al, 2021; Maouche et al, 2021; Szabo et al, 2021) and demonstrated results similar to those for our DaraD/P cohort.…”

Beyond Clinical Trials in Patients With Multiple Myeloma: A Critical Review of Real-World Results

“…reported data on the use of several pomalidomide-based triplets in the US, even though some of them have not yet been authorized in Europe (e.g., carfilzomib-pomalidomide-dexamethasone [KPd] and ixazomib-pomalidomide-dexamethasone [IPd]). Overall, 348 patients received a pomalidomide-based triplet, in most cases as a third or subsequent line of treatment, with favorable TTNT with PVd vs. IPd and KPd ( 52 ). In the phase III OPTIMISMM trial, PVd showed similar outcomes, with a median PFS of 11 months in a population of patients with a median of 2 prior lines of therapy ( 48 ).…”

“…analyzed data from patients with ≥2 prior lines of treatment treated with several combinations of novel agents with the backbones Rd or Pd. In this study, a subgroup of patients was treated with the KRd triplet (n=218), showing an overall dismal prognosis, as compared with that in patients treated with daratumumab-Rd and other Rd-containing combinations (median DOT: 7 months) ( 52 ). The DOT was shorter than that in the ASPIRE trial (16.5 months).…”

“…As already mentioned, Davies et al. reported data (with few survival data, due to the short follow-up) on 99 patients treated with Dara-Rd and 149 with Dara-Pd who were heavily pretreated (median of 4 prior lines of therapy) ( 52 ).…”