Association between response kinetics and outcomes in relapsed/refractory multiple myeloma: analysis from TOURMALINE-MM1.
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ABSTRACT:
SUBMITTER: Garderet L
PROVIDER: S-EPMC6127091 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Association between response kinetics and outcomes in relapsed/refractory multiple myeloma: analysis from TOURMALINE-MM1.
Garderet Laurent L Laubach Jacob P JP Stoppa Anne-Marie AM Hari Parameswaran P Cavo Michele M Ludwig Heinz H Mateos María-Victoria MV Luptakova Katarina K Lin Jianchang J Yung Godwin G van de Velde Helgi H Berg Deborah D Moreau Philippe P Richardson Paul G PG
Leukemia 20180312 9
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Project description:Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE-MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time-to-event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M-protein] and progression-free survival [PFS]) outcomes observed in TOURMALINE-MM1. Models reliably described observed safety and efficacy results; prior immunomodulatory drug therapy and race were significant covariates for diarrhea and rash events, respectively, whereas M-protein dynamics were sufficiently characterized using TTE models of relapse and dropout. Moreover, baseline M-protein was identified as a significant covariate for observed PFS. The developed framework represents an integrated approach to describing safety and efficacy with MM therapy, enabling the simulation of prospective trials and potential alternate dosing regimens.
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Project description:Ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) showed clinical efficacy over placebo-Rd in patients with relapsed/refractory multiple myeloma (MM) in the TOURMALINE-MM1 trial. Over a median follow-up of ∼85 months, as patients showed disease progression, they received subsequent novel therapies that confounded the overall survival (OS) benefit. Here, we conducted a post hoc analysis in 148 patients from seven countries defined as emerging markets, with limited access to novel therapies for MM during the trial period, to describe the impact of these therapies on OS. Patients were randomised to ixazomib-Rd (n = 71) or placebo-Rd (n = 77). The median progression-free survival (PFS) was 18.7 versus 10.2 months, with ixazomib-Rd versus placebo-Rd (hazard ratio [HR], 0.504; p = 0.008) demonstrating a statistically significant improvement as observed in the primary trial. The median OS improved by 32.6 months with ixazomib-Rd over placebo-Rd (63.5 vs. 30.9 months; HR, 0.794; p = 0.261); however, the statistically significant benefit seen in PFS was not observed for OS. Improvement with ixazomib-Rd over placebo-Rd was observed in overall response (81.7% vs. 64.9%; odds ratio [OR], 2.38; p = 0.019) and complete response (22.5% vs. 3.9%; OR, 7.57; p < 0.001). Patient-reported quality of life and use of subsequent therapies were similar across treatment groups. No new safety concerns were identified. Compared with the main cohort, median OS was 10 months longer with ixazomib-Rd and 21 months shorter with placebo-Rd in this subgroup, indicating a clinically meaningful survival benefit of ixazomib-Rd treatment in this patient population with limited access to subsequent novel therapies.
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