Dataset Information

Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non-canonical NF-?B pathway activation.

ABSTRACT: OBJECTIVES:Evaluating potential relationships between progression-free survival (PFS) and tumor gene expression patterns and mutational status was an exploratory objective of the phase 3 TOURMALINE-MM1 study (NCT01564537) of ixazomib-lenalidomide-dexamethasone (IRd) vs placebo-Rd in 722 patients with relapsed/refractory multiple myeloma (MM). METHODS:We utilized gene expression and mutation data from screening bone marrow aspirates to identify tumors with non-canonical nuclear factor-?B (NF-?B) signaling pathway activation. RESULTS:DNA/RNA sequencing data were available for 339 (47.0%)/399 (55.2%) patients; 49/339 (14.5%) patients had non-canonical NF-?B pathway gene mutations (tumor-necrosis-factor receptor-associated factor 2, 3 [TRAF2, TRAF3], baculoviral-inhibitor-of-apoptosis repeat-containing 2/3 [BIRC2/3]), and PFS was significantly longer with IRd vs placebo-Rd in these patients (hazard ratio [HR] 0.23). In patients with lower TRAF3 expression (median not reached vs 11 months, HR 0.47) and higher NF-?B-inducing kinase (NIK) expression (median not reached vs 14 months, HR 0.45), both associated with non-canonical NF-?B pathway activation, PFS was significantly longer with IRd vs placebo-Rd. TRAF3 expression was decreased in patients harboring t(4;14) and 1q21 amplification, suggesting increased non-canonical NF-?B pathway activation. CONCLUSIONS:Adding ixazomib to Rd provides clinical benefit in MM tumors with increased non-canonical NF-?B pathway activity. This is a potential mechanism for activity in 1q21 amplified high-risk tumors.

SUBMITTER: Dash AB

PROVIDER: S-EPMC7497066 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non-canonical NF-κB pathway activation.

Dash Ajeeta B AB Zhang Jacob J Shen Lei L Li Bin B Berg Deborah D Lin Jianchang J Avet-Loiseau Hervé H Bahlis Nizar J NJ Moreau Philippe P Richardson Paul G PG Di Bacco Alessandra A

European journal of haematology 20200601 3

<h4>Objectives</h4>Evaluating potential relationships between progression-free survival (PFS) and tumor gene expression patterns and mutational status was an exploratory objective of the phase 3 TOURMALINE-MM1 study (NCT01564537) of ixazomib-lenalidomide-dexamethasone (IRd) vs placebo-Rd in 722 patients with relapsed/refractory multiple myeloma (MM).<h4>Methods</h4>We utilized gene expression and mutation data from screening bone marrow aspirates to identify tumors with non-canonical nuclear fac ...[more]

PMID: 32350909

Similar Datasets

Project description:BackgroundWe have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice.MethodsA total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05.ResultsIn the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable.ConclusionsOur analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.

Dataset Information

Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non-canonical NF-?B pathway activation.

Publications

Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non-canonical NF-κB pathway activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure