Abstract
Background
Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide-dexamethasone (Rd) for pts with MM who have received at least 1 prior therapy. Approval was based on the phase 3 TOURMALINE-MM1 study (NCT01564537), in which ixazomib showed a consistent progression-free survival (PFS) benefit in combination with Rd (IRd) in the ITT population as well as in prespecified subgroups including pts with high-risk cytogenetic abnormalities [del17, t(4;14), t(14;16), +1q], and who received ≥2 prior therapies. An exploratory objective was to evaluate potential relationships between treatment outcomes, tumor gene expression patterns, and mutational status. The NF-κB pathway has been implicated in the development of several malignant disorders. In MM, pro-survival signals from the stromal microenvironment lead to activation of the canonical and non-canonical NF-κB pathway; ~17% of MM tumors have mutations in key genes regulating the non-canonical NF-κB pathway, which is thought to decrease dependence of the MM cell on the stromal microenvironment, a potential mechanism of chemoresistance. Prior data have shown clinical benefit of bortezomib in tumors with non-canonical pathway activation. We utilized gene expression profiles and mutation data to identify tumors with non-canonical NF-κB pathway activation and analyzed its impact on PFS in RRMM pts treated with IRd or placebo-Rd.
Methods
Cytogenetic analyses (FISH), DNA-Seq (hybridization-based targeted MM-specific mutation panel; >400x target mean coverage per sample on ~1200 genes), and RNA-Seq (whole transcriptome sequencing with 50 x 106 total paired reads per sample; 100 bp read length) of CD138+ cells were performed on bone marrow aspirates collected at screening. Presence of mutations in key pathway genes and decreased TRAF3 expression were used as surrogates for non-canonical NF-κB pathway activation.
Results
In the ITT population, DNA-Seq data were available for 46% (339/722) and RNA-Seq data for 58% (419/722) of pts. 14.5% (49/339) of pts had mutations in TRAF2, TRAF3, and BIRC2/BIRC3 genes, which are known negative regulators of NIK, a key intermediate of the non-canonical NF-κB pathway. Impact of these mutations on PFS was analyzed across the treatment arms. An increased magnitude of benefit was observed in pts with mutations when treated with IRd vs Rd (HR=0.23, 95% CI 0.088−0.58, p=0.00086; HR=0.8, 95% CI 0.54−1.2, p=0.29 for wildtype). Low TRAF3 expression was previously shown to be associated with increased non-canonical NF-κB activity and could be due to loss-of-function mutations, chromosomal deletions, and/or epigenetic silencing. In TOURMALINE-MM1, correlation of TRAF3 expression (dichotomized based on the global median) with PFS showed a larger magnitude of clinical benefit following IRd treatment vs placebo-Rd in pts with low TRAF3 expression (HR=0.47, 95% CI 0.3−0.73, p=0.0006; HR=0.75, 95% CI 0.47−1.2, p=0.21 for TRAF3 high). Interestingly, while the median PFS for IRd was similar between pts with high and low TRAF3 expression (HR=0.88, 95% CI 0.54−1.4), a difference was observed in pts treated with placebo-Rd, in whom the median PFS for patients with low TRAF3 expression was 9 months shorter vs pts with high TRAF3 expression (HR=0.54, 95% CI 0.36−0.81). Also, decreased expression of TRAF3 was observed in pts harboring t(4;14) and +1q abnormalities as well as in pts with ≥2 prior therapies, suggesting increased activation of the non-canonical NF-κB pathway in these pt subgroups. This observation would in part explain the larger magnitude of benefit with IRd observed in pts with high-risk cytogenetics and ≥2 prior therapies in the TOURMALINE-MM1 study.
Conclusions
Addition of ixazomib to Rd backbone therapy has shown a benefit in RRMM subgroups. Our data suggest that IRd provides a larger magnitude of benefit in pts with tumors harboring a constitutively activated non-canonical NF-κB pathway. Using a much larger dataset, we confirm the previous observation of bortezomib activity in this molecularly defined population. Though deletions of NF-κB modulators are known to be associated with t(4;14) MM, this is the first instance in which increased activation of the non-canonical NF-κB pathway has been shown in MM tumors harboring +1q21. The correlation between +1q21 and increased non-canonical NF-κB pathway activity and its prognostic implication in MM will be discussed.
Dash:Takeda Pharmaceuticals International Co.: Employment. Zhang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shen:Takeda Pharmaceuticals International Co.: Employment. Li:Takeda Pharmaceuticals International Co.: Employment. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lin:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Avet-Loiseau:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Di Bacco:Takeda Pharmaceuticals International Co.: Employment.
