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Clinical benefit of ixazomib plus lenalidomide‐dexamethasone in myeloma patients with non‐canonical NF‐κB pathway activation
Author(s) -
Dash Ajeeta B.,
Zhang Jacob,
Shen Lei,
Li Bin,
Berg Deborah,
Lin Jianchang,
AvetLoiseau Hervé,
Bahlis Nizar J.,
Moreau Philippe,
Richardson Paul G.,
Di Bacco Alessandra
Publication year - 2020
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.13435
Subject(s) - lenalidomide , relb , cancer research , dexamethasone , medicine , multiple myeloma , oncology , hazard ratio , nf κb , nfkb1 , biology , gene , transcription factor , genetics , inflammation , confidence interval
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‐κB (NF‐κB) 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‐κB 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‐κB‐inducing kinase (NIK) expression (median not reached vs 14 months, HR 0.45), both associated with non‐canonical NF‐κB 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‐κB pathway activation. Conclusions Adding ixazomib to Rd provides clinical benefit in MM tumors with increased non‐canonical NF‐κB pathway activity. This is a potential mechanism for activity in 1q21 amplified high‐risk tumors.