Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non-canonical NF-κB pathway activation.
Eur J Haematol
; 105(3): 274-285, 2020 Sep.
Article
em En
| MEDLINE
| ID: mdl-32350909
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-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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Protocolos de Quimioterapia Combinada Antineoplásica
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NF-kappa B
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Mieloma Múltiplo
Tipo de estudo:
Clinical_trials
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Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article