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Optimizing the value of lenalidomide maintenance by genetic profiling - an analysis of 556 Myeloma XI trial patients

Prediction of individual patient benefit from lenalidomide (Len) maintenance post autologous transplant (ASCT) remains challenging. We investigated here extended molecular profiling for outcome prediction in NCRI Myeloma XI (MyXI) trial patients. MyXI patients randomized to Len maintenance or observation post-ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q) and del(17p) and co-occurrence of risk markers computed. PFS, PFS2 and OS were calculated from maintenance randomization, and groups compared using Cox proportional hazards regression. 556 MyXI patients, 17% with double hit MM (≥2 risk markers), 32% with single hit (1 risk marker) and 51% without risk marker, were analyzed. Single hit MM derived the highest PFS benefit from Len maintenance, specifically isolated del(1p), del(17p) and t(4;14), with approximately 40-fold (HR 0.02; 95% CI: 0.002-0.24; P=0.0012), 10-fold (HR 0.1; 95% CI: 0.02-0.58; P=0.0095) and 7-fold (HR 0.14; 95% CI: 0.04-0.45; P=0.0009) reduced risk of progression or death (PFS) compared to observation, respectively. This benefit translated into improved PFS2 HR 0.27 (95% CI: 0.13-0.54; P=0.0002) and OS HR 0.41 (95% CI: 0.18-0.93; P=0.03) for this group of patients over observation; median PFS was 10.9 vs. 57.3 months for observation vs. Len maintenance. Patients with isolated gain(1q) derived no benefit, and double hit MM limited benefit, regardless or risk lesions involved, from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway.

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S1029 Lenalidomide Lenalidomide is a TNF-α secretion inhibitor with IC50 of 13 nM in PBMCs. Lenalidomide (CC-5013) is a ligand of ubiquitin E3 ligase cereblon (CRBN), and it causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide promotes cleaved caspase-3 expression and inhibit VEGF expression and induces apoptosis.

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Apoptosis related VEGFR Caspase E3 Ligase E3 ligase Ligand TNF-alpha