Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients

Shah, Vallari; Sherborne, Amy L.; Johnson, David C.; Ellis, Sidra; Price, Amy; Chowdhury, Farzana; Kendall, Jack; Jenner, Matthew; Drayson, Mark T.; Owen, Roger G.; Gregory, Walter M.; Morgan, Gareth J.; Davies, Faith E.; Cook, Gordon; Cairns, David A.; Houlston, Richard S.; Jackson, Graham; Kaiser, Martin

doi:10.1038/s41375-020-0750-z

Cited by 34 publications

(55 citation statements)

References 15 publications

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“…Response to panobinostat in this study was associated with a median 20 months prolongation of PFS, and while the study was not powered to detect a statistically significant prolongation of PFS, this represents a clinically meaningful extension of PFS for those with panobinostat‐responsive disease. Importantly, a recent molecular profiling analysis from the Medical Research Council Myeloma IX 27 and XI 28 trials has demonstrated that the 33% of patients with MM with a high‐risk SKY92 (a 92‐gene prognostic signature, MMprofiler TM , SkylineDx) profile and/or two adverse risk translocations (‘double‐hit’) derive no benefit from lenalidomide maintenance 29 . This substantial proportion of patients represents a group where the excepted standard of care for maintenance is deficient and alternative, orally bioavailable agents, such as panobinostat need to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of single‐agent panobinostat consolidation improves responses after sub‐optimal transplant outcomes in multiple myeloma

et al. 2020

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Summary Panobinostat is a pan‐deacetylase inhibitor that modulates the expression of oncogenic and immune‐mediating genes involved in tumour cell growth and survival. We evaluated panobinostat‐induced post‐transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three‐times weekly (TIW) on alternate weeks of 28‐day cycles commencing 8–12 weeks post‐transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9–9·7) months of panobinostat. In responders, T‐lymphocyte histone acetylation increased after both three cycles (P < 0·05) and six cycles (P < 0·01) of panobinostat when compared to baseline, with no differences in non‐responders. The reduction in the proportion of CD127+CD8+ T cells and CD4:CD8 ratio was significantly greater, after three and six cycles of panobinostat compared to pre‐transplant, in non‐responders when compared to responders. Whole marrow RNA‐seq revealed widespread transcriptional changes only in responders with baseline differences in genes involved in ribosome biogenesis, oxidative phosphorylation and metabolic pathways. This study confirmed the efficacy of panobinostat as a single agent in multiple myeloma and established acetylation of lymphocyte histones, modulation of immune subsets and transcriptional changes as pharmacodynamic biomarkers of clinical benefit.

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Section: Discussionmentioning

confidence: 99%

Phase II trial of single‐agent panobinostat consolidation improves responses after sub‐optimal transplant outcomes in multiple myeloma

et al. 2020

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“…An RNA microarray platform (MyPRS) was the first to identify distinct low‐ (LR) and high‐risk (HR) myeloma subgroups 3,4 . A second platform identified additional subgroups (EMC92) 5‐7 . Both of them predicted outcome in patients treated with conventional chemotherapy 4–6,8 …”

Section: (A) Response All Patients N (%) Gene Expression Profiling mentioning

confidence: 99%

Gene expression profiling predicts relapse‐free and overall survival in newly diagnosed myeloma patients treated with novel therapies

et al. 2021

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“…Wide mRNA-transcriptome profiling was assessed using Clariom D Human array (Thermo Fisher Scientific, Waltham, MA, USA). [46][47][48] A detailed description is provided within the Supplemental file. Gene Set Enrichment Analysis (GSEA) was applied on global protein-coding gene expression profiles: significant gene sets were selected based on nominal p-value < 0.05 and FDR<0.25.…”

Section: Transcriptome Profilingmentioning

confidence: 99%

Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88

Sacco

Federico

Giacomini

et al. 2021

Blood

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The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström's Macroglobulinemia (WM). WM is still an incurable disease, and patients succumb due to disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR-signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 also confirmed at protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and non-canonical NFkB cascades were down-regulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3 and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

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Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients

Cited by 34 publications

References 15 publications

Phase II trial of single‐agent panobinostat consolidation improves responses after sub‐optimal transplant outcomes in multiple myeloma

Phase II trial of single‐agent panobinostat consolidation improves responses after sub‐optimal transplant outcomes in multiple myeloma

Gene expression profiling predicts relapse‐free and overall survival in newly diagnosed myeloma patients treated with novel therapies

Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88

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