Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

BackgroundWe previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression.MethodsGene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology.ResultsBM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival.ConclusionsOur results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.

Download Full-text

In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1018 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1018-1018 ◽

Cited By ~ 2

Author(s):

Yen-Shen Lu ◽

Sara A. Hurvitz ◽

Fei Su ◽

Wei He ◽

Debu Tripathy ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Phase Iii ◽

Large Set ◽

Premenopausal Patients ◽

Low Expression

1018 Background: The Phase III MONALEESA-7 study (NCT02278120) is the first dedicated trial of endocrine therapy (ET) ± a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in premenopausal patients (pts) with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) ABC. The study demonstrated that the addition of ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (TAM) + goserelin (GOS) significantly extended progression-free survival (PFS; hazard ratio [HR] 0.55; Tripathy D, et al. Lancet Oncol. 2018). Here we present a gene expression analysis of baseline tumor mRNA from MONALEESA-7. Methods: Premenopausal pts with HR+/HER2− ABC were treated with RIB or placebo (PBO) + GOS with either an NSAI (letrozole or anastrozole) or TAM. Baseline archival tumor samples from 360 of 672 intent-to-treat (ITT) pts were evaluated for gene expression (RIB n = 185; PBO n = 175) using a customized NanoString nCounter® GX 800-gene panel containing relevant breast cancer, CDK, and proliferation pathway–related genes. Pt subgroups were classified as having low or high mRNA expression using median expression as the cutoff. Results: PFS benefit in the biomarker-assessed group was similar to that in the ITT population. A trend toward a more pronounced PFS benefit with RIB was observed in pts with high vs low expression of CCND1 (HR 0.38 vs 0.67, respectively), IGF1R (HR 0.33 vs 0.77), and ERBB3 (HR 0.33 vs 0.76). The PFS benefit seen with RIB also trended to be greater in pts with low vs high expression of CCNE1 (HR 0.38 vs 0.65, respectively) and MYC (HR 0.37 vs 0.69). The PFS benefit with RIB was similar in pts with high vs low expression of FGFR1 (HR 0.45 vs 0.61, respectively), ESR1 (HR 0.57 vs 0.57), and tumor proliferation genes, such as MKI67 (HR 0.50 vs 0.51). Conclusions: This is the first gene expression analysis of a large set of premenopausal pts with ABC. The benefit with RIB was generally consistent across gene expression subgroups, although the magnitude varied in certain subsets. This analysis suggests that there may be unique resistance mechanisms to ET ± CDK4/6 inhibitors in premenopausal pts with ABC. Clinical trial information: NCT02278120.

Download Full-text