Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.
Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs’ specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease.
Bruton tyrosine kinase plays a critical role in hastening cell proliferation. Bruton tyrosine kinase inhibitors are a class of immunotheraputic agents that disrupt this signaling pathway. Ibrutinib, a novel Bruton tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of Waldenstrom macroglobulinemia in patients who have failed treatment with other agents, has emerged as an important therapeutic agent in the management of Waldenstrom macroglobulinemia and other plasma cell dyscrasias. Ibrutinib has shown to increase progression free survival and improve overall mortality. We present a review of ibrutinib, beginning with an overview of the Bruton tyrosine kinase pathway and clinically relevant gene mutations impacting treatment and prognosis for patients with Waldenstrom macroglobulinemia, followed by evidence supporting therapeutic indications for ibrutinib, and detailing its safety and efficacy evidence, current clinical guidelines, adverse effects and their management, and finally challenges of drug resistance. We also present findings on newly developed Bruton tyrosine kinase inhibitors in the therapeutic pipeline to provide readers insight into this rapidly evolving corner of oncology pharmacy practice.
Introduction. Waldenström Macroglobulinemia (WM) is a low- grade B-cell lymphoma with a heterogeneous clinical presentation. In many patients, the diagnosis is preceded by an asymptomatic precursor state of IgM monoclonal gammopathy of undetermined significance (MGUS) and smoldering WM. However, little is known about the mechanisms involved in the progression from asymptomatic WM to symptomatic WM. Exosomes are small vesicles secreted by cells that enable the transfer of nucleic acids, proteins and lipids between distant cells in the organism. Because of the active role of exosomes in promoting tumor growth and metastasis, we investigated the microRNA content of circulating exosomes in patients at different stages of WM in order to identify possible markers of progression. Methods.We isolated exosomes by ultracentrifugation from the peripheral blood plasma of 101 patients with WM and 10 normal donors. The WM cases included 7 patients with IgM MGUS, 42 patients with smoldering WM and 52 patients with symptomatic WM. We first profiled microRNAs from the exosomes of 14 patients and 5 normal controls using the TaqMan Array Human MicroRNA A Card (Thermo Fisher Scientific) which enables the quantitation of 377 human microRNAs. Exosomes from an additional group of 14 individuals (2 normal donors, 8 patients with asymptomatic WM and 4 patients with symptomatic WM) were profiled with the Oncology Panel of the Firefly Multiplex Circulating miRNA Assay (Abcam), which measures the expression level of 68 different human microRNAs. Following these analyses, a group of 33 microRNAs deregulated between patients' groups was selected and a custom microRNA panel was built to allow quantitation of these microRNAs with the Firefly Multiplex Circulating miRNA Assay (Abcam). The level of expression of these 33 microRNAs was measured in a group of 80 individuals comprised of healthy controls (n=8), patients with asymptomatic WM including IgM MGUS and smoldering WM (n=34) and patients with previously untreated symptomatic WM (n=11), relapsed WM (n=21) and refractory WM (n=6). Additionally, exosomes were imaged using electron microscopy with immunogold labeling for the detection of the exosome-specific receptors CD63 and CD81. Results. Imaging with electron microscopy showed vesicles with a size ranging from 50 to 150 nm and expressing CD63 and CD81, thus validating our ultracentrifugation method for exosome isolation. Among the 33 microRNAs analyzed, 12 were significantly deregulated between WM patients and healthy controls (P<0.05), of which 6 were upregulated and 6 downregulated. When comparing patients with IgM MGUS and smoldering WM to patients with symptomatic WM, the expression level of 7 microRNAs differed significantly (P<0.05), including 2 microRNAs underexpressed and 5 microRNAs overexpressed in symptomatic patients. Among the microRNAs whose expression most significantly correlated with disease progression were let-7d, miR-93-5p, miR-103a-3p, miR-192-5p and miR-320b. Conclusion. The microRNA content of circulating exosomes differs at different stages of WM progression. This could potentially be used to further define prognostic markers of progression in patients with WM, specifically progression from asymptomatic WM to overt WM. The study of these deregulated microRNAs' effect on in vitro and in vivo WM models can help us gain insights on mechanisms of disease progression in WM. Disclosures Castillo: Janssen: Honoraria; Abbvie: Research Funding; Pharmacyclics: Honoraria; Biogen: Consultancy; Otsuka: Consultancy; Millennium: Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy. Roccaro:Takeda Pharmaceutical Company Limited: Honoraria. Hermine:Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Research Funding; Celgene: Research Funding. Ghobrial:Noxxon: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria.
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