scholarly journals Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Stephan M. Tirier ◽  
Jan-Philipp Mallm ◽  
Simon Steiger ◽  
Alexandra M. Poos ◽  
Mohamed H. S. Awwad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Clinical Decision Making ◽  
Clonal Evolution ◽  
Γδ T Cells ◽  
Interaction Network ◽  
Clinical Decision ◽  
Refractory Multiple Myeloma ◽  
Chromosome 1Q

AbstractVirtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.

scholarly journals Single-Cell Transcriptomes Combining with Consecutive Genomics Reveal Clonal Evolution and Gene Regulatory Networks in Relapsed and Refractory Multiple Myeloma

2022 ◽  
Vol 9 ◽  
Author(s):  
Jiadai Xu ◽  
Yue Wang ◽  
Zheng Wei ◽  
Jingli Zhuang ◽  
Jing Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Cell ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Clonal Evolution ◽  
Previous Treatment ◽  
Extramedullary Plasmacytoma ◽  
Single Nucleotide Variants ◽  
Refractory Multiple Myeloma ◽  
Gene Regulatory

This study attempted to investigate how clonal structure evolves, along with potential regulatory networks, as a result of multiline therapies in relapsed/refractory multiple myeloma (RRMM). Eight whole exome sequencing (WES) and one single cell RNA sequencing (scRNA-seq) were performed in order to assess dynamic genomic changes in temporal consecutive samples of one RRMM patient from the time of diagnosis to death (about 37 months). The 63-year-old female patient who suffered from MM (P1) had disease progression (PD) nine times from July 2017 [newly diagnosed (ND)] to Aug 2020 (death), and the force to drive branching-pattern evolution of malignant PCs was found to be sustained. The mutant-allele tumor heterogeneity (MATH) and tumor mutation burden (TMB) initially exhibited a downward trend, which was then upward throughout the course of the disease. Various somatic single nucleotide variants (SNVs) that had disappeared after the previous treatment were observed to reappear in later stages. Chromosomal instability (CIN) and homologous recombination deficiency (HRD) scores were observed to be increased during periods of all progression, especially in the period of extramedullary plasmacytoma. Finally, in combination with WES and scRNA-seq of P1-PD9 (the nineth PD), the intro-heterogeneity and gene regulatory networks of MM cells were deciphered. As verified by the overall survival of MM patients in the MMRF CoMMpass and GSE24080 datasets, RUNX3 was identified as a potential driver for RRMM.

scholarly journals Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1969
Author(s):  
Aline Rangel-Pozzo ◽  
Pak Yu ◽  
Sadhana LaL ◽  
Yasmin Asbaghi ◽  
Luiza Sisdelli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Genomic Instability ◽  
Clinical Decision Making ◽  
Three Dimensional ◽  
Clinical Decision ◽  
Response To Treatment ◽  
Average Intensity ◽  
Patient Response ◽  
Smoldering Multiple Myeloma

The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

P-060: Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single cell transcriptomics

2021 ◽  
Vol 21 ◽  
pp. S71-S72
Author(s):  
Karsten Rippe ◽  
Stephan Tirier ◽  
Jan-Philipp Mallm ◽  
Simon Steiger ◽  
Alexandra Poos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Cell ◽  
Drug Response ◽  
Refractory Multiple Myeloma

scholarly journals Jumping Translocations of Chromosome 1q in Multiple Myeloma: Evidence for a Mechanism Involving Decondensation of Pericentromeric Heterochromatin

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1732-1741 ◽  
Author(s):  
Jeffrey R. Sawyer ◽  
Guido Tricot ◽  
Sandy Mattox ◽  
Sundar Jagannath ◽  
Bart Barlogie
Keyword(s):  
Multiple Myeloma ◽  
Clonal Evolution ◽  
Chromosome 1 ◽  
Pericentromeric Heterochromatin ◽  
Chromosome 1Q ◽  
Numerical Aberrations ◽  
Cytogenetic Evidence ◽  
Acrocentric Chromosomes ◽  
Cytogenetic Evolution ◽  
Proliferative Advantage

Abstract Karyotypes in multiple myeloma (MM) are complex and exhibit numerous structural and numerical aberrations. The largest subset of structural chromosome anomalies in clinical specimens and cell lines involves aberrations of chromosome 1. Unbalanced translocations and duplications involving all or part of the whole long arm of chromosome 1 presumably occur as secondary aberrations and are associated with tumor progression and advanced disease. Unfortunately, cytogenetic evidence is scarce as to how these unstable whole-arm rearrangements may take place. We report nonrandom, unbalanced whole-arm translocations of 1q in the cytogenetic evolution of patients with aggressive MM. Whole-arm or “jumping translocations” of 1q were found in 36 of 158 successive patients with abnormal karyotypes. Recurring whole-arm translocations of 1q involved chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delineated breakpoint present in three patients involved a whole-arm translocation of 1q to band 5q15. Three recurrent translocations of 1q10 to the short arms of different acrocentric chromosomes have also been identified, including three patients with der(15)t(1;15)(q10;p10) and two patients each with der(21)t(1;21)(q10;p13) and der(22)t(1;22) (q10;p10). Whole-arm translocations of 1q10 to telomeric regions of nonacrocentric chromosomes included der(12)t(1;12) (q10;q24.3) and der(19)t(1;19)(q10;q13.4) in three and two patients, respectively. Recurrent whole-arm translocations of 1q to centromeric regions included der(16)t(1;16)(q10;q10) and der(19)t(1;19)(q10;p10). The mechanisms involved in the 1q instability in MM may be associated with highly decondensed pericentromeric heterochromatin, which may permit recombination and formation of unstable translocations of chromosome 1q. The clonal evolution of cells with extra copies of 1q suggests that this aberration directly or indirectly provides a proliferative advantage.

scholarly journals Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma

2020 ◽  
Vol 4 (14) ◽  
pp. 3295-3301
Author(s):  
Joaquin Martinez-Lopez ◽  
Sandy W. Wong ◽  
Nina Shah ◽  
Natasha Bahri ◽  
Kaili Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Clinical Care ◽  
Progression Free Survival ◽  
Clinical Decision ◽  
Routine Practice ◽  
Clinical Value ◽  
The Impact ◽  
Measurable Residual Disease

Abstract Few clinical studies have reported results of measurable residual disease (MRD) assessments performed as part of routine practice. Herein we present our single-institution experience assessing MRD in 234 multiple myeloma (MM) patients (newly diagnosed [NDMM = 159] and relapsed [RRMM = 75]). We describe the impact of depth, duration, and direction of response on prognosis. MRD assessments were performed by next-generation sequencing of immunoglobulin genes with a sensitivity of 10−6. Those achieving MRD negativity at 10−6, as well as 10−5, had superior median progression-free survival (PFS). In the NDMM cohort, 40% of the patients achieved MRD negativity at 10−6 and 59% at 10−5. Median PFS in the NDMM cohort was superior in those achieving MRD at 10−5 vs <10−5 (PFS: 87 months vs 32 months; P < .001). In the RRMM cohort, 36% achieved MRD negativity at 10−6 and 47% at 10−5. Median PFS was superior for the RRMM achieving MRD at 10−5 vs <10−5 (PFS: 42 months vs 17 months; P < .01). Serial MRD monitoring identified 3 categories of NDMM patients: (A) patients with ≥3 MRD 10−6 negative samples, (B) patients with detectable but continuously declining clonal numbers, and (C) patients with stable or increasing clonal number (≥1 log). PFS was superior in groups A and B vs C (median PFS not reached [NR], NR, 55 respectively; P < .001). This retrospective evaluation of MRD used as part of clinical care validates MRD as an important prognostic marker in NDMM and RRMM and supports its use as an endpoint in future clinical trials as well as for clinical decision making.

scholarly journals Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single cell transcriptomics in real-world pancreatic cancer biopsies

2020 ◽  
Author(s):  
Jaewon Lee ◽  
Vincent Bernard ◽  
Alexander Semaan ◽  
Maria Monberg ◽  
Jonathan Huang ◽  
...  
Keyword(s):  
Single Cell ◽  
Clinical Decision Making ◽  
De Novo ◽  
Ex Vivo ◽  
Clinical Decision ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblast ◽  
Parental Tumor

Abstract Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. However, the long-term fidelity of recently deployed ex vivo preclinical platforms, such as patient-derived organoids (PDOs), remains unknown. Through single-cell RNA sequencing (scRNA-seq), we identify substantial transcriptomic evolution of PDOs propagated from the parental tumor, which may alter predicted drug sensitivity. In contrast, scRNA-seq is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast (CAF) subclasses, and predict a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. While PDOs continue to enable prospective therapeutic prediction, our analysis also demonstrates the complementarity of using orthogonal de novo biopsies from PDAC patients paired with scRNA-seq to inform clinical decision-making.

scholarly journals Single-cell ATAC and RNA sequencing reveal pre-existing and persistent subpopulations of cells associated with relapse of prostate cancer

2021 ◽  
Author(s):  
S Taavitsainen ◽  
N Engedal ◽  
S Cao ◽  
F Handle ◽  
S Prekovic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Cell ◽  
Treatment Response ◽  
Rna Sequencing ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Early Treatment Response ◽  
Clinical Models ◽  
Cell Subpopulations ◽  
Accessible Chromatin

AbstractProstate cancer is profoundly heterogeneous and patients would benefit from methods that stratify clinically indolent from more aggressive forms of the disease. We employed single-cell assay for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identified pre-existing and treatment-persistent cell subpopulations that possess transcriptional stem-like features and regenerative potential when subjected to treatment. We found distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent stem-like cells were able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal hitherto unrecognized molecular predictors of treatment response. This suggests that high analytical resolution of pre-clinical models may powerfully inform clinical decision-making.

scholarly journals The Agony of Choice—Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4701
Author(s):  
Irene Strassl ◽  
Martin Schreder ◽  
Normann Steiner ◽  
Jakob Rudzki ◽  
Hermine Agis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Decision Making ◽  
Nk Cell ◽  
Clinical Stage ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Clinical Trial Data ◽  
Clinical Decision ◽  
Preclinical Development ◽  
Comprehensive Overview

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody–drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.

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