ABSTRACT
Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.
ABSTRACT
STUDY QUESTION: What is the influence of age and chemotherapy regimen on the longitudinal blood anti-Müllerian hormone (AMH) variations in a large series of adolescents and young adult (AYA) (15-24 years old) and non-AYA (25-35 years old) lymphoma patients? SUMMARY ANSWER: In case of alkylating regimen treatment, there was a deep and sustained follicular depletion in AYA as well as non-AYA patients; however in both groups, the ovarian toxicity was extremely low in cases of non-alkylating treatments. WHAT IS KNOWN ALREADY: AMH is now well-recognised to be a real-time indicator of ovarian follicular depletion and recovery in women treated by chemotherapy. Its longitudinal variations may discriminate between highly and minimally toxic protocols regarding ovarian function. It has been shown, in different cancer types, that age, type of chemotherapy regimen and pre-treatment AMH levels are the main predictors of ovarian recovery. Large studies on longitudinal AMH variations under chemotherapy in lymphoma patients are few but can provide the opportunity to assess the degree of follicle loss at a young age. STUDY DESIGN, SIZE, DURATION: This prospective cohort study was conducted in the Fertility Observatory of the Lille University Hospital. Data were collected between 2007 and 2016. Non-Hodgkin or Hodgkin lymphoma patients (n = 122) between 15 and 35 years old were prospectively recruited before commencing chemotherapy. Patients were treated either by a non-alkylating protocol (ABVD group; n = 67) or by an alkylating regimen (alkylating group; n = 55). PARTICIPANTS/MATERIALS, SETTING, METHODS: Serial AMH measurements were performed at baseline (AMH0), 15 days after the start of chemotherapy (AMH1), 15 days before the last chemotherapy cycle (AMH2), and at time 3, 6, 9, 12, 18 and 24 months from the end of chemotherapy. The whole study population was divided into two groups according to age: AYA (15-24; n = 65) and non-AYA (25-35; n = 57). All patients received a once monthly GnRH agonist injection during the whole treatment period. A linear mixed model was used to account for the repeated measures of single patients. MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, non-AYA patients had higher BMI and lower AMH levels than AYA patients. All AYA and non-AYA patients having received ABVD protocols had regular cycles at 12 months of follow-up. In case of alkylating regimens, amenorrhoea was more frequent in non-AYA patients than in AYA patients at 12 months (37% vs 4%, P = 0.011) and at 24 months (24% vs 4%, P = 0.045). We distinguished a similar depletion phase from AMH0 to AMH2 between ABVD and alkylating groups but significantly different recovery phases from AMH2 to AMH + 24 months. AMH recovery was fast and complete in case of ABVD protocols whatever the age: AMH reached pre-treatment values as soon as the 6th month of follow-up in the AYA group (mean (95% CI) in log AMH M0 vs M6: 3.07 (2.86 to 3.27) vs 3.05 (2.78 to 3.31), P = 1.00) and in the non-AYA group (mean (95% CI) in log AMH M0 vs M6: 2.73 (2.40 to 3.05) vs 2.47 (2.21 to 2.74), P = 1.00). In contrast, no patients from the alkylating group returned to pre-treatment AMH values whatever the age of patients (AYA or non-AYA). Moreover, none of the AMH values post-chemotherapy in the non-AYA group were significantly different from AMH2. Conversely in the AYA group, AMH levels from 6 months (mean (95% CI) in log AMH: 1.79 (1.47 to 2.11), P < 0.001) to 24 months (mean (95% CI) in log AMH: 2.16 (1.80 to 2.52), P ≤ 0.001) were significantly higher than AMH2 (mean (95% CI) in log AMH: 1.13 (0.89 to 1.38)). Considering the whole study population (AYA and non-AYA), pre-treatment AMH levels influenced the pattern of the AMH variation both in alkylating and ABVD protocols (interaction P-value = 0.005 and 0.043, respectively). Likewise, age was significantly associated with the pattern of the recovery phase but only in the alkylating group (interaction P-value =0.001). BMI had no influence on the AMH recovery phase whatever the protocol (interaction P-value = 0.98 in alkylating group, 0.72 in ABVD group). LIMITATIONS, REASONS FOR CAUTION: There was a large disparity in subtypes of protocols in the alkylating group. The average duration of chemotherapy for patients treated with alkylating protocols was longer than that for patients treated with ABVD. WIDER IMPLICATIONS OF THE FINDINGS: These results make it possible to develop strategies for fertility preservation according to age and type of protocol in a large series of young lymphoma patients. In addition, it was confirmed that young age does not protect against ovarian damage caused by alkylating agents. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Agence Régionale de Santé Hauts de France and Agence Onco Hauts-de-France who provided finances for AMH dosages (n° DOS/SDES/AR/FIR/2019/282). There are no competing interests. TRIAL REGISTRATION NUMBER: DC-2008-642 and CNIL DEC2015-112.
Subject(s)
Fertility Preservation , Hodgkin Disease , Adolescent , Adult , Anti-Mullerian Hormone , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/therapeutic use , Counseling , Dacarbazine/therapeutic use , Doxorubicin/therapeutic use , Female , Hodgkin Disease/drug therapy , Humans , Longitudinal Studies , Prospective Studies , Vinblastine/therapeutic use , Young AdultABSTRACT
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.
Subject(s)
Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , Exome Sequencing/methods , Multiple Myeloma/genetics , Neoplastic Cells, Circulating , Adult , Aged , Aged, 80 and over , Bone Marrow/pathology , DNA Copy Number Variations/genetics , Disease Progression , Female , Humans , Liquid Biopsy/methods , Male , Middle Aged , Multiple Myeloma/pathology , Mutation/genetics , Precision Medicine/methodsABSTRACT
Multiple myeloma (MM) is a plasma cell tumor marked by clonal evolution and preceded by a premalignant stage, which progresses via molecular pathway deregulation, including MYC activation. This activation relates to translocation or gain of the MYC locus and deregulation of upstream pathways such as IRF4, DIS3/LIN28B/let-7, or MAPK. Precision medicine is an approach to predict more accurately which treatment strategies for a particular disease will work in which groups of patients, in contrast to a "one-size-fits-all" approach. The knowledge of mechanisms responsible for MYC deregulation in MM enables identification of vulnerabilities and therapeutic targets in MYC-driven tumors. MYC can be targeted directly or indirectly, by interacting with several of its functions in cancer. Several such therapeutic strategies are evaluated in clinical trials in MM. In this review, we describe the mechanism of MYC activation in MM, the role of MYC in cancer progression, and the therapeutic options to targeting MYC.
Subject(s)
Multiple Myeloma/drug therapy , Proto-Oncogene Proteins c-myc/physiology , Apoptosis , DNA Replication , Humans , Immunologic Factors/therapeutic use , Interferon Regulatory Factors/physiology , Multiple Myeloma/etiology , Protein Biosynthesis/drug effects , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Proto-Oncogene Proteins c-myc/genetics , ras Proteins/physiologyABSTRACT
The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.
Subject(s)
Bone Marrow/metabolism , Extracellular Matrix/metabolism , Multiple Myeloma/metabolism , Proteome , Annexin A2/metabolism , Case-Control Studies , Galectin 1/metabolism , Gene Expression Profiling , Humans , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Survival Analysis , Tumor MicroenvironmentABSTRACT
MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC-dependent cancers as well.
Subject(s)
Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Multiple Myeloma/genetics , RNA Interference , RNA-Binding Proteins/genetics , Animals , Case-Control Studies , Cell Cycle/genetics , Cell Line, Tumor , Cluster Analysis , Disease Models, Animal , Gene Expression Profiling , Genes, myc , Heterografts , Humans , Mice , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Prognosis , RNA-Binding Proteins/metabolismABSTRACT
Current trajectory of clinical care is heading in the direction of personalized medicine. In an ideal scenario, clinicians can obtain extensive diagnostic and prognostic information via minimally-invasive assays. Information available in the peripheral blood has the potential to bring us closer to this goal. In this review we highlight the contributions of circulating tumor cells and circulating tumor DNA and RNA (ctDNA/ctRNA) towards cancer therapeutic field. We discuss clinical relevance, summarize available and upcoming technologies, and hypothesize how future care could be impacted by a combined study.
Subject(s)
Biomarkers, Tumor/blood , Circulating Tumor DNA/blood , Neoplasms/blood , Neoplastic Cells, Circulating/metabolism , DNA, Neoplasm/genetics , Humans , Mutation , Neoplasms/genetics , Precision MedicineABSTRACT
The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.
Subject(s)
Multiple Myeloma/pathology , Neovascularization, Pathologic/drug therapy , Animals , Antibodies/therapeutic use , Bone Marrow , Cell Movement , Clone Cells/pathology , Disease Progression , Endothelial Cells/pathology , Mice , Multiple Myeloma/blood supply , Multiple Myeloma/drug therapy , Neovascularization, Pathologic/prevention & control , Secondary Prevention , Vascular Endothelial Growth Factor Receptor-2/immunologyABSTRACT
Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Indeed, the BM niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM niche is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a noncellular compartment including the extracellular matrix (ECM) and the liquid milieu (cytokines, growth factors, and chemokines). In this paper we discuss how the interaction between the malignant plasma cell and the BM microenvironment allowed myeloma progression through cell homing and the new concept of premetastatic niche.
Subject(s)
Bone Marrow/immunology , Cytokines/immunology , Models, Immunological , Multiple Myeloma/immunology , Animals , HumansSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Mobilization , Multiple Myeloma/drug therapy , Stem Cells/drug effects , Boronic Acids/administration & dosage , Bortezomib , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Follow-Up Studies , Humans , Middle Aged , Peripheral Blood Stem Cell Transplantation , Prognosis , Pyrazines/administration & dosage , Remission Induction , Retrospective Studies , Thalidomide/administration & dosage , Vincristine/administration & dosageABSTRACT
Two cases of apparent unilateral renal obstruction in which lesser contralateral obstructions were not seen are presented. In both cases, relief of the more severe obstruction resulted in an unmasking of the milder contralateral lesion.
Subject(s)
Organometallic Compounds , Pentetic Acid , Ureteral Obstruction/diagnostic imaging , Adult , Cystitis/complications , Furosemide , Humans , Male , Radionuclide Imaging , Technetium Tc 99m Pentetate , Ureteral Obstruction/congenital , Ureteral Obstruction/etiologyABSTRACT
The mechanisms of prolonged renal cortical tracer retention in Tc-99m DTPA scintigraphy are discussed and a variety of examples are presented.
Subject(s)
Kidney Cortex/diagnostic imaging , Kidney Diseases/diagnostic imaging , Organometallic Compounds , Pentetic Acid , Technetium , Adolescent , Adult , Diagnosis, Differential , Humans , Kidney Cortex/metabolism , Kidney Diseases/physiopathology , Male , Middle Aged , Organometallic Compounds/metabolism , Pentetic Acid/metabolism , Radionuclide Imaging , Renal Circulation , Technetium/metabolism , Technetium Tc 99m Pentetate , Time Factors , Tomography, X-Ray ComputedABSTRACT
A renopleural fistula was detected on a Tc-99m DTPA renal study during evaluation for possible post-traumatic urinoma.
Subject(s)
Fistula/diagnostic imaging , Kidney Diseases/diagnostic imaging , Pleural Diseases/diagnostic imaging , Urinary Fistula/diagnostic imaging , Wounds and Injuries/complications , Adult , Fistula/etiology , Humans , Kidney Diseases/etiology , Male , Pleural Diseases/etiology , Radionuclide Imaging , Urinary Fistula/etiologyABSTRACT
A diffuse pattern of homogeneous tracer uptake is seen by I-131 scintigraphy in a patient with widespread miliary lung metastases due to papillary thyroid carcinoma. This case report emphasizes the need to include metastatic thyroid carcinoma in the differential diagnosis of miliary lung nodules.