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JAMA Feb 2022
Topics: Biopsy; Bone Marrow; Bortezomib; Dexamethasone; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Multiple Myeloma; United States
PubMed: 35103765
DOI: 10.1001/jama.2021.25306 -
Clinical and Translational Medicine Mar 2022Multiple myeloma (MM) is a clinically and biologically heterogeneous plasma-cell malignancy. Despite extensive research, disease heterogeneity and relapse remain a big...
BACKGROUND
Multiple myeloma (MM) is a clinically and biologically heterogeneous plasma-cell malignancy. Despite extensive research, disease heterogeneity and relapse remain a big challenge in MM therapeutics. We tried to dissect this disease and identify novel biomarkers for patient stratification and treatment outcome prediction by applying single-cell technology.
METHODS
We performed single-cell RNA sequencing (scRNA-seq) and variable-diversity-joining regions-targeted sequencing (scVDJ-seq) concurrently on bone marrow samples from a cohort of 18 patients with newly diagnosed MM (NDMM; n = 12) or refractory/relapsed MM (RRMM; n = 6). We analysed the malignant clonotypes using scVDJ-seq data and conducted data integration and cell-type annotation through the CCA algorithm based on gene expression profiling. Furthermore, we identified disease status-specific genes and modules by comparison of NDMM and RRMM datasets and explored the findings in a larger MM cohort from the MMRF CoMMpass study.
RESULTS
We found that all the myeloma cells in either diagnosed or relapsed samples were dominated by a major clone, with a few subclones in several samples (n = 5). Next, we investigated the universal transcriptional features of myeloma cells and identified eight meta-programs correlated with this disease, especially meta-programs 1 and 8 (M1 and M8), which were the most significant and related to cell cycle and stress response, respectively. Furthermore, we classified the malignant plasma cells into eight clusters and found that the cell numbers in clusters 2/6/7 were exclusively higher in relapsed samples. Besides, we identified several attractive candidates for biomarkers (e.g. SMAD1 and STMN1) associated with disease progression and relapse in our dataset and related to overall survival in the CoMMpass dataset.
CONCLUSIONS
Our data provide insights into the heterogeneity of MM as well as highlight the relevance of intra-tumour heterogeneity and discover novel biomarkers that might be a potent therapy.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Prognosis; RNA-Seq; Exome Sequencing
PubMed: 35297204
DOI: 10.1002/ctm2.757 -
Cells Jul 2022Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with... (Review)
Review
Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with associated osteolytic lesions is a hallmark of MM and develops in the majority of MM patients. Approximately half of patients with bone disease will experience skeletal-related events (SREs), such as spinal cord compression and pathologic fractures, which increase the risk of mortality by 20-40%. At the cellular level, bone disease results from a tumor-cell-driven imbalance between osteoclast bone resorption and osteoblast bone formation, thereby creating a favorable cellular environment for bone resorption. The use of osteoclast inhibitory therapies with bisphosphonates, such as zoledronic acid and the RANKL inhibitor denosumab, have been shown to delay and lower the risk of SREs, as well as the need for surgery or radiation therapy to treat severe bone complications. This review outlines our current understanding of the molecular underpinnings of bone disease, available therapeutic options, and highlights recent advances in the management of MM-related bone disease.
Topics: Biological Products; Bone Neoplasms; Bone Resorption; Diphosphonates; Humans; Multiple Myeloma
PubMed: 35954151
DOI: 10.3390/cells11152308 -
Future Oncology (London, England) Jan 2022Idecabtagene vicleucel (ide-cel), a novel chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), has recently gained approval by the... (Review)
Review
Idecabtagene vicleucel (ide-cel), a novel chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), has recently gained approval by the US FDA for relapsed and refractory multiple myeloma (RRMM) after multicenter trials have demonstrated unprecedented results in this difficult-to-treat subgroup of patients. As the first CAR T-cell product approved for myeloma, ide-cel is poised to become a practice-changing treatment option. This first-in-class therapeutic offers hope for more durable remissions, as well as better quality of life, following a single infusion in a group of patients that previously had little hope. This paper reviews the ide-cel product in terms of design, pharmacology, efficacy and toxicity as described in studies reported to date.
Topics: Antineoplastic Agents, Immunological; Drug Resistance, Neoplasm; Humans; Immunotherapy, Adoptive; Multiple Myeloma; Neoplasm Recurrence, Local; Progression-Free Survival; Receptors, Chimeric Antigen
PubMed: 34854741
DOI: 10.2217/fon-2021-1090 -
Haematologica Mar 2024Initial results of the phase I trial of talquetamab, a bispecific antibody targeting GPRC5D and CD3, were reported in December of 2022 for the treatment of relapsed or...
Initial results of the phase I trial of talquetamab, a bispecific antibody targeting GPRC5D and CD3, were reported in December of 2022 for the treatment of relapsed or refractory multiple myeloma in the fourth line or later setting. It demonstrated a similar efficacy profile and durability of response to teclistamab, the first bispecific antibody therapy to be approved in multiple myeloma. Additionally, it has less infections than teclistamab but demonstrates unique class-specific side effects including skin, oral, and nail-related adverse events. Despite this, it is still a highly efficacious and well-tolerated therapy that will add to the armamentarium of therapeutics against heavily pretreated multiple myeloma.
Topics: Humans; Multiple Myeloma; Neoplasms, Plasma Cell; Antibodies, Bispecific; Skin
PubMed: 37855056
DOI: 10.3324/haematol.2023.283931 -
Journal of the National Comprehensive... Dec 2020Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the...
Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.
Topics: Bone Marrow; Humans; Medical Oncology; Multiple Myeloma; Plasma Cells; Plasmacytoma
PubMed: 33285522
DOI: 10.6004/jnccn.2020.0057 -
Transplantation and Cellular Therapy Jan 2024Since 2021, 2 B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapies-idecabtagene vicleucel (ide-cel), and ciltacabtagene... (Review)
Review
Chimeric Antigen Receptor T Cell Therapy for Myeloma: Where Are We Now and What Is Needed to Move Chimeric Antigen Receptor T Cells Forward to Earlier Lines of Therapy? Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.
Since 2021, 2 B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapies-idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel)-have been approved by the US Food and Drug Administration (FDA) for treating relapsed or refractory multiple myeloma (RRMM) after 4 or more prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. The 2 products have shown unprecedented activity in RRMM, but relapses remain common, and access to and safety of CAR-T therapy in patients with rapidly progressing advanced disease are not ideal. Sequencing CAR-T therapy with other options, including the 2 recently approved BCMA-directed T cell-engaging bispecific antibodies teclistamab and elranatamab, has become increasingly challenging owing to data showing inferior outcomes from CAR-T therapy after prior BCMA-directed therapy. This has led to the consideration of CAR-T therapy earlier in the course of disease for myeloma, when T cells are potentially healthier and the myeloma is less aggressive. To address the question of earlier use of CAR-T therapy, several trials are either ongoing or planned, and results have recently been reported for 2 randomized trials of CAR-T therapy showing improved progression-free survival compared to standard of care therapy in second-line (CARTITUDE-4) or third-line therapy (KarMMA-3). With the anticipation of the FDA possibly expanding approval of CAR-T to earlier lines of myeloma therapy, the American Society for Transplantation and Cellular Therapy convened a group of experts to provide a comprehensive review of the studies that led to the approval of CAR-T therapy in late-line therapy for myeloma, discuss the recently reported and ongoing studies designed to move CAR-T therapy to earlier lines of therapy, and share insights and considerations for sequencing therapy and optimization of patient selection for BCMA-directed therapies in current practice.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Neoplasm Recurrence, Local; Neoplasms, Plasma Cell; Cell- and Tissue-Based Therapy; Antibodies, Bispecific
PubMed: 37913909
DOI: 10.1016/j.jtct.2023.10.022 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2021Patients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone,...
BACKGROUND
Patients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide is often used. However, many patients are refractory to or have toxicities from bortezomib and there is a need for bridging therapy. We have used a modified regimen incorporating the second-generation proteasome inhibitor carfilzomib (carfilzomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide [KD-PACE]) instead of bortezomib for relapsed/refractory multiple myeloma.
PATIENTS AND METHODS
This 2-center retrospective study included consecutive patients receiving KD-PACE for relapsed or refractory multiple myeloma, plasma cell leukemia, or extramedullary myeloma. The primary outcome was the feasibility of KD-PACE as a bridging therapy to a more definitive treatment option.
RESULTS
Fifty-two patients were included. The median age was 57 years, and 67% were male. Thirty-one patients were bridged with KD-PACE to autologous hematopoietic stem cell transplant (29%), allogenic hematopoietic stem cell transplant (27%), or a clinical trial (12%). Patients bridged to autologous hematopoietic stem cell transplant, allogenic hematopoietic stem cell transplant, or a clinical trial had a superior progression-free survival (8.3 months vs 2.3 months in the nonbridged group; P < .001) and overall survival (median, 16.7 months vs 4.3 months in the nonbridged group; P < .001). No unexpected toxicities occurred from the treatment regimen.
CONCLUSION
KD-PACE is a promising treatment option for select patients with advanced/aggressive forms of myeloma requiring rapid disease control before a more definitive salvage therapy such as auto/allotransplantation or a clinical trial.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Plasma Cell; Male; Middle Aged; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Recurrence; Salvage Therapy; Survival Analysis; Treatment Outcome
PubMed: 33985931
DOI: 10.1016/j.clml.2021.03.013 -
Blood Cancer Journal May 2022Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all... (Review)
Review
Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasm Staging; Paraproteinemias; Prognosis
PubMed: 35637223
DOI: 10.1038/s41408-022-00679-5 -
Surgical Pathology Clinics Jun 2023Genetic characterization of myeloma at diagnosis by interphase fluorescence in situ hybridization and next-generation sequencing (NGS) can assist with risk... (Review)
Review
Genetic characterization of myeloma at diagnosis by interphase fluorescence in situ hybridization and next-generation sequencing (NGS) can assist with risk stratification and treatment planning. Measurable residual disease (MRD) status after treatment, as evaluated by next-generation flow cytometry or NGS on bone marrow aspirate material, is one of the most important predictors of prognosis. Less-invasive tools for MRD assessment such as liquid biopsy approaches have also recently emerged as potential alternatives.
Topics: Humans; Multiple Myeloma; Pathology, Molecular; In Situ Hybridization, Fluorescence; Plasmacytoma; Prognosis; Neoplasm, Residual; High-Throughput Nucleotide Sequencing; Flow Cytometry
PubMed: 37149365
DOI: 10.1016/j.path.2023.01.005