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The Lancet. Oncology Jul 2023Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the... (Review)
Review
Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the basis of data published until Dec 31, 2022. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs) measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed. The IMWG criteria for the definition of renal response should be used. Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment. Mechanical approaches do not increase overall survival. Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment.
Topics: Humans; Multiple Myeloma; Dexamethasone; Antineoplastic Agents; Renal Insufficiency; Antineoplastic Combined Chemotherapy Protocols; Bortezomib
PubMed: 37414019
DOI: 10.1016/S1470-2045(23)00223-1 -
Expert Review of Anticancer Therapy 2023Multiple myeloma is a B-cell malignancy caused by proliferating plasma cells in the bone marrow microenvironment in collaboration with various cell lineage subsets and... (Review)
Review
INTRODUCTION
Multiple myeloma is a B-cell malignancy caused by proliferating plasma cells in the bone marrow microenvironment in collaboration with various cell lineage subsets and growth factors without any perfect regulation and tendency to clonal heterogeneity. Despite remarkable improvement in MM treatment and the overall survival of patients, multiple myeloma remains an incurable disease with the tendency to relapse. Therefore, there is an urgent need for new therapeutic options to provide a stabilized response to treatment with long-term duration.
AREAS COVERED
Elranatamab (PF-06863135), is a novel heterodimeric humanized full-length bispecific IgG2 kappa antibody derived from 2 mAbs, the anti-BCMA mAb (PF-06863058) and the anti-CD3 mAb (PF-06863059), not yet licensed in routine use. This binding affinity of elranatamab to BCMA and CD3 has been optimized to potentially prompt more potent T cell-mediated anti-myeloma activity. Subcutaneous (s.c.) administration of elranatamab is superior in comparison to intravenous (i.v.), thus it is associated with lower incidence of adverse events, even in higher doses.
EXPERT OPINION
Currently, elranatamab is being investigated in a few clinical studies, and the preliminary results are very encouraging. At the time of writing this review there were no full papers published and all of the data in the literature were based on abstract presentations which carry limitations.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; T-Lymphocytes; Antibodies, Monoclonal; Immunotherapy; Tumor Microenvironment
PubMed: 37434334
DOI: 10.1080/14737140.2023.2236303 -
Journal of the National Comprehensive... Dec 2023The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome...
The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Medical Oncology; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 38081133
DOI: 10.6004/jnccn.2023.0061 -
Blood Nov 2023Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this...
Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.
Topics: Humans; Multiple Myeloma; Multiomics; Mutation; Transcriptome; Tumor Microenvironment
PubMed: 37390336
DOI: 10.1182/blood.2023019758 -
Blood Nov 2023Multiple myeloma remains an incurable disease plagued by high relapse rates. Deeper and more sustainable responses, however, have been consistently shown to improve... (Review)
Review
Multiple myeloma remains an incurable disease plagued by high relapse rates. Deeper and more sustainable responses, however, have been consistently shown to improve outcomes and could eventually pave the way to achieving a cure. Our understanding of disease response has surpassed complete response (CR), because the current definitions are suboptimal, and the treatment goal should aim even beyond stringent CR, toward molecular and flow CR, that is, measurable residual disease (MRD) negativity. It has been more than 20 years since the discrepancy in the outcome between patients in CR with and without MRD has been demonstrated, and the field has come a long way from multiparameter flow cytometry to next-generation flow and next-generation sequencing, able to detect up to a limit of detection of a single myeloma cell from 1 million healthy counterparts. This review aims to summarize the current available data regarding MRD but also its potential future use as a coprimary outcome both in clinical and trial settings as a survival surrogate as well as its use to evaluate treatment efficacy and for adaptive response-based and early-rescue therapy. Furthermore, we discuss whether these concepts are applicable in different settings (eg, newly diagnosed and relapsed/refractory myeloma, patients who are eligible and ineligible for tansplant, and standard- and high-risk disease).
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Treatment Outcome; Neoplasm, Residual; Flow Cytometry
PubMed: 37471603
DOI: 10.1182/blood.2023020284 -
Blood Jul 2023Immunomodulatory agents (IMiDs) are a cornerstone of treatment for patients with multiple myeloma. IMiDs are used in therapeutic combinations at all stages of disease... (Review)
Review
Immunomodulatory agents (IMiDs) are a cornerstone of treatment for patients with multiple myeloma. IMiDs are used in therapeutic combinations at all stages of disease and are approved as a single-agent maintenance treatment after autologous stem cell transplantation. However, patients become resistant to ongoing therapy over time and inevitably relapse. It is only in the last decade that the mechanism of IMiD action has been elucidated; through binding to the cereblon component of the CRL4CRBN E3 ubiquitin ligase, a set of neosubstrates is designated for degradation by the proteasome. In myeloma cells, this includes the zinc-finger B-cell transcription factors Ikaros and Aiolos, which, in turn, lead to decreased levels of IRF4 and c-MYC and cell death. As our knowledge of IMiD mechanism of action has advanced, the ability to study resistance mechanisms has also developed. This review explores the existing work on IMiD resistance and proposes areas of future research that may advance our understanding and management of this common clinical condition.
Topics: Humans; Multiple Myeloma; Immunomodulating Agents; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Neoplasm Recurrence, Local; Biology; Ubiquitin-Protein Ligases
PubMed: 36929172
DOI: 10.1182/blood.2023019637 -
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 -
Small (Weinheim An Der Bergstrasse,... Oct 2023Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play...
Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.
Topics: Animals; Mice; Bortezomib; Multiple Myeloma; Extracellular Vesicles; Mesenchymal Stem Cells; Cell Communication
PubMed: 37282762
DOI: 10.1002/smll.202301748 -
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 -
Leukemia & Lymphoma 2023Smoldering multiple myeloma (SMM) is an asymptomatic condition with heterogeneous biology and various risks of progression to symptomatic disease. The best-known risk... (Review)
Review
Smoldering multiple myeloma (SMM) is an asymptomatic condition with heterogeneous biology and various risks of progression to symptomatic disease. The best-known risk stratification models are Mayo-2018, and IWWG based on tumor burden. Recently, the personalized risk assessment tool PANGEA was introduced. New markers of SMM progression, including genomic and immune characteristics of plasma cells (PCs) and tumor microenvironment, are under investigation, and some have been incorporated into traditional scoring systems. Only one phase 3 clinical trial demonstrated an overall survival benefit of lenalidomide for high-risk SMM patients. The study has limitations, and most guidelines recommend observation or participation in clinical trials for high-risk SMM. High-intensity time-limited treatment strategies for high-risk SMM demonstrated deep responses in single-arm studies. But these treatments can cause adverse effects in asymptomatic patients.This review aims to understand better the risk of SMM progression from a clinical and biological point of view.
Topics: Humans; Smoldering Multiple Myeloma; Multiple Myeloma; Risk Factors; Lenalidomide; Risk Assessment; Disease Progression; Tumor Microenvironment
PubMed: 37229535
DOI: 10.1080/10428194.2023.2216818