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Drugs Oct 2023Talquetamab (talquetamab-tgvs; TALVEY), a humanized, bispecific G-protein coupled receptor family C group 5 member D (GPRC5D)-directed CD3 T-cell engager, is being... (Review)
Review
Talquetamab (talquetamab-tgvs; TALVEY), a humanized, bispecific G-protein coupled receptor family C group 5 member D (GPRC5D)-directed CD3 T-cell engager, is being developed by Janssen for the treatment of multiple myeloma (MM). In early August 2023, talquetamab was granted accelerated approval in the USA for the treatment of adults with relapsed or refractory MM (RRMM) and in late August 2023, talquetamab was granted conditional marketing authorisation in the EU for the treatment of adult patients with RRMM. This article summarizes the milestones in the development of talquetamab leading to this first approval for RRMM.
Topics: Adult; Humans; Antibodies, Bispecific; Multiple Myeloma
PubMed: 37792138
DOI: 10.1007/s40265-023-01945-x -
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 -
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 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Multiple Myeloma; Antineoplastic Agents
PubMed: 37646699
DOI: 10.1056/NEJMe2307370 -
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 -
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 -
Journal of Clinical Oncology : Official... Apr 2024Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years.
PURPOSE
Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years.
METHODS
To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data.
RESULTS
Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, loss, translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited.
CONCLUSION
Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.
Topics: Humans; Multiple Myeloma; Prognosis; Melphalan; Hematopoietic Stem Cell Transplantation; Genomics; Transplantation, Autologous; Retrospective Studies
PubMed: 38194610
DOI: 10.1200/JCO.23.01277 -
Home Healthcare NowMultiple myeloma (MM) is a cancer that arises from plasma cells in bone marrow. Approximately 35,730 Americans received a new diagnosis and MM will claim the lives of an... (Review)
Review
Multiple myeloma (MM) is a cancer that arises from plasma cells in bone marrow. Approximately 35,730 Americans received a new diagnosis and MM will claim the lives of an estimated 12,590 people in 2023. Complications of the disease process include anemia, leukopenia, thrombocytopenia, renal failure, severe pain, bone loss, and hypercalcemia. Patients with MM have a high risk for pathological fractures. For most forms of MM there are effective treatments that may result in long-term remission using multi-drug regimens. Although the medications approved in the United States to treat MM generally produce good outcomes, they have serious, and potentially life-threatening adverse effects. In addition, patients with specific genetic variations are at high risk for relapse. Communication with the oncology team and early intervention in the event of adverse effects of medications, complications of the disease process, or evidence of relapse are important to obtain the best possible outcome. Patients are easily overwhelmed with a three- to four-drug treatment regimen with some drugs given intravenously and/or subcutaneously at the clinic, and others taken orally at home on specific days of each 28-day cycle. Home care nursing is needed to assess for tolerance, adverse effects, and to address patient concerns. Medication management and teaching are very important in guiding patients to safely manage a schedule that changes daily. In addition, the high risk of pathological fractures and serious injury if the patient should fall supports the need for physical and occupational therapy fall prevention and safety education and exercise programs to help avert decline in functional status and combat cancer-related fatigue.
Topics: Humans; Multiple Myeloma; Antineoplastic Agents
PubMed: 38709580
DOI: 10.1097/NHH.0000000000001249 -
Nature Cancer Dec 2023Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody,...
Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.
Topics: Humans; Dexamethasone; Genomics; Immunotherapy; Lenalidomide; Multiple Myeloma; Tumor Microenvironment
PubMed: 37945755
DOI: 10.1038/s43018-023-00657-1