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Nature Medicine Sep 2023Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory...
Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3-4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3-4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359 .
Topics: Humans; Multiple Myeloma; B-Cell Maturation Antigen; Progression-Free Survival; Remission Induction
PubMed: 37582952
DOI: 10.1038/s41591-023-02528-9 -
Blood Jan 2024Multiple myeloma (MM) is primarily a disease of older patients. Until recently, geriatric aspects in the context of MM have been poorly investigated. Treatment outcomes... (Review)
Review
Multiple myeloma (MM) is primarily a disease of older patients. Until recently, geriatric aspects in the context of MM have been poorly investigated. Treatment outcomes for geriatric patients with MM are often compromised by comorbidities and an enhanced susceptibility to adverse events from therapy. Assessment of patient frailty has become more frequent and will be useful in the context of significant and continuous advances in therapy. The recent emergence of immunotherapy with CD38 monoclonal antibodies and upcoming immunooncology drugs, such as bispecific antibodies, will lead to additional therapeutic progress. The applicability of these new molecules to older and frail patients is a key clinical question. Here, we present 2 patient cases derived from clinical practice. We review current frailty scores and standards of care for older, newly diagnosed patients with MM, including frail subgroups, and discuss ways to tailor treatment, as well as treatment perspectives in this population.
Topics: Humans; Aged; Frailty; Frail Elderly; Multiple Myeloma; Geriatric Assessment; Treatment Outcome
PubMed: 36693134
DOI: 10.1182/blood.2022017635 -
Annual Review of Medicine Jan 2024Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable... (Review)
Review
Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable suite of new therapies developed over the last 25 years has enabled durable disease control in most patients. This article briefly introduces the clinical features of multiple myeloma and aspects of multiple myeloma biology that modern therapies exploit. Key current and emerging treatment modalities are then reviewed, including cereblon-modulating agents, proteasome inhibitors, monoclonal antibodies, other molecularly targeted therapies (selinexor, venetoclax), chimeric antigen receptor T cells, T cell-engaging bispecific antibodies, and antibody-drug conjugates. For each modality, mechanism of action and clinical considerations are discussed. These therapies are combined and sequenced in modern treatment pathways, discussed at the conclusion of the article, which have led to substantial improvements in outcomes for multiple myeloma patients in recent years.
Topics: Humans; Multiple Myeloma; Immunotherapy; Proteasome Inhibitors; Antibodies, Monoclonal; Biological Therapy
PubMed: 37729027
DOI: 10.1146/annurev-med-050522-033815 -
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 -
Nature Medicine Sep 2023B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T...
B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
Topics: Humans; Multiple Myeloma; Antigenic Drift and Shift; DNA Copy Number Variations; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Immunotherapy; Antibodies; Membrane Proteins
PubMed: 37653344
DOI: 10.1038/s41591-023-02491-5 -
Advances in Therapy Aug 2023The introduction of novel immunotherapies has transformed the treatment landscape in multiple myeloma (MM). The addition of these agents has significantly improved...
The introduction of novel immunotherapies has transformed the treatment landscape in multiple myeloma (MM). The addition of these agents has significantly improved patient outcomes; however, MM remains largely incurable, with heavily pretreated patients suffering from shorter survival times. To address this unmet need, the focus has shifted toward novel mode of action therapies, such as bispecific antibodies (BsAb), which simultaneously bind to immune effector cells and myeloma cells. Currently, there are several T cell-redirecting BsAb being developed that target BCMA, GPRC5D, and FcRH5. These BsAb show impressive clinical activity for the relapsed/refractory population targeted and will likely become an essential part of MM treatment protocols in the future. In this podcast, the authors summarize and highlight some of the T cell-redirecting BsAb currently in development for the treatment of relapsed/refractory MM with a focus on the data reported at the oral session for BsAb at the American Society of Hematology's 2022 meeting from clinical phase 1 and 2 studies. The six presentations reported the latest safety and efficacy data for the BsAb: talquetamab, elranatamab, teclistamab, forimtamig, and alnuctamab.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; T-Lymphocytes; Immunotherapy; Antineoplastic Agents
PubMed: 37328635
DOI: 10.1007/s12325-023-02551-9 -
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 -
Nature Communications Sep 2023Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of...
Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27 and CD27 T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations.
Topics: Adult; Humans; Animals; Mice; Multiple Myeloma; T-Lymphocytes; Programmed Cell Death 1 Receptor; Lenalidomide; Clone Cells
PubMed: 37730678
DOI: 10.1038/s41467-023-41562-6 -
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 -
Nature Medicine Sep 2023Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a...
Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.5% achieved VGPR or better and 38.7% achieved CR or stringent CR. Among exploratory endpoints, median duration of response, progression-free survival (PFS) and overall survival were 10.3, 8.8 and 34.2 months, respectively, and ide-cel expansion in blood and bone marrow correlated with clinical efficacy and postinfusion reduction of soluble BCMA. Patients with PFS ≥ 18 months had more naive and less exhausted T cells in apheresis material and improved functional T cell phenotype in the drug product compared with those with less durable responses. These results confirm ide-cel safety, tolerability and efficacy and describe T cell qualities that correlate with durable response. Clinicaltrials.gov identifier : NCT02658929 .
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Follow-Up Studies; Cytokine Release Syndrome
PubMed: 37592106
DOI: 10.1038/s41591-023-02496-0