European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma.
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ABSTRACT:
SUBMITTER: Bruno B
PROVIDER: S-EPMC8327729 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival, although an overall survival benefit was not observed in all trials. Moreover, follow up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens such as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant has not been extensively evaluated. In the case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that, in young and fit patients, may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets, and chimeric antigen receptor-T cells. Despite encouraging preliminary results, longer follow up and larger patient numbers are needed before the clinical use of these novel therapies can be widely recommended.
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Project description:The pace of innovation of multiple myeloma therapy in recent years is remarkable with the advent of monoclonal antibodies and the approval of novel agents with new mechanisms of action. Emerging therapies are on the horizon for clinical approval with significant implications in extending patient survival and advancing closer to the goal of a cure, especially in areas of immunotherapy such as chimeric antigen receptor T cells, bispecific T cell engager antibodies, antibody drug conjugates, newer generations of monoclonal antibodies, and small molecule inhibitor and modulators. This review provides an update of current myeloma therapeutics in active preclinical and early clinical development and discusses the mechanism of action of several classes of novel therapeutics.
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Project description:The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.
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Project description:ObjectivesAmong advanced multiple myeloma (MM) patients, B-cell maturation antigen (BCMA) specific targets like Belantamab Mafodotin (belamaf) and CAR T-cell therapies have been shown to improve clinical outcomes, but at significant costs. To compare the expected costs per quality-adjusted life years (QALYs) gained among a hypothetical cohort of triple refractory MM patients treated with one of three BCMA-directed therapies: (1) idecabtagene vicleucel (ide-cel), (2) ciltacabtagene autoleucel (cilta-cel), and (3) belamaf for up to 20 months.MethodsIn this cost-effectiveness analysis, we built a Monte Carlo Markov Chain microsimulation model using estimates and parameters from the evidence on MM treatment for 10 000 hypothetical patients between the ages for 40 and 80. We assigned expected years of life remaining and made varying assumptions about survival beyond 5 years.ResultsWe predicted total cost of treatment for CAR-T therapy to be six times greater than for belamaf, but the QALYs gained from treatment are 6 to 8 times greater. Ide-cel was weakly dominated by cilta-cel and our base-case incremental cost effectiveness ratio (ICER) comparing cilta-cel with belamaf was $109,497 per QALY gained, averaging $123,618 in probabilistic sensitivity analyses.ConclusionsThese findings hinge on the assumption of longer-term survival but suggest that the use of CAR-T therapy is approaching standard ICER thresholds.
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Project description:Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 - 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents - small molecules as well as therapeutic antibodies - that hold promise to further improve outcome in MM.
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Project description:The melphalan-prednisone regimen has been considered as standard therapy for patients with multiple myeloma (MM) for many years. Recently, high-dose chemotherapy with stem-cell support has extended progression-free survival and increased overall survival, and it is now considered conventional therapy in younger patients. However, most patients relapse and the salvage treatment is not very effective. New active drugs, including immunomodulatory agents, thalidomide (Thal) and lenalidomide, and the proteasome inhibitor bortezomib, have shown promising anti-myeloma activity. These novel treatments are aimed at overcoming resistance of tumour cells to conventional chemotherapy, acting both directly on myeloma cells and indirectly by blocking the interactions of myeloma cells with their local microenvironment and suppressing growth and survival signals induced by autocrine and paracrine loops in the bone marrow. Thal has been widely studied, mostly in combination regimens in patients with relapsed MM and, more recently, in front-line therapy, showing efficacy in terms of response rate and event-free survival. Bortezomib has been found to possess remarkable activity, especially in combination with other chemotherapeutic agents, in relapsed/refractory and newly diagnosed MM, as well as in patients presenting adverse prognostic factors. Lenalidomide, in combination with dexamethasone, is showing high overall response rates in relapsed and refractory MM and promising results also in first-line therapy. In this paper, the results of the most significant trials with Thal, bortezomib and lenalidomide are reported. Several ongoing clinical studies will hopefully allow the identification of the most active combinations capable of improving survival in patients with MM.
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Project description:Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.
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Project description:Although treatment outcomes of multiple myeloma patients have improved significantly during the last two decades, myeloma is still an incurable disease. There are newly emerging immunotherapies to treat multiple myeloma including monoclonal antibodies, antibody-drug conjugate, bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy. Impressive response rate and clinical efficacy in heavily pretreated myeloma patients led to the FDA approval of the first myeloma CAR-T therapy in March 2021. Among many different targets for myeloma CAR-T therapies, B Cell Maturation Antigen (BCMA) has been the most successful target so far, but other targets which can be used either for single-target or dual-target CAR-T's are actively being explored. Clinical efficacy and safety of current myeloma CAR-T therapies will be presented here. Potential mechanisms leading to resistance include clearance of CAR-T cells, antigenic escape, and immunosuppressive tumor microenvironment. Novel strategies to enhance myeloma CAR-T will also be described. In this article, we provide a comprehensive review of the current data and the future directions of myeloma CAR-T therapies.
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Project description:Treatment of relapsed and/or refractory multiple myeloma (RRMM) utilizing the novel therapeutic target of the B-cell maturation antigen (BCMA) has demonstrated incredible results, leading to regulatory approval of BCMA-targeted chimeric antigen receptor (CAR)-T cell therapies in RRMM. With now two approved BCMA-targeted CAR-T cell therapies, investigators globally are working to build off and improve upon BCMA-targeted therapies. We discuss long-term data from the pivotal study that led to CAR-T approval, a phase 3 trial supporting their use in earlier lines, and novel manufacturing platforms to decrease vein-to-vein time. We highlight five key abstracts from the 2023 ASCO Annual Meeting that showcase these exciting updates in BCMA-directed CAR-T cell therapies in RRMM.
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