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Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies., Competing Interests: Declaration of interests PR-O reports personal fees derived from consulting or advisory board roles from Celgene-BMS, Janssen, Roche, AbbVie, Pfizer, GSK, Sanofi, and H3Biomedicine; steering committee membership from Celgene-BMS, Regeneron, and Janssen; speaker's bureau fess from Janssen, Celgene-BMS, GSK, Sanofi, and AbbVie; and a travel grant from Pfizer. SU reports grants and personal fees from AbbVie, Amgen, BMS, EdoPharma, Genentech, Gilead, GSK, Merck, Sanofi, and Seagen; speakers’ bureau fees, consulting and advisory board participation, and steering committee membership from Janssen; participation on advisory boards from Karyopharm Therapeutics, Oncopeptides, Secura Bio, SkylineDx, and Takeda; and grants from Moderna, TeneoBio, and Pharmacyclics, outside the submitted work. ADC reports personal fees and participation on advisory boards from GSK; personal fees from Bristol Myers Squibb, Janssen, AbbVie, Pfizer, iTeos, Ichnos, Arcellx, and Legend; personal fees and participation on advisory boards from Genentech/Roche; participation on advisory boards from Novartis, outside the submitted work; and has a patent licensed for Novartis. NWCJvdD reports personal fees from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, Bristol Myers Squibb/Celgene, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier, outside the submitted work. JGP-L reports personal fees from Janssen and GSK, outside the submitted work. MVM reports personal fees from Janssen, Celgene/Bristol Myers Squibb, Novartis, GSK, Sanofi, Amgen, Pfizer, AbbVie, and Regeneron, outside the submitted work. HE reports personal fees and research support from Bristol Myers Squibb/Celgene, Janssen, Sanofi, and GSK; and personal fees from Amgen, Takeda, and Novartis; outside the submitted work. MM reports personal fees from Janssen, Bristol Myers Squibb, WebMD global, GSK, and CDR-Life; and research funding from Siemens and BeiGene; outside the submitted work. BAD reports advisory board participation and consulting fees from COTA and Janssen; personal fees from Multiple Myeloma Research Foundation; honoraria for CME-related activities from Plexus Communications; research funding from Amgen and GSK; and involvement as an independent reviewer of a clinical trial for BMS; outside the submitted work. NP reports research funding and accomodation expenses from Amgen, Bristol Myers Squibb, Janssen, Takeda, and The Binding Site; research funding from Sanofi, and personal fees from Pfizer, outside the submitted work. PJH reports personal fees from Antengene, Gilead, iTeos Therapeutics, Janssen, Novartis, and Pfizer, outside the submitted work. W-JC reports personal fees from AbbVie, Amgen, Pfizer, Sanofi, Regeneron, GSK, and Novartis; and grants and personal fees from Bristol Myers Squibb, Janssen, and Novartis, outside the submitted work. GG reports personal fees from and is a shareholder of XNK Therapeutics Sweden, and personal fees from Fujimoto Pharmaceutical corporation, outside the submitted work. FS reports personal fees from AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, BMS, Novartis, SkyliteDX, Pfizer, and Daiki-Sankyo, outside the submitted work. JCY reports personal fees from Janssen, Sanofi, BMS, Regeneron, GSK, Pfizer, Menarini, outside the submitted work. EZ reports personal fees from Janssen, Bristol Myers Squibb, Amgen, and Takeda, outside the submitted work. RP reports personal fees and travel support from GSK and Janssen; and personal fees from Pfizer, AbbVie, Bristol Myers Squibb, and Sanofi, outside the submitted work. CN reports personal fees and participation on advisory boards from Janssen; personal fees from Bristol Myers Squibb, Sanofi, GSK, Pfizer, AstraZeneca, and DKSH; and personal fees and participation on advisory boards from Amgen, outside the submitted work. YL reports grants and personal fees from Janssen; personal fees from Sanofi, NexImmune, Caribou, Bristol Myers Squibb, Regeneron, and Genentech; and personal fees and participation on data safety monitoring boards from Pfizer, outside the submitted work. AC reports personal fees from AbbVie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genetech/Roche, GSK, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme, outside the submitted work. JM reports personal fees from Amgen, Sanofi, Bristol Myers Squibb, Janssen, and Takeda, outside the submitted work. MC reports personal fees from Janssen, Celgene/Bristol Myers Squibb, GSK, Sanofi, Amgen, Menarini-Stemline, AbbVie, and Pfizer, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort., Methods: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 10 8 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing., Findings: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported., Interpretation: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy)., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests SJS is an adviser or consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene (Juno), Genentech (Roche), LoxoOncology, Novartis, and Tessa Therapeutics; reports honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech (Roche), LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics; reports steering committee participation for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer; reports research support from AbbVie, Acerta, Celgene (Juno), DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics; and reports a patent with Novartis. CST reports honoraria from AbbVie, BeiGene, Janssen, Novartis, and Roche, and research support from AbbVie and Janssen. NW reports personal fees from Celgene (Bristol Myers Squibb), Kite (Gilead), and Novartis, and travel support from Celgene and Novartis. JPM is a consultant for Juno; reports honoraria from AlloVir, Juno, and Kite; reports research support from AlloVir, Astellas, Bellicum, Fresenius Biotech, Gamida Cell, Juno, Kite, Novartis, and Pluristem; reports participation on a speakers bureau for Kite; and reports assistance with manuscript preparation from ArticulateScience. HH is an adviser or consultant for Gilead, Roche, Nordic Nanovector, Novartis, and Takeda, and reports honoraria from Novartis. EKW is an adviser or consultant for Cambium Medical Technologies, Celldex, Novartis, Partner Therapeutics, cyclics, and Verastem; reports research support from Amgen, Celldex, Juno, Novartis, and Partner Therapeutics; and owns stocks in Cambium Medical Technologies and Cambium Oncology. SJ reports research support from Kite and Novartis, and personal fees from Juno, Kite, and CRISPR Therapeutics. MRB is a consultant for Celgene, CRISPR Therapeutics, Juno, Kite, and Novartis; reports research support from Novartis; and reports participation on speakers bureaus for Celgene and Kite. SRF reports personal fees from Novartis. JRW is an adviser or consultant for Celgene, Curis, Genentech, Janssen, Juno, Kite, MorphoSys, and Novartis, and reports research support from Celgene, Curis, Forty Seven, Genentech, Janssen, Kite, Novartis, and Unum. IF is an adviser or consultant for AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Roche, and Seattle Genetics, and reports honoraria from AbbVie, Gilead, Janssen, Novartis, Roche, and Seattle Genetics. PJH reports travel support from Celgene, Janssen, La Jolla, and Novartis. SM is an adviser or consultant for Merck and Novartis; reports research support from Kiadis Pharma; reports speaker fees from Celgene, Cellex, DNA Prime, Jazz Pharma, Kiadis Pharma, Miltenyi Biotec, and Novartis; reports participation in an expert panel for Bellicum and Kite (Gilead); reports participation in a data and safety monitoring board for Miltenyi Biotec; and reports travel support from Celgene, Cellex, the European Hematology Association and the European Society for Blood and Marrow Transplantation, the German Society of Hematology and Medical Oncology, the International Society for Cellular Therapy, Kiadis Pharma, Kite (Gilead), Merck, and Miltenyi Biotec. TT is an adviser or consultant for Merck, Novartis, and Takeda; reports honoraria from Bristol Myers Squibb, Fuji Pharma, Kyowa Kirin, Merck, Nippon Shinyaku, Pfizer, Takeda, and Teijin Pharma; reports research support from Astellas, Chugai, Kyowa Kirin, Novartis, and Sanofi; reports grants from the Japan Society for the Promotion of Science and the Japan Science and Technology Agency; and reports assistance with manuscript preparation from Janssen and Novartis. GS is an adviser or consultant for AbbVie, Allogene, Autolus, BeiGene, Celgene, Epizyme, Genmab, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, Roche, and VelosBio, and reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Epizyme, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, and Roche. KI reports grants from Celgene, Daiichi Sankyo, and Novartis, and personal fees from Celgene and Novartis. MJK is an adviser or consultant for, and reports travel support from, Amgen, Bristol Myers Squibb, Celgene, Janssen, Kite (Gilead), Merck, Miltenyi Biotec, Novartis, and Roche, and reports research support from Celgene, Roche, and Takeda. NW-J is an adviser or consultant for ADC Therapeutics, Bayer, Epizyme, Gilead, Grünenthal, Janssen, Karyopharm, and Regeneron, and reports research support from ADC Therapeutics, Astex, Juno, and Regeneron. KK is an adviser or consultant for AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen, and Novartis; reports honoraria from Celgene, Chugai, Janssen, Kyowa Kirin, Merck, Mundi, Novartis, Ono, Sumitomo Dainippon, and Takeda; and reports research support from AbbVie, Celgene, Chugai, Eisai, Janssen, Kyowa Kirin, Ono, Novartis, and Takeda. MM-P, XH, and RT are employees of Novartis. RTM is an adviser or consultant for AlloVir, Artiva, CRISPR Therapeutics, CytoDyn, Incyte, and Novartis; reports honoraria from Bristol Myers Squibb (Celgene), Incyte, Intellia, Kite, Omeros, Orca BioSystems, and PACT Pharma; reports research support from Juno and Novartis; reports participation in a data and safety monitoring board for Athersys and Novartis; and has a patent with Athersys. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An active role for the immune system in controlling the malignant plasma cell clone in myeloma has been postulated for many years. The clinical states of monoclonal gammopathy of undetermined significance, plateau phase disease, and smoldering myeloma all suggest that a significant host-tumor interaction is taking place. The fundamental role of the cytotoxic T cell in tumor elimination and control has been exemplified by the dramatic efficacy of adoptive T-cell therapies in many hemopoietic malignancies. However, tumor-host cross-talk results in suppression of the endogenous cytotoxic T-cell response against the malignant plasma cell. Whereas patients with myeloma do not clinically exhibit a T-cell immunodeficiency state, with, for example, increased mycobacterial infections, a number of abnormalities of T-cell function are evident. The major abnormalities of T cells include clonal expansions and associated immunosenescence, alterations of regulatory T cells/T helper 17 cells (Treg/Th17 ratio) and acquired membrane abnormalities, due to trogocytosis, which result in acquired Treg cells. Dendritic cell dysfunction associated with impaired antigen processing and presentation caused by abnormalities of the bone marrow microenvironment plays an additional role. In this perspective, we examine the T-cell abnormalities in myeloma and postulate that, whereas cytotoxic T cells interacting with the tumor are dysfunctional, residual T cells still function adequately against external pathogens and thus protect patients from the infections normally associated with a generalized T-cell immunodeficiency state. The so-called 3 E's of host-tumor interaction (elimination, equilibrium, and escape) are clearly reflected in the immune landscape and clinical behavior of myeloma., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM.

Murine T cells do not endogenously upregulate CD80 expression but rather acquire CD80 from antigen presenting cells (APC) during CD28 ligation. Murine CD80+ memory T cells undergo apoptosis in the presence of high levels of antigen while naive CD80+ T cells are capable of acting as APC and T cell:T cell ligation induces anergy and unresponsiveness to antigen rechallenge. Reversing T cell unresponsiveness may be a key factor in the development of immunotherapy strategies for patients with myeloma. We have determined that B7+ T cells (CD80+ or CD86+) are common in patients with myeloma (n = 45), can be either CD4 or CD8, tend to be associated with stable disease and are polyclonal memory T cells (CD45RO). CD80 mRNA expression was present in CD80+ monocytes but not in CD3+ cells with a similar level of CD80 antigen expression. CD80 and CD86 antigen expression was upregulated on B cells but not T cells during incubation with trimeric human CD40 ligand (huCD40LT) + IL-2. Although there was a gradual loss of expression during in vitro culture, CD80+ T cells could be purified for further study. We conclude that B7 expression is common on T cells of patients with myeloma but that this is acquired rather than endogenously produced. B7+ CD45RO+ T cells constitute a population of memory T cells chronically exposed to antigen and warrant further study.