{"id":71222,"date":"2023-04-27T15:06:51","date_gmt":"2023-04-27T14:06:51","guid":{"rendered":"https:\/\/touchoncology.com\/?p=71222"},"modified":"2023-07-24T15:40:17","modified_gmt":"2023-07-24T14:40:17","slug":"teclistamab-monotherapy-for-the-treatment-of-adult-patients-with-relapsed-and-refractory-multiple-myeloma","status":"publish","type":"post","link":"https:\/\/touchoncology.com\/haematological-malignancies\/journal-articles\/teclistamab-monotherapy-for-the-treatment-of-adult-patients-with-relapsed-and-refractory-multiple-myeloma\/","title":{"rendered":"Teclistamab Monotherapy for the Treatment of Adult Patients with Relapsed and Refractory Multiple Myeloma"},"content":{"rendered":"
Multiple myeloma<\/span>\u00a0(MM<\/span>) is the\u00a0<\/span>second most common<\/span>\u00a0ha<\/span>ematological malignancy,<\/span>\u00a0with upwards of\u00a035,000<\/span>\u00a0diagnoses in the USA<\/span>\u00a0each year.1,2<\/sup><\/span>\u00a0<\/span>It remains a leading cause of blood cancer–<\/span>related mortality\u00a0worldwide<\/span>,<\/span>\u00a0and although therapeutic advances have allowed for significant improvements in the median overall survival,3,4<\/sup><\/span>\u00a0<\/span>the majority of patients still experience cycles of relapse that are eventually fatal<\/span>.5<\/sup><\/span>\u00a0While\u00a0<\/span>patients\u00a0with MM<\/span>\u00a0<\/span>are living longer,<\/span>\u00a0a subgroup with\u00a0<\/span>high-risk disease\u00a0at diagnosis<\/span><\/span>\u00a0still does<\/span>\u00a0poorly, with\u00a0a\u00a0<\/span>median overall survival<\/span>\u00a0of\u00a0<\/span>nearly<\/span>\u00a03<\/span>\u00a0years.<\/span><\/span><\/span>6<\/sup><\/span>\u00a0<\/span>Outcomes are also dismal in\u00a0<\/span>patients with\u00a0<\/span>disease that is refractory\u00a0<\/span>to the major modern therapies\u00a0including thalidomide analogue<\/span>s, proteosome inhibitors and anti-CD38 monoclonal antibodies<\/span><\/span><\/span>.7<\/sup><\/span>\u00a0Together, these unmet needs have driven the development of immunotherapy for\u00a0<\/span>relapsed\u00a0and\u00a0<\/span>refractory multiple myeloma<\/span>\u00a0(RRMM<\/span>)<\/span>.<\/p>\n Toward<\/span>\u00a0this end, immune cell redirecting therapies were developed following the discovery of suitable MM cell-surface markers and novel drug engineering technologies. Chimeric antigen receptor\u00a0(CAR)-<\/span>T\u00a0<\/span>cells\u00a0<\/span><\/span><\/span>showed robust responses in RRMM\u00a0compared with\u00a0B cell maturation antigen (BCMA<\/span>),<\/span>\u00a0<\/span><\/span>leading\u00a0<\/span>to the approval of cellular therapies for\u00a0<\/span>MM<\/span>\u00a0\u2013<\/span>\u00a0idecabtagene<\/span>\u00a0vicleucel in\u00a02021\u00a0<\/span><\/span>and\u00a0<\/span>ciltacabtagene autoleucel<\/span>\u00a0in\u00a02022<\/span>.8\u201311<\/sup><\/span>\u00a0<\/span>Available data on\u00a0idecabtagene<\/span>\u00a0vicleucel<\/span>\u00a0and\u00a0ciltacabtagene autoleucel<\/span>\u00a0in RRMM, however, suggest that most\u00a0<\/span>patients will\u00a0<\/span>experience disease progression<\/span>\u00a0after initial response.9,11<\/sup><\/span><\/span>\u00a0Moreover, the need for patient-specific manufacturing and access to specialized cellular therapy centre<\/span>s continue to limit\u00a0CAR T<\/span>\u00a0cell access for patients with rapid disease progression or in\u00a0under-served<\/span>\u00a0areas.<\/p>\n Successful adaptive immune redirection has also been shown with bispecific antibodies (BsAbs<\/span>) against various established and emerging MM\u00a0<\/span>cell targets.\u00a0<\/span>This review follows the\u00a0US Food and Drug Administration<\/span>\u00a0(<\/span>FDA)<\/span>\u00a0approval of\u00a0teclistamab \u2013 the<\/span>\u00a0first-in-kind commercially available BsAb for RRMM.12<\/sup><\/span>\u00a0<\/span>Teclistamab is a T\u00a0<\/span>cell-redirecting antibody that targets CD3 on the surface of T cells and\u00a0BCMA<\/span>\u00a0expressed on the surface of myeloma cells\u00a0(BCMA\u00d7<\/span>CD3)<\/span>. It was approved for use as monotherapy\u00a0i<\/span>n\u00a0<\/span>2022<\/span>\u00a0based on<\/span>\u00a0data from the MajesTEC-1 trial published in June 2022.<\/span><\/span>13<\/sup><\/span>\u00a0Teclistama<\/span>b and similar agents in development enable T cell redirection with similar potency to\u00a0CAR T<\/span>\u00a0cells but without the delay required for patient-specific manufacturing.<\/p>\n In this article<\/span>, we review the mechanism of action of this<\/span>\u00a0BCMA\u00d7<\/span>CD3 antibody, the clinical data supporting the approval of teclistamab and its impact on the treatment paradigms for RRMM.<\/p>\n BCMA, also known as TNFRSF-17 or CD269, is a small transmembrane protein member of\u00a0the\u00a0<\/span>tumou<\/span>r necrosis factor\u00a0(TNF)<\/span><\/span>\u00a0<\/span>receptor superfamily. It is selectively induced during\u00a0plasma cell<\/span>\u00a0(PC<\/span>) differentiation,14<\/sup><\/span>\u00a0with transcription and cell-surface expression concentrated in subsets of mature B\u00a0<\/span>cells,\u00a0PC<\/span>s and plasmacytoid dendritic cells.15,16<\/sup><\/span>\u00a0Select\u00a0<\/span>datasets<\/span>\u00a0<\/span>have also suggested low-level transcription on neurons and astrocytes,17<\/sup><\/span>\u00a0though other studies have not supported this association.18,19<\/sup><\/span><\/p>\n BCMA has two ligands, BAFF\/BLys and APRIL, which are integral to maintaining\u00a0bone marrow\u00a0<\/span>PC<\/span>\u00a0survival and homeostasis\u00a0(as\u00a0<\/span>reviewed in\u00a0Eckhert et al. and Romano et al.)<\/span>.20,21<\/sup><\/span>\u00a0<\/span>Stimulation with APRIL or BAFF activates\u00a0the\u00a0<\/span>NF-\u03ba<\/span>B, AKT and\u00a0mitogen-activated protein kinase<\/span>\u00a0(<\/span>MAPK)<\/span>8\/c-Jun N-terminal kinase (<\/span>JNK)<\/span>\u00a0signall<\/span>ing cascades,<\/span>\u00a0resulting in the upregulation of anti-apoptotic proteins,22<\/sup><\/span>\u00a0adhesion molecules, cell-cycle regulators, angiogenesis factors, immunosuppressive molecules and inflammatory cytokines\u00a0<\/span>(Figure 1A<\/span><\/span><\/span>)<\/span>.23\u201326<\/sup><\/span>\u00a0Both ligands also bind to\u00a0transmembrane activator calcium modulator and cyclophilin ligand interactor<\/span>\u00a0(<\/span>TACI)<\/span>, a larger homologue<\/span>\u00a0receptor of the\u00a0<\/span>TNF\u00a0<\/span>receptor<\/span>\u00a0superfamily, and mediate PC differentiation and T cell-independent\u00a0immunoglobulin (Ig)<\/span>\u00a0<\/span>isotype switching.27<\/sup><\/span>\u00a0The role of BCMA activation, however, is restricted to\u00a0maintaining<\/span>\u00a0PCs and antigen presentation by B cells.26<\/sup><\/span>\u00a0BCMA has a soluble form derived from\u00a0the\u00a0<\/span>cleavage of the membrane BCMA mediated by \u03b3-secretase.28<\/sup><\/span>\u00a0This soluble form has shown to sequester BAFF and mediate immunosuppression by preventing normal B\u00a0<\/span>cell and\u00a0<\/span>PC\u00a0<\/span>development.29<\/sup><\/span><\/p>\n \u00a0 BCMA is overexpressed in\u00a0MM,<\/span><\/span>30<\/sup><\/span>\u00a0and NF-\u03ba<\/span>B overactivation\u00a0i<\/span>s a hallmark of MM tumou<\/span>rigenesis.31<\/sup><\/span>\u00a0<\/span>In patients with MM,\u00a0<\/span>s<\/span>oluble BCMA is also significantly elevated\u00a0<\/span>compared\u00a0with\u00a0<\/span>healthy individuals,<\/span>\u00a0and higher\u00a0<\/span>soluble BCM<\/span><\/span>A\u00a0(sBCMA)\u00a0<\/span><\/span>levels correlate with immune paresis, disease burden and adverse outcomes.28,32<\/sup><\/span>\u00a0Preclinical studies demonstrated that antibodies with ligand–<\/span>blocking activity could promote cytotoxicity\u00a0in\u00a0<\/span>MM cell lines as naked antibodies or as antibody\u2013<\/span>drug conjugates by inhibiting APRIL-dependent activation of NF-\u03ba<\/span>B in a dose-dependent manner\u00a0in vitro<\/em><\/span>.33<\/sup><\/span>\u00a0BCMA was later validated as a suitable\u00a0CAR T<\/span>\u00a0target.15<\/sup><\/span>\u00a0Altogether, these studies paved the way\u00a0<\/span>for<\/span>\u00a0the development and clinical investigation of anti-BCMA antibody\u2013<\/span>drug conjugates,\u00a0CAR T<\/span>\u00a0and now BsAb therapies against RRMM\u00a0<\/span>(<\/span>Figure 1B<\/span><\/span><\/span>).<\/span><\/p>\n BsAbs are T\u00a0<\/span>cell–<\/span>engaging (TCE<\/span>) therapies designed to redirect T\u00a0<\/span>cell cytotoxicity towards cell-surface tumou<\/span>r antigens\u00a0(<\/span>Figure 1B<\/span><\/span><\/span>)<\/span>. TCE therapies have been developed in various formats, including bispecific\u00a0<\/span><\/span>Ig<\/span>G-like antibodies or shorter molecules comprisMechanisms of\u00a0a<\/span>ction<\/h1>\n
Overview of\u00a0B cell maturation antigen\u00a0<\/span>as a target<\/h2>\n
<\/p>\n
<\/span>Bispecific antibody therapy development for\u00a0relapsed\u00a0and\u00a0<\/span>refractory multiple myeloma<\/span><\/span><\/h2>\n