Abstract
B-cell maturation antigen (BCMA)-targeting bispecific antibodies and bispecific T-cell engagers (BiTEs) redirect T-cells to BCMA-expressing multiple myeloma (MM) cells. These MM cells are subsequently eliminated via various mechanisms of action including the release of granzymes and perforins. Several phase 1, dose-escalation studies show pronounced activity of BCMA-targeting bispecific antibodies, including teclistamab, AMG420 and CC-93269, in heavily pretreated MM patients. Cytokine release syndrome is the most common adverse event, which can be adequately managed with tocilizumab or steroids. Several clinical trials are currently evaluating combination therapy with a BCMA-specific bispecific antibody, based on preclinical findings showing that immunomodulatory drugs or CD38-targeting antibodies enhance the activity of bispecific antibodies. In addition, bispecific antibodies, targeting other MM cell surface antigens (i. e. GPRC5D, CD38 and FcRH5), are also evaluated in early phase clinical trials. Such bispecific antibodies, targeting other antigens, may be given to patients with low baseline BCMA expression, disease with substantial heterogeneity in BCMA expression, following prior BCMA-targeted therapy, or combined with BCMA bispecific antibodies to prevent development of antigen escape.
Highlights
Immunotherapy in multiple myelomaImmunotherapeutic agents are increasingly used for the treatment of both newly diagnosed and relapsed/refractory multiple myeloma (MM) patients [1,2,3]
We have recently provided the preclinical rationale for the use of the BCMAxCD3 bispecific antibody www.oncotarget.com teclistamab (JNJ-7957) [14]
The most common adverse event related to teclistamab was cytokine release syndrome (CRS), which occurred in 56% of patients
Summary
Immunotherapeutic agents are increasingly used for the treatment of both newly diagnosed and relapsed/refractory multiple myeloma (MM) patients [1,2,3]. Pretreatment of effector cells with lenalidomide or pomalidomide enhanced AMG701-mediated lysis of MM cells [25, 26] These data provide the rationale for clinical trials evaluating the combination of a bispecific antibody or BiTE with an IMiD. Newly diagnosed MM patients with high-risk cytogenetic abnormalities, who have a poor prognosis, may benefit from the incorporation of a BCMA-targeting bispecific antibody into their upfront treatment strategy. This is supported by our finding that the ex vivo activity of teclistamab was not affected by presence of high-risk cytogenetic abnormalities. A combination of bispecific antibodies, simultaneously targeting different antigens, may mitigate tumor antigen escape
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