Abstract
Simple SummaryDespite rapid advances in the development of novel agents over the last decade for the treatment of multiple myeloma (MM), MM remains an incurable disease. Therefore, the development of novel targeting therapies with different mechanisms of action is needed to achieve a deep and durable response for the cure of MM. Recently, an antibody-drug conjugate (ADC), belanatmab mafadotin, which targets B cell membrane antigen (BCMA) on plasma cells, was approved for the treatment of relapsed or refractory MM in 2020. To date, immunotherapies including bi-specific or tri-specific antibodies, adoptive cellular therapy using autologous chimeric antigen (CAR)-T cells, allogeneic CAR-natural killer (NK) cells, and checkpoint inhibitors have been developed for MM, and a variety of clinical trials are currently underway or planned. This review presents an update on the most recent clinical and preclinical advances with a focus on results from clinical trials in progress with BCMA-targeted immunotherapies or the development of other novel targets in MM.Despite rapid advances in treatment approaches of multiple myeloma (MM) over the last two decades via proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), their efficacies are limited. MM still remains incurable, and the majority of patients shortly relapse and eventually become refractory to existing therapies due to the genetic heterogeneity and clonal evolution. Therefore, the development of novel therapeutic strategies with different mechanisms of action represents an unmet need to achieve a deep and highly durable response as well as to improve patient outcomes. The antibody-drug conjugate (ADC), belanatmab mafadotin, which targets B cell membrane antigen (BCMA) on plasma cells, was approved for the treatment of MM in 2020. To date, numerous immunotherapies, including bispecific antibodies, such as bispecific T cell engager (BiTE), the duobody adoptive cellular therapy using a dendritic cell (DC) vaccine, autologous chimeric antigen (CAR)-T cells, allogeneic CAR-natural killer (NK) cells, and checkpoint inhibitors have been developed for the treatment of MM, and a variety of clinical trials are currently underway or are expected to be planned. In the future, the efficacy of combination approaches, as well as allogenic CAR-T or NK cell therapy, will be examined, and promising results may alter the treatment paradigm of MM. This is a comprehensive review with an update on the most recent clinical and preclinical advances with a focus on results from clinical trials in progress with BCMA-targeted immunotherapies and the development of other novel targets in MM. Future perspectives will also be discussed.
Highlights
Multiple myeloma (MM) is a B cell malignancy characterized by an expansion of clonal plasma cells in the bone marrow (BM) with the production of an excess of monoclonal immunoglobulins (M-protein), progressive immune dysfunction, and osteolytic bone disease [1]
A variety of novel immunotherapeutic approaches which act with different mechanisms have emerged to achieve deep and highly durable responses in MM, including bispecific or trispecific T cell engagers (BiTEs) and antibodies [45,46,47], antibody drug conjugates (ADCs) [48], adoptive cellular therapy using dendritic cell vaccines, autologous chimeric antigen (CAR)-T cells or allogenic Chimeric Antigen Receptor (CAR)-natural killer (NK) cells [49,50] and immune checkpoint blockade by immune checkpoint inhibitors [51]. These immunotherapies have been conducted in a variety of clinical trials with promising results except for checkpoint inhibitors, leading to the approval for the use of belantamab mafodotin; an afucosylated humanized IgG1 anti-B cell membrane antigen (BCMA) monoclonal antibodies (mAbs) conjugated with monometyl auristatin F (MMAF); a proteasome-resistant maleimidocaproyl linker to a microtubule-disrupting agent, for patients with refractory MM (RRMM) that have been heavily pretreated with proteasome inhibitors (PIs), IMiD, and anti-CD38mAb were intolerant to the mAb [52,53,54,55,56] in 2020
We demonstrated that a humanized anti-CD26 IgG1 mAb inhibited human OC differentiation in in vitro and in vivo studies [82,83]
Summary
Multiple myeloma (MM) is a B cell malignancy characterized by an expansion of clonal plasma cells in the bone marrow (BM) with the production of an excess of monoclonal immunoglobulins (M-protein), progressive immune dysfunction, and osteolytic bone disease [1]. A variety of novel immunotherapeutic approaches which act with different mechanisms have emerged to achieve deep and highly durable responses in MM, including bispecific or trispecific T cell engagers (BiTEs) and antibodies (duobody) [45,46,47], antibody drug conjugates (ADCs) [48], adoptive cellular therapy using dendritic cell vaccines, autologous chimeric antigen (CAR)-T cells or allogenic CAR-natural killer (NK) cells [49,50] and immune checkpoint blockade by immune checkpoint inhibitors [51] These immunotherapies have been conducted in a variety of clinical trials with promising results except for checkpoint inhibitors, leading to the approval for the use of belantamab mafodotin; an afucosylated humanized IgG1 anti-B cell membrane antigen (BCMA) mAb conjugated with monometyl auristatin F (MMAF); a proteasome-resistant maleimidocaproyl linker to a microtubule-disrupting agent, for patients with RRMM that have been heavily pretreated with PI, IMiD, and anti-CD38mAb were intolerant to the mAb [52,53,54,55,56] in 2020. This review provides an update on the most recent clinical trials and their relevant preclinical findings in novel cellular immunotherapeutic strategies against MM, especially ADCs, bi-specific or tri-specific T cell engagers or antibodies, autologous CAR-T cells, and allogenic CAR-NK cells, targeting BCMA or other novel targets and future perspectives
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