Rapid Progress in Immunotherapies for Multiple Myeloma: An Updated Comprehensive Review

Abstract

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.

BCMA in Multiple Myeloma—A Promising Key to Therapy

“…The most common symptoms of ocular toxicity presented as blurred vision and dry eye. Although the exact mechanism for the cornea AEs is unclear, a micropinocytosis-dependent internalization of ADCs in the cornea itself may cause toxicity by the linker-payload and dividing corneal epithelial cells [ 39 , 40 ], leading to dose reduction and/or application delays. The prophylaxis with corticosteroids eye drops showed no significant effects.…”

“…Processes include CAR-T cells being produced after leukapheresis of peripheral white blood cells of the patients or healthy donors to obtain CD3+ T cells for autologous vs. allogeneic CAR-T cells. Thereafter, the collected white blood cells, following a stimulation of T cells, express CD3 and CD28 or 4-1-BB by coated beads with mAb [ 39 ]. In a subsequent step, these activated T cells are transduced with a gene via a lentiviral vector, which encodes a receptor to the tumor-specific antigen on tumor cells, and are able to express CAR gens [ 39 ].…”

“…Thereafter, the collected white blood cells, following a stimulation of T cells, express CD3 and CD28 or 4-1-BB by coated beads with mAb [ 39 ]. In a subsequent step, these activated T cells are transduced with a gene via a lentiviral vector, which encodes a receptor to the tumor-specific antigen on tumor cells, and are able to express CAR gens [ 39 ]. The main characteristic of CAR-T cells is that they use a CAR against antigen of tumor cells such as BCMA, CD19, CD138 (syndecan-1), Orphan G-protein-coupled receptor class C group 5 member D (GPRC5D) and immunoglobulin kappa light chain [ 71 , 72 , 73 ].…”

“…Idecabtagene Vicleucel (former Ide-cel; bb2121) is a second generation BCMA targeted CAR-T cell incorporating a single chain variable fragment, a 4-1BB co-stimulating domain and a CD3Zeta signaling domain, inducing cytotoxicity against MM cells independently of BCMA expression or soluble BCMA [ 39 , 75 ]. Registrational indications of idecabtagene vicleucel CAR-T therapies include single-arm studies with RRMM patients who were initially triple-class-exposed or triple-class-refractory [ 27 ].…”

“…The improvement of the efficacy of CAR-T cells in MM will be the focus for the development of the next generation of CAR-T cells. The main characterization will be in producing a multi-specific CAR-T cell responding to lower levels of targeted-antigen on MM cells and to improve the anti-tumor immune response [ 39 ].…”