The field of multiple myeloma (MM) has seen significant therapeutic advances over the last decade including the recent advent of Chimeric Antigen Receptor T cell (CAR-T) therapy. Currently there are two FDA approved CAR-T products for MM, both targeting B cell maturation antigen (BCMA). These agents have demonstrated striking therapeutic efficacy in patients with advanced disease and are now also approved in earlier relapse. CAR-T therapy is associated with unique toxicities including cytokine release syndrome, neurotoxicity, hypogammaglobulinemia, risk of infections and cytopenias. While response rates are dramatic, most patients ultimately experience disease progression due to therapeutic resistance potentially arising from lack of persistence and exhaustion of CAR-T cells, emergence of antigen negative variants, and the immunosuppressive tumor microenvironment. Significant efforts in the field are dedicated towards improving the efficacy and mitigating the toxicity of CAR-T cell therapy. In this publication, we review the approved and investigational CAR-T models for MM.
Immunotherapy, including immune checkpoint blockade, CART cells and bispecific antibodies have resulted in dramatic improvements in outcomes for patients with hematological malignancies, demonstrating the unique potency of the immune system in targeting malignant cells. The development of cancer vaccines aims to evoke an activated effector cell population and a memory response to provide long term immune surveillance to protect from relapse. Developing a potent cancer vaccine relies on identifying appropriate antigen targets, enhancing antigen presentation, and overcoming the immune suppressive milieu of the micro-environment. Critical advances include the identification of neoantigens as targets for high affinity T cells, multi-antigenic targets via whole-cell or multi-peptide platforms, dendritic cell-based strategies, and adjunct immunoregulatory agents to enhance response. In the present review, we examine the current understanding of immune dysregulation in hematologic malignancies, the rationale for cancer vaccines, and the clinical and immunologic response data available from preclinical and clinical settings.
With upfront use of triplet- and quadruplet-based regimens coupled with autologous stem cell transplant (ASCT) and maintenance lenalidomide, a high proportion of multiple myeloma (MM) patients are achieving deep and durable responses. Yet, myeloma invariably relapses, with refractoriness to one or more drugs at first relapse. This therapeutic gap has been partially filled by T-cell engager (TCE) therapies that have demonstrated remarkable response rates and prolonged remissions in heavily pretreated patients with MM, providing off-the-shelf immunotherapy options leading to the U.S. Food and Drug Administration (FDA) approval of three bispecific TCEs teclistamab, elranatamab, and talquetamab. We review the most salient aspects of TCE design and clinical experience in MM treatment. Combination approaches overcome resistance mechanisms, while earlier TCE use could enhance depth and durability of response. Outpatient step-up dosing (SUD) further enables community adoption.
Precursor plasma cell disorders include monoclonal gammopathy of undermined significance (MGUS) and smoldering multiple myeloma (SMM). These conditions carry a variable risk of progression to symptomatic myeloma and there are ongoing efforts to improve risk stratification to identify patients that are at highest risk of progression. Advanced imaging plays a crucial role in diagnosis and monitoring, and more sensitive tools to measure serum monoclonal proteins and circulating tumor cells are being developed. The data for early intervention in SMM continues to evolve, with several phase III studies demonstrating benefit compared to observation. There are ongoing studies evaluating the role of combination and T cell immunotherapies in patients with precursor plasma cell disorders. This review will highlight the current state of the art tools in diagnosis, risk stratification, and data for early interception in patients with precursor plasma cell dyscrasias.
