Keeping Myeloma in Check: The Past, Present and Future of Immunotherapy in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma is the second most common hematological malignancy and while patients can have long responses to therapy, most patients will eventually develop treatment-resistant disease. Over the last thirty years, improved understanding of multiple myeloma and therapeutic advancements have dramatically improved outcomes for patients. Recently, advances in immunotherapy have revolutionized standard-of-care therapies and provided therapeutic options for patients with heavily pretreated, relapsed refractory multiple myeloma. Immunotherapy is a rapidly evolving field, and this review encompasses the immunotherapies that are currently used to treat myeloma patients as well as recent advances that are poised to advance myeloma therapeutics in the coming years. ABSTRACT: Multiple myeloma is an incurable disease of malignant plasma cells and an ideal target for modern immune therapy. The unique plasma cell biology maintained in multiple myeloma, coupled with its hematological nature and unique bone marrow microenvironment, provide an opportunity to design specifically targeted immunotherapies that selectively kill transformed cells with limited on-target off-tumor effects. Broadly defined, immune therapy is the utilization of the immune system and immune agents to treat a disease. In the context of multiple myeloma, immune therapy can be subdivided into four main categories: immune modulatory imide drugs, targeted antibodies, adoptive cell transfer therapies, and vaccines. In recent years, advances in all four of these categories have led to improved therapies with enhanced antitumor activity and specificity. In IMiDs, modified chemical structures have been developed that improve drug potency while reducing dose limiting side effects. Targeted antibody therapies have resulted from the development of new selectively expressed targets as well as the development of antibody drug conjugates and bispecific antibodies. Adoptive cell therapies, particularly CAR-T therapies, have been enhanced through improvements in the manufacturing process, as well as through the development of CAR constructs that enhance CAR-T activation and provide protection from a suppressive immune microenvironment. This review will first cover in-class breakthrough therapies for each of these categories, as well as therapies currently utilized in the clinic. Additionally, this review will explore up and coming therapeutics in the preclinical and clinical trial stage.