Harnessing the Immune System to Fight Multiple Myeloma

Simple Summary Multiple myeloma treatment has developed enormously within the last two decades. Most recently immunotherapies have been introduced. Monoclonal antibodies targeting the plasma cell surface marker CD38, daratumumab and isatuximab, have revolutionized the standard of care treatment, and CAR T-cell therapy has been FDA-approved for the treatment of relapsed, refractory multiple myeloma. However, many other immunotherapeutic principles are under current clinical testing. It is well described that immune dysfunction is present in multiple myeloma and worsens by disease progression and may even be involved in the transformation to malignancy from benign precursor states, smoldering myeloma, and MGUS. Thus, attempts to revive and engage the innate and adaptive immune system are appealing. The ultimate goal is the cure or prevention of cancer development. In this review, the reader receives basic information on the immune dysfunction in multiple myeloma, a thorough summary of the ways to harness the immune system in treatment, the current status of clinical development, and future aspects. Abstract Multiple myeloma (MM) is a heterogeneous plasma cell malignancy differing substantially in clinical behavior, prognosis, and response to treatment. With the advent of novel therapies, many patients achieve long-lasting remissions, but some experience aggressive and treatment refractory relapses. So far, MM is considered incurable. Myeloma pathogenesis can broadly be explained by two interacting mechanisms, intraclonal evolution of cancer cells and development of an immunosuppressive tumor microenvironment. Failures in isotype class switching and somatic hypermutations result in the neoplastic transformation typical of MM and other B cell malignancies. Interestingly, although genetic alterations occur and evolve over time, they are also present in premalignant stages, which never progress to MM, suggesting that genetic mutations are necessary but not sufficient for myeloma transformation. Changes in composition and function of the immune cells are associated with loss of effective immune surveillance, which might represent another mechanism driving malignant transformation. During the last decade, the traditional view on myeloma treatment has changed dramatically. It is increasingly evident that treatment strategies solely based on targeting intrinsic properties of myeloma cells are insufficient. Lately, approaches that redirect the cells of the otherwise suppressed immune system to take control over myeloma have emerged. Evidence of utility of this principle was initially established by the observation of the graft-versus-myeloma effect in allogeneic stem cell-transplanted patients. A variety of new strategies to harness both innate and antigen-specific immunity against MM have recently been developed and intensively tested in clinical trials. This review aims to give readers a basic understanding of how the immune system can be engaged to treat MM, to summarize the main immunotherapeutic modalities, their current role in clinical care, and future prospects.