Harnessing the Immune System to Fight Multiple Myeloma

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.

The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma

“…However, despite the huge improvement in the treatment, MM remains an incurable disease due to the emergence of drug resistance and recurrent relapses [ 46 ]. Although genetic alterations have a certain role in MM pathogenesis, many of them are already present in the pre-malignant stage, suggesting that genetic mutations are necessary but not sufficient for MM progression [ 47 ]. Other extrinsic factors such as the interaction with immunosuppressive TME could be involved in MM evolution.…”

Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors

“…A myriad of interactions between immune cells and MM cells are currently being studied towards identification of novel therapeutic approaches or are developed in the clinics as immunotherapy and immune-stimulating drugs ( 70 , 71 ).…”

The Prognostic Value of Classical Immunoparesis in Multiple Myeloma

“…In addition to genetic mutations and clonal evolution, a loss of effective immune surveillance may drive malignant transformation. The complex interaction of cPC with the bone marrow microenvironment contributes to expanding the immunosuppressive cell populations [4]. Consequently, a progressive increase in M protein (the involved Ig in IIMM or the involved FLC in LCMM) and a decrease in the uninvolved Igs (uIgs) are expected in untreated MM patients.…”