Editor’s Note: With the 20th anniversary of The Hematologist serving as a springboard, we are launching “Then and Now,” in which we revisit a topic that we covered in the first year of publication. This series of articles will highlight the incredible progress that hematology has made over two decades. In our inaugural article of this type, Dr. Madhav Dhodapkar takes a fresh look at the role of the immune system in controlling multiple myeloma, highlighting how some of the hypotheses from “then” have translated to treatments “now.”
Twenty years ago, the first issue of The Hematologist contained a “Diffusion” article1 titled “A Fine Balance Between Immunity and Cancer,” about a publication describing early immune alterations in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM).2 A prevailing dogma in immunology at the time was that the immune system largely ignores the development of tumors, as they originate from “self” tissues.3 As discussed by Dr. Peter Lee in the Diffusion article,1 these studies were among the first to show that, in the context of human premalignancy, the human immune system specifically recognizes preneoplastic lesions.2,4,5 These data provided two new major insights. First, both adaptive and innate immunity contribute to specific immune recognition of human premalignant lesions.2,4 Second, while immune cells in patients with active malignancy exhibit features of dysfunction, even advanced tumors remain susceptible to killing by autologous T cells if the immune cells are optimally activated.5
Immune Alterations in Premalignancy
Over the past two decades, the findings from these papers have been extensively reproduced and extended to several other human tumors, including solid tumors and their preneoplastic counterparts.6 The capacity to evade immune surveillance is now well-established as a hallmark of cancer. In recent years, high-dimensional analyses, including single-cell genomics and spatial technologies, have begun to provide additional granularity relating to the properties of immune cells and their distribution in MGUS and MM. Research has provided a more detailed understanding of the immune landscape in premalignant lesions and an appreciation that some aspects of immune dysfunction may begin as early as MGUS.7,8 Progression to clinical MM is associated with a decline in stem cell-like memory T cells, which have proven to be critical for long-term immune protection in murine models.7 New biology about spatial regulation of these immune responses is also emerging, consistent with the concept that myeloma is a multifocal disease.6
Despite these advances, there is much more to learn. There is marked heterogeneity in the immune system and immune fitness among individual patients. This variance was prominently manifested in recent studies of cellular immune responses to messenger RNA vaccines administered to these patients during the COVID-19 pandemic.9 Antigen-specific B- and T-cell responses to these vaccines may differ by more than 10-fold among patients, and the mechanisms underlying this variance remain unclear. There is also a need for a better understanding of the antigenic targets of immune response to individual tumors and the molecular/cellular mechanisms that underlie the functional alterations in immune cells in patients with MGUS and MM. Finally, understanding this biology in the context of underlying tumor and host genetics and other non-immune cells is another area of exploration.
Immune Sensitivity of Clinical MM
The surprising finding from the initial studies — that tumor cells from patients with even advanced or relapsed MM remain highly susceptible to killing by their own T cells — has now been translated to the clinic following the success of T-cell redirection with bispecific antibodies in patients with MM.10 Indeed, initial clinical trials of CD3-bispecific antibodies were conducted in patients whose disease had relapsed following multiple lines of therapy. Together with the clinical success of chimeric antigen receptor (CAR) T-cell therapies, monoclonal antibodies, and immunomodulatory drugs in MM, a new era of immune-based therapies in MM may be emerging.11
However, despite the impressive responses to current therapies, most patients remain at risk for disease recurrence. The biology and properties of the immune system and the immune microenvironment may impact the durability of response to current immune therapies,11,12 and these factors will need to be considered when choosing and sequencing immune-based therapies. This is likely to be relevant both for protection from tumors and general immunologic health, including the risk of infections associated with some of these therapies.10 Knowing the genomic complexity of myeloma, the immune system and its capacity for long-term memory may be the best bet for durable unmaintained control of tumors. The clinical efficacy of current therapies already suggests that immune-based therapies can become the backbone of future clinical management in MM.
Implications for Immune Prevention
In the early papers, the underlying premise of the observations of immune recognition of human preneoplastic lesions was that such a response could be harnessed to mediate effective immune prevention of MM. Advances in genetics have also led to the recognition that even preneoplastic lesions such as MGUS can be genetically complex and heterogeneous. However, in principle, such genomic complexity may also create new targets or neo-antigens for the immune system. This concept was already evident in the early studies, with the observation that immune responses to preneoplastic lesions were specific to each patient and not shared with common myeloma cell lines.4 Therefore, the immune system, with its specificity and capacity for long-term immunologic memory, may again be the best bet for safe and effective prevention. Randomized controlled trials have now demonstrated that immunomodulatory drugs can lead to clinically meaningful reduction in the risk of clinical malignancy in patients with high-risk smoldering MM.13 While this approach is not tumor-specific and carries the risk of short and long-term toxicity, it provides proof-of-principle that immune modulation could lead to effective prevention of clinical malignancy.
Conclusions
The concept that the immune system can be highly effective in treating MM has, in the past 20 years, moved from a hypothesis and early proof-of-concept to a well-established therapeutic principle guiding overall clinical management.11 The immune system will likely be shown to be even more effective for preventing the malignancy itself (or at least for altering the evolution of tumors and emergence of high-risk genomic lesions) in the future, as hematologists learn to manipulate the “fine balance” alluded to in the original piece in The Hematologist.1 Such strategies will need to be nontoxic and limited-duration interventions but may fundamentally change the landscape and incidence of plasma cell neoplasms in humans in the years to come.
Competing Interests
Dr. Dhodapkar indicated no relevant conflicts of interest.
