Two clones, one niche: how CH shapes the MM microenvironment Free

In this issue of Blood, Lionetti et al describe their in-depth analysis of a cohort of 106 patients with newly diagnosed multiple myeloma (MM), finding concurrent clonal hematopoiesis (CH) in 22.6% of patients and noting that the presence of CH is associated with an altered tumor-promoting bone marrow microenvironment despite the CH and MM having distinct clonal origins.¹ 

MM, an incurable blood cancer arising from neoplastic plasma cells, is preceded in almost all cases by a premalignant phase known as monoclonal gammopathy (MG). The factors that promote the progression from MG to overt MM are multifactorial and incompletely understood but include somatic genetic evolution and the development of an altered tumor microenvironment (TME) that favors progression. The altered TME that supports growth of neoplastic plasma cells is also believed to contribute to a dysfunctional immune system in patients with MM, leading to abnormal tumor cell surveillance and increased infectious complications. Whether this abnormal TME is a cause or consequence of MM progression remains an open question.

CH arises from the expansion of hematopoietic stem cells (HSCs) carrying somatic mutations in genes that are frequently mutated in myeloid neoplasms. In addition to an increased risk of myeloid neoplasms, CH is associated with numerous adverse outcomes including higher rates of cardiovascular disease, a consequence of hyperactive inflammatory signaling in the mutant myeloid cells.² We and others have shown that the presence of CH is associated with adverse outcomes in patients with non-Hodgkin lymphoma, MM, and Waldenström macroglobulinemia, including an increased risk of progression and therapy-related myeloid neoplasms.^3-5 However, the pathophysiologic drivers of these findings, particularly how CH can influence outcomes in these various lymphoid malignancies, remain poorly understood.

Lionetti et al used targeted next-generation sequencing from 106 patients with newly diagnosed MM to identify CH in 22.6% of the cohort. This rate is similar to that seen in other MM patient cohorts evaluated with similar technology and is consistent with this group’s prior work demonstrating that CH and MG of undetermined significance occur independently.^4,6 CH was associated with higher revised international staging system, but not with worse disease outcomes, although these analyses are limited by the relatively small sample size and short median follow-up of 27 months. In 27 patients, sequential samples were available for analysis of clonal evolution, demonstrating that some clones grow whereas others do not. In 2 cases with a TP53 mutation, clonal expansion was observed during lenalidomide treatment, consistent with prior reports.⁷ The strong age association seen in both CH and MM raises the possibility of a common disease origin. To determine whether the MM and CH were clonally related, the authors used fluorescence-activated cell sorting to separate and analyze HSCs and MM cells from 8 patients with CH. They did not identify shared mutations suggestive of a common clonal origin for both diseases. This is consistent with prior data demonstrating that myeloid neoplasms that arise in patients with MM are clonally distinct.⁸ 

Finally, to evaluate whether CH alters the TME in ways that could promote MM progression, the authors performed single-cell RNA sequencing and interaction network analyses in 16 patients, half of whom had CH. They found that patients with CH have a more inflammatory TME characterized by increased interferon gamma and tumor necrosis factor-α signaling between monocyte and T-cell subsets. They also observed fewer naive T cells and less antigen presentation by dendritic cells as well as increased expression of exhaustion markers on CD8⁺ T cells in patients with CH. All of these changes would be expected to promote escape from immune surveillance and tumor cell survival while also influencing the response to and toxicity of immune-targeted therapies. It is unlikely that CH directly promotes the development of MM given the lack of an association between the 2 diagnoses noted in this article. However, CH may still impact later progression and response to therapy. We have previously shown that the presence of CH at the time of chimeric antigen receptor T-cell treatment in patients with non-Hodgkin lymphoma is associated with increased risk of cytokine release syndrome.^9,10 Whether this effect is mediated by the hyperinflammatory TME in patients with CH reported here requires further evaluation. In addition, how the inflammatory phenotype in the TME might affect MM outcomes or explain the known immune dysfunction observed in patients with MM is intriguing and requires validation in larger patient cohorts. Efforts to develop laboratory models to dissect the detailed molecular interaction between CH and MM cells are needed to develop new therapeutic approaches to restore normal immune function in MM patients.

Conflict-of-interest disclosure: A.S.S. has received consulting fees from Novartis.