Seminars in hematology最新文献

Melanoma Antigen Genes (MAGE) are expressed in a broad range of cancers, including multiple myeloma. MAGE have been under investigation for more than 3 decades as targets for immune therapy, while in parallel, interrogation of their functions has revealed activities that may be particularly critical in multiple myeloma. MAGE-C1 is expressed in about 75% of newly diagnosed cases and this is maintained through the natural history of the disease. In contrast, MAGE-A3 is expressed in about 35% of newly diagnosed cases, but this increases to more than 75% after relapse. MAGE-A3 expression was associated with poor clinical outcome and resistance to chemotherapy. Translational studies have revealed that MAGE-A3 regulates cell cycling and apoptosis in myeloma cells. Genomic, gene expression, and multiomic studies demonstrate relations with high-risk subgroups of patients. MAGE-A3 mediates these functions through partnership with Kap1 to form a ubiquitin ligase complex. Structural analysis of the interaction between MAGE-A3 and Kap1 gives insight into the biochemical activity and substrate specificity and suggests novel pharmacologic strategies to inhibit them. These studies demonstrating MAGE-A3 oncogenic functions suggest that it may also be a suitable target for small molecule inhibition in multiple myeloma that may be broadly applicable to other cancers that express it.

In the United States, Black people experience multiple myeloma (MM) at a frequency that is more than double that of White people and experience much higher rates of mortality. Despite bearing a disproportionate impact of both MM incidence and mortality, Black patients are significantly underrepresented in most MM clinical trials. This is in part because Black patients experience a higher prevalence of hemoglobinopathies and Duffy-null phenotype, which affect hemoglobin and neutrophil levels, respectively, potentially excluding patients from clinical trials. The Multiple Myeloma Research Foundation (MMRF) has convened a series of Health Equity Summits that include a focus on creating inclusive clinical trials for MM. The present paper, an output of the most recent workshop, focuses on the role of laboratory reference ranges as a barrier to clinical trial participation and offers tangible steps to improve the enrollment of a diverse and representative population.

Smoldering multiple myeloma (SMM) was first described over 40 years ago yet much is still unknown including which patients will ultimately progress to symptomatic multiple myeloma (MM). The genetics of the premalignant clone and the immune microenvironment in which it exists is now well understood to both play a role in disease progression. However, the clinical risk models available to help identify patients at most risk of progression still rely primarily on data reflecting volume of disease rather than underlying biology. While it is of upmost importance to accurately diagnose patients with SMM to avoid over or under treatment, efforts are ongoing to tease out if early intervention is indeed warranted for a subgroup of patients with SMM. This article will review the history and biology of SMM, discuss the utility of existing risk models, and examine the efforts to date which have challenged standard management.

Chromosome 1q copy number variations, collectively termed +1q, are 1 of the most common cytogenetic abnormalities in multiple myeloma. 1q abnormalities are associated with overexpression of a high-risk gene signature promoting cell proliferation, apoptosis resistance, genomic instability, and treatment resistance, and acquisition or expansion of +1q subclones mediate disease development and relapse. While there remains significant controversy as to whether the presence of +1q is itself an independent driver of poor prognosis or is simply a marker of other high-risk features, +1q has recently been incorporated into multiple prognostic scoring models as a new high-risk cytogenetic abnormality. In this review, we present possible underlying genetic mechanisms of high-risk disease in +1q myeloma, implications for subclonal development, its role in modifying the tumor microenvironment, current evidence for clinical significance in newly-diagnosed and relapsed patients, and current controversies in +1q classification and prognostication.