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Discovering new biology and vulnerabilities in high-risk disease from the MMRF CoMMpass study

An IW Myeloma conference update from
the MMRF and Myeloma Solutions Fund

Remarkable advances in the treatment of multiple myeloma (MM) have significantly improved outcomes over the past 30 years. However, there remain certain subtypes of MM – including those patients that harbor t(4;14) translocations – that are at increased risk of relapse and adverse events. Understanding the biology of these high-risk MM subtypes is critical to developing more effective therapies. The Multiple Myeloma Research Foundation’s (MMRF) CoMMpass study has done more to advance our understanding of the biology of MM, including high-risk disease, than any other single study. An overview of findings from the CoMMpass study, which enrolled 1149 patients and followed them for 8 years, was presented by Dr. Larry Boise from Winship Cancer Institute of Emory University at iwMyeloma 2024 (watch interview). As highlighted by Dr. Boise, this study has provided foundational data for publications identifying structural variants (Barwick et al.) and genomic hotspots (Maura et al.) associated with poor outcome as well as personal risk assessment (Maura et al.). By integrating multiple genomic data sets, this study provided a more complete view of the biology of high-risk MM (Keats et al.)

A new layer of genomic data for CoMMpass tumor samples was presented by Dr. Ben Barwick, who characterized over 400 CoMMpass samples for the presence of DNA methylation – a chemical modification on DNA that is tightly linked to gene expression. These data showed that DNA methylation in MM was dramatically different than normal plasma cells, with MM losing approximately one-third of the DNA methylation found in normal plasma cells. These DNA methylation losses primarily occurred in regions of the genome that are the last to replicate during cell division, suggesting they resulted from cellular proliferation, something normal plasma cells rarely undergo. Furthermore, interrogation of unique DNA methylation programs between different MM subtypes also showed that the Proliferation subtype – which is not defined by any specific genetic alteration, but rather a high rate of cellular growth and poor outcome – had lower levels of DNA methylation compared to other MM subtypes. This occurred in these same late replicating regions of the genome where DNA methylation losses were generally observed in MM, but also at specific genomic elements that are bound by a group of factors known as the E2F transcription factors that control cell division, pointing to specific mechanisms that drive the Proliferation high-risk MM subtype.

Although each MM subtype has a unique ‘epigenetic’ or DNA methylation signature, the t(4;14) subtype was by far the most unique. While this is not entirely surprising given that t(4;14) translocations result in overexpression of NSD2 – an enzyme involved in epigenetic regulation – this is a previously unappreciated aspect of t(4;14) biology. Specifically, NSD2 deposits methylation on histone 3 lysine 36 (H3K36), and Dr. Barwick showed that this excess H3K36 methylation in the t(4;14) subtype also results in higher levels of DNA methylation. Dr. Barwick’s MSF award is focused on exploiting the unique epigenetic program of t(4;14), which he believes leads to a more immunological quiescent cancer.

This work complements several other research programs focused on tackling t(4;14) also presented at iwMyeloma 2024, including those from Dr. Boise, who is looking at how the apoptosis threshold of t(4;14) MM can be altered to make cells more sensitive to therapies; Dr. Arun Wiita who leveraged CoMMpass to identify CD70 as a new immune target in MM; Dr. Yubao Wang who has generated innovative models to precisely measure NSD2 function and identify new targets in t(4;14); and Dr. Faith Davies who presented novel approaches to targeting the Ras pathway in high-risk and t(4;14) MM. Cumulatively, these complementary research programs, sponsored in part through Myeloma Solutions Fund research grants and continual interrogation of samples from the MMRF CoMMpass study, are uncovering novel biology and new paradigms for targeting t(4;14) and high-risk MM.

The Myeloma Solutions Fund recognizes the significant contributions that the CoMMpass study continues to deliver. To visit their website please click here.