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The Role of Genetic Mutations in Multiple Myeloma Outcomes

Nalley, Catlin

doi: 10.1097/01.COT.0000534145.53709.f4
Opinion

A new study has been launched that aims to provide further insight into the role genetic mutations play in the management of multiple myeloma, including treatment response and patient outcomes.

“There are significant knowledge gaps about multiple myeloma, and among these gaps is the role of genetic mutations in response to treatment and the related outcomes for patients,” noted Brian G.M. Durie, MD, International Myeloma Foundation Chairman, in a statement. “This study has the potential to provide valuable real-world evidence that can help advance care for patients.”

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Study Details

The primary objective of the research, which is spearheaded by the International Myeloma Foundation (IMF), is to determine the overall survival of patients with multiple myeloma and the t(11;14) translocation, which is present in an estimated 16-24 percent of FISH-tested multiple myeloma cases (Leukemia 2017;32:131-138, Blood 2016;127:2955-2962).

“The idea evolved over the last 2-4 years as we were looking more closely at the types of patients with multiple myeloma and particularly the patients who have the t(11;14) translocation,” Durie told Oncology Times. “What became very clear is that these patients are identified as having increased levels of the protein Bcl-2 present in the myeloma cells.” This is important, Durie noted, because Bcl-2 prevents apoptosis and as a result helps sustain the growth of myeloma.

Blocking Bcl-2 has proven to be an effective treatment for myeloma and there are a number of agents that can be utilized in this approach, including venetoclax, according to Durie. “There is evidence that venetoclax alone as a single therapy could be remarkably effective in patients who have the t(11;14) translocation, but also in combination in others who may have some increase in Bcl-2, but may not have the t(11;14) translocation.

“And so, because of the potential for the selective precision approach to therapy, it became necessary to better understand the natural history of myeloma patients with the t(11;14) translocation,” he continued. This desire to fill in gaps in knowledge is the origin of the research project, Durie noted. “We want to improve our understanding of the t(11;14) translocation and its role in multiple myeloma therapy as a potentially new selective precision medicine approach.”

The study will include IMF researchers from at least 30 participating sites worldwide who will retrospectively review and characterize outcomes of 1,500 multiple myeloma patients with the t(11;14) translocation identified on FISH.

Secondary objectives of the study include response rates, progression-free survival, time to progression, time to next treatment, duration of responses, and overall survival with different regimens among patients with the t(11;14) translocation. The research also aims to determine prognostic factors for overall survival as well as identify the range of co-existing genetic abnormalities in this patient population.

“Myeloma patients can have a variety of chromosomal abnormalities and the t(11;14) translocation is just one of them,” noted Durie. “So, a key objective of the study is to see if patients who have this translocation also have a bad prognostic chromosomal factor, which can lead to poorer outcomes.

“Conversely, do these patients have good risk features, such as trisomies, which could make the potential outcome even better,” he continued. “So, [this study] aims to understand the presence of the t(11;14) translocation not just in isolation, but as a part of the larger picture of the disease.”

Researchers are currently in the data-gathering phase, according to Durie, and several hundred of the patient materials have been collected. The anticipated timeline is for analysis to occur in May/June and investigators are hopeful that they “will have a data analysis that would allow for the submission of scientific abstract for the ASH Annual Meeting in December 2018,” Durie noted. “At the same time, we will be preparing a full publication of the data.”

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Potential Impact

Given the gaps in understanding regarding multiple myeloma and the role of genetic mutations, this study has the potential to make a significant impact in the treatment of this patient population.

“Identification of the subset of patients with the t(11;14) translocation as the dominant chromosome abnormality who, in turn, could selectively benefit from this targeted approach of therapy is hugely important,” Durie concluded. “This could be a proof-of-principle demonstrating that the identification and targeting of a molecular subgroup of patients can be a way forward for the future.”

Catlin Nalley is associate editor.

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