Whole-genome sequence of smoldering myeloma and MGUS may predict outcome

“In the last few years, the whole genome sequence has [identify] “Genome events that define most myeloma,” said Maura, an assistant professor and senior researcher at the Myeloma Genome Laboratory at the Sylvester Center for Cancer Research. OncLive.. “Hello, you [can] By defining events, you can see which precursors have or do not have these events. The presence of these events can be seen to be associated with a variety of clinical outcomes. “

In a recently published study Nature Communications, Landgren, Maura, and colleagues Whole-genome sequence in patients with MGUS and smoldering myeloma See if we can identify a genomic signature that can predict the progression to multiple myeloma. The results showed that clinically stable cases of these two precursor states were characterized by different genomic landscapes and changes in genomic events and the temporal acquisition of progressive entities that define myeloma.

According to Maura, one of the genomic signatures of interest in this study was APOBEC. This was previously observed in patients with recurrent multiple myeloma. The researchers said that the patients who finally proceeded with the study already had this signature when they had MGUS, but those who did not progress did not have this signature.

“Suddenly, I was able to see the MGUS Pandora’s box with the lid off. [those who will progress to] Myeloma vs [those who will] Landgren, the first leader in the Sylvester Center for Comprehensive Cancer Center’s treatment program, said: OncLive.. “We still have to deal with many questions. For example. [we know that] If the patient has [a specific] Signature, that’s a bad thing. But if they don’t have it, can they still develop it later? What is the conversion rate? We do not know. “Landgren added that a large follow-up is planned to investigate this further.

In an interview with OncLiveLandgren and Maura highlighted the evolution of genomic testing in multiple myeloma, further discussed studies using whole-genome sequencing in patients with precursor status, and highlighted the next step in the study. ..

OncLive®: What influenced this study to further investigate the status of myeloma precursors?

Land Glen: For a very long time, it has been recognized that some people who have monoclonal proteins in their blood do not have multiple myeloma. Others have multiple myeloma, [which] It is the second most common blood cancer in adults. [This disease presents] There are 35,000 people in the United States each year, and more than 130,000 live without cure for the disease.A few years ago, there was a debate in the 1960s. [regarding these] Proteins; One group thought there was no association between these proteins and cancer, while others felt they were probably. In the 1970s, the consensus was: [the question remained open and up for debate]..

It makes you [the realm of] MGUS, this basically means we don’t know. In reality, people appear with these proteins for a variety of reasons. Doctors can order blood tests, and suddenly you see these proteins. Patients wonder, “What will happen to me? Will I develop myeloma?” People live with this uncertainty. In the 1980s [investigators were starting to realize that] Some people have more protein than others.So these did not fit this term [of MGUS, so investigators] They came up with the idea that they could call it smoldering myeloma. However, MGUS and smoldering myeloma are similar. Smoldering myeloma contains only a small amount of these proteins. Blood test for 40 years [have been performed] Some people still develop myeloma every 3, 6, or 12 months, [while others] Have got [these proteins] And never make progress. Over the years, we have studied blood-based markers and other types of markers to determine if we can identify people who develop myeloma early.

In 2009, I was the lead investigator in a study that clearly demonstrated that anyone who develops myeloma has these proteins in the blood year. [in advance].. There was a collection of about 100,000 blood samples taken each year for many people.We have identified all people with myeloma and have since discovered them year after year. [those proteins] To everyone. It clearly showed that you need to have protein to develop cancer. But the questions that have puzzled us for more than a decade were: [go on to] Develop [the disease] To the person [not]??

To answer that question, I first had to ask myself if they were linked. The answer was yes.There is [challenges to] We are doing these types of studies because we need a large amount of DNA when studying whole-genome sequences. A huge number of cells are required for the technology to work.You basically already [are] On the way [to having] sick. The real question lies with people with very low levels of illness, can you still answer this question? Until now, that wasn’t possible.This study utilizes a whole new technology [that requires] Low input DNA. I was able to break the code.

Maura: This study aims to answer one of the most important questions for the myeloma community.Some scientists [have] A very important study recently published has shown that certain genomic drivers are associated with advanced patients.However, restrictions [in those] Studies have shown that most of them focus on smoldering myeloma. [number] Of cells [they are able to collect].. [Others used] It focuses on a small part of the genome, so you can capture a small part of the event.

Over the last few years, whole-genome sequences have emerged, demonstrating the potential to reveal key genomic events that define myeloma. [Whole-genome sequencing] It is comprehensive and provides most of the answers we were looking for, answers that were not possible in other previous studies. This is all possible with this technology.

Tell us more about the goals of this study and its key discoveries. What did the patient population look like?

Land Glen: This study focuses especially on people with very low levels of illness.this is [those with] MGUS makes this research very unique. As you can imagine, when studying a person with smoldering myeloma, there are already so many cells. For 1000 people, many develop myeloma. However, if there are 1000 people using MGUS, the percentage will be low. For those individuals who are trying to make progress [examining this is] Equally important. For the first time, this study focuses on whole-genome sequencing, especially for people with very low disease burden.

We have shown that certain genomic signatures have been activated. For example, a signature called APOBEC is known to be associated with invasive, solid, and metastatic cancers.We saw [this signature] Recurrent myeloma.However, looking at cases of these early illnesses, eventually patients who are already advanced [had APOBEC] When they had MGUS.The· [patients] Did not progress, did not have [APOBEC].. It’s a big observation.It [shows us that we] it can [predict] Myeloma [before it occurs with these signatures].. Other single variant hotspots, or templated inserts, [were also observed].. Chromothripsis, for example, also distinguishes these cases from each other.

The problem now is [whether a person who does not have these genomic signatures now] You can develop them later. [We need to know the rate of conversion.] To this end, we are already planning to launch a large follow-up survey here in Miami. There, we welcome patients with MGUS and smoldering myeloma to come to this test. [The study] You can also come back every year if you have a low-risk signature [so that they can] Test vertically]Make sure you answer this question.We are also working on the development of early intervention studies for treatment. [patients] Based on these signatures.

Maura: We are currently in this area that predicting the risk of patient progression is based on indirect measurements of disease burden. Developed by the Mayo Clinic and the Spanish group, there are different prognostic scores that are effective in patient identification. [who are] Very high risk. These patients probably already have multiple myeloma.It’s just a matter of time [for the disease] Enlarge [cause] Symptomatology. In just a few months, less than two years, most of these patients progress.These scores are low [effective in] Forecast [those with] Medium and low risk.That is [why] Our research is important. All our patients have enrolled, [those with] MGUS and smoldering multiple myeloma were all medium-risk and low-risk.Nothing was at high risk [patients]..The· [patients] Those who progressed were those who progressed from medium-risk or low-risk to multiple myeloma. This is also an important consideration.

Despite the limited cohort, the data were clean because less than 50 patients were talking.The cohort was not contaminated by high-risk patients or [those with] Multiple myeloma that has not yet been diagnosed. This asymptomatic population of myeloma is important, especially when trying to estimate or understand a large population. [through] Retrospective study. That is another advantage. APOBEC, Chromothripsis, Template Insertion-All these events can only be detected in an accurate way using whole-genome sequencing. Therefore, the whole genome sequence is important. APOBEC can be detected in exome data, but with less accuracy. [are left with] Many uncertainties.

The whole genome sequence is very robust. [either] you have [it] Or you don’t have [it], And if you don’t have it, you’re sure you don’t have it. That is another advantage.

Finally, the first genome-defining event that could be timed by performing a slightly more complex analysis using mutations that are constant over time is acquired in multiple myeloma around the age of 20 years. I showed that. [Patients with] Smoldering myeloma and advanced MGUS [did so] In a similar time frame: 20 or 30 years of life.What was interesting [patients with] MGUS or smoldering myeloma that did not progress, [events were acquired] In 50 and 60 years of life. I don’t know if these patients will progress, but [hypothesize] Most of these patients follow the same pathway required by multiple myeloma and progress in the following cases: [they are] Over 100 years [of age]..

reference

Oben B, Froyen G, Maclachlan KH, and other whole-genome sequences reveal the precursor status of advanced myeloma and stable myeloma as two different entities. Nut common.. 2021; 12 (1): 1861. doi: 10.1038 / s41467-021-22140-0