Whole-Genome Sequencing in Smoldering Myeloma and MGUS Could Predict Outcomes

Ola Landgren, MD, PhD

Whole-genome sequencing in patients with precursor multiple myeloma conditions such as smoldering myeloma or monoclonal gammopathy of uncertain significance (MGUS) may help predict which patients will go on to develop the disease, according to study authors Ola Landgren, MD, PhD, and Francesco Maura, MD.

“In the past 2 or 3 years, we have shown that whole-genome sequencing has the potential to [identify] most myeloma-defining genomic events,” Maura, an assistant professor and principal investigator of the myeloma genomic lab at Sylvester Comprehensive Cancer Center, told OncLive. “If you [can] define events, you can see which patients with precursor disease have these events, and which do not. You can see that the presence of these events is associated with different clinical outcomes.”

In a study recently published in Nature Communications, Landgren, Maura, and colleagues, explored the utility of whole-genome sequencing in patients with MGUS and smoldering myeloma to see whether they could identify genomic signatures that could predict progression to multiple myeloma. Results indicated that clinically stable cases of these 2 precursor conditions are characterized by different genomic landscapes and by variations in the temporal acquisition of myeloma-defining genomic events vs progressive entities.

One genomic signature of interest in the study was APOBEC, which has previously been observed in patients with relapsed multiple myeloma, according to Maura. Investigators noted that the patients who eventually progressed on the study already had this signature when they had MGUS, while those who did not progress did not have this signature.

“All of a sudden, we were able to lift off the lid on the Pandora's box of MGUS and see [those who will progress to] myeloma vs [those who will] not,” Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, told OncLive. “Many questions still need to be addressed. For example, [we know that] if a patient has [a specific] signature, that is a bad thing. However, if they do not have it, could they still develop it later? What is the rate of conversion? We do not know.” A large follow-up study is planned to examine this further, Landgren added.

In an interview with OncLive, Landgren and Maura highlighted the evolution of genomic testing in multiple myeloma, further discussed their research with whole-genome sequencing in patients with precursor conditions, and spotlighted next steps for research.

OncLive®: What inspired this research to further examine myeloma precursor conditions?

Landgren: For a very long time, it has been recognized that some individuals who have proteins in the blood that are monoclonal do not have multiple myeloma. Others have multiple myeloma, [which] is the second most common blood cancer in adults. [This disease presents] in 35,000 people every year in the United States, and over 130,000 people are living with this disease without a cure. Years back, in the 1960s, there was a debate [regarding these] proteins; 1 group thought that there was no association between these proteins and the cancer, while others felt that maybe there was. In the 1970s, the consensus was that [the question remained open and up for debate].

That takes you into [the realm of] MGUS, which basically means we do not know. In reality, people show up with these proteins for various reasons. Doctors can order blood tests, and all of a sudden, you see these proteins. The patient wonders, ‘What is going to happen with me? Will I develop myeloma or not?’ People are living with this uncertainty. In the 1980s, [investigators were starting to realize that] some people have more protein than others; as such, they didn't fit with this terminology [of MGUS, so investigators] came up with the idea that they could call that smoldering myeloma. However, MGUS and smoldering myeloma are sort of the same thing; smoldering myeloma just has a little bit more of these proteins. For 40 years, blood tests [have been performed] every 3, 6, or 12 months and some people still develop myeloma, [while others] have [these proteins] and never progress. For many years, we have studied blood-based markers and other types of markers to determine whether we could identify those who are going to develop myeloma early on.

In 2009, I was the lead investigator on a study that definitively showed that any person who developed myeloma had these proteins in their blood years [in advance]. We had a collection of almost 100,000 blood samples that were drawn every year for many people. We identified all people who had myeloma, and then we went backward year by year and found [those proteins] in every person. That definitively showed that you need to have the protein to develop the cancer. However, the question that still puzzled us for more than 10 years was: Is there a better way to identify those who will [go on to] develop [the disease] vs those who will [not]?

To answer that question, we needed to first ask ourselves whether they were linked; the answer was, yes. There are [challenges to] doing these types of studies, because you need to have a lot of DNA if you are studying whole-genome sequencing. You need to have so many cells for the technology to work. You basically have people who already [are] halfway [to having] the disease. The real question is in those who have a very low level of disease, could you still address this question? Until now, that was not possible. This study takes advantage of a brand-new technology [that requires] low-input DNA. We were able to crack the code.

Maura: This study aimed to answer 1 of the most important questions for the myeloma community. Some scientists [have] recently published very important studies showing that certain genomic drivers are associated with patients who progress. However, the limitation [in those] studies is that most of them are focused on smoldering myeloma because of the [number] of cells [they are able to collect]. [Others used] technologies that are focused on a small fraction of the genomes, so they are able to capture just a small fraction of events.

In the past 2 or 3 years, whole-genome sequencing has emerged and has shown the potential to reveal important myeloma-defining genomic events. [Whole-genome sequencing] is comprehensive and provides most of the answers that we were looking for, answers that the other previous studies could not; this is all possible with this technology.

Could you expand on the goals of this study and its key findings? What did the patient population look like?

Landgren: The study particularly focused on people with very low levels of disease; this is [those with] MGUS, which makes this study very unique. As you can imagine, if you study people with smoldering myeloma, they already have so many cells. If you have 1000 people, many will develop myeloma. However, if you have 1000 people with a MGUS, the proportion is going to be lower. For those individuals who are going to progress, [examining this is] equally important. This study, for the first time, focused on whole-genome sequencing, with a particular interest in people with very low disease burden.

What we showed was that we have an activation of certain genomic signatures. For example, a signature called APOBEC is known to be associated with aggressive, solid, and metastatic cancer. We have seen [this signature] in relapsed myeloma. However, when we look at these early disease cases, the patients who eventually progress already [had APOBEC] when they had the MGUS. The [patients] who did not progress, did not have [APOBEC]. That is a huge observation; that [shows us that we] can [predict] myeloma [before it occurs with these signatures]. Other single-variant hotspots, or templated insertions, [were also observed]. For example, chromothripsis also distinguishes these cases from each other.

The question now is [whether a person who does not have these genomic signatures now] can develop them later. [We need to know the rate of conversion.] To this end, we are already planning to open a large follow-up study, here, in Miami, where patients with MGUS and smoldering myeloma will be welcome to come for this test. [The study] will also allow them to come back on an annual basis if they have the low-risk signatures [so that they can] be tested longitudinally to] definitively answer this question. We are also working to develop early intervention studies to treat [patients] based on these signatures.

Maura: Where we are now in the field is that the prediction of the risk of whether patients will progress is based on indirect measurement of disease burden. We have a different prognostic score that was developed by Mayo Clinic and the Spanish group, that is effective in identifying patients [who are] very high risk. We consider these patients to probably already have multiple myeloma; it is just a matter of time [for the disease] to expand and [cause] symptoms. In just a few months, less than 2 years, most of these patients will progress. These scores are less [effective in] predicting [those with] intermediate and low risk. That is [why] our study is important. All our patients enrolled, [those with] MGUS and smoldering multiple myeloma, were all intermediate and low risk. We did not have any high-risk [patients]. The [patients] who progressed were those who did so from an intermediate or low risk to multiple myeloma. That is another important consideration.

Despite the limited cohort, because we're talking about less than 50 patients, the data were clean; the cohort was not contaminated by high-risk patients or by [those with] multiple myeloma that was not yet diagnosed. It is important because this population of myeloma without symptoms is a big problem when you try to extrapolate or understand a large population, particularly [through] retrospective studies. That is another advantage. APOBEC, chromothripsis, templated insertions—all these events can only be detected in an accurate way using whole-genome sequencing. That is why whole-genome sequencing is important. You can detect APOBEC with exome data, but it is less accurate, and you [are left with] a lot of uncertainty.

Whole-genome sequencing is pretty robust; [either] you have [it] or you don't have [it], and if you don’t have it, then you’re sure you don’t have it. That is another advantage.

Finally, we performed a bit of a complicated analysis using mutations that are constant over time and we showed that the first genomic-defining events that we were able to time are acquired in multiple myeloma around the second decade of life. [Patients with] smoldering myeloma and MGUS who progressed [did so] in a similar time window: the second or third decade of life. What was interesting is that in the [patients with] MGUS or smoldering myeloma who did not progress, [events were acquired] in the fifth and six decades of life. We don't know whether these patients will progress, but we can also [hypothesize] that most of these patients, if they take the same path that multiple myeloma requires, will progress when [they are] more than 100 years [of age].

Reference

Oben B, Froyen G, Maclachlan KH, et al. Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities. Nat Commun. 2021;12(1):1861. doi:10.1038/s41467-021-22140-0