About 3 years ago, researchers from Dana-Farber Cancer Institute launched PROMISE (Predicting Progression of Developing Myeloma in a High-Risk Screen Population; ClinicalTrials.gov identifier NCT03689595), a large, ambitious screening study to identify individuals at high risk of developing multiple myeloma. The goal of the study is to enroll 30,000 people aged 30 and older in the United States and Canada who have a first-degree relative diagnosed with multiple myeloma or one of its precursor conditions—monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, or Waldenström’s macroglobulinemia—or are persons of African or African American descent with or without a family history of multiple myeloma. The study is also enrolling individuals aged 18 and older who have a family history of blood cancer in two or more first- and second-degree relatives. (For full disclosure, I am a participant in the PROMISE study.)
“Our hope is that in the future, no one will have to experience anemia or a bone fracture from myeloma. That is the potential benefit of this type of early myeloma screening.”— Irene M. Ghobrial, MD
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Although age is a critical risk factor in the development of this relatively rare cancer—most of the nearly 35,000 new cases of myeloma each year are diagnosed in people older than age 651—persons of African and African American descent have a threefold increased prevalence of the cancer compared with White individuals, even after adjusting for socioeconomic and other risk factors; and those with a familial history have between a twofold and fourfold increased risk. All of this indicates a potential inherited genetic predisposition among these populations2—a suggestion that is gaining traction after the first results of the PROMISE study were published earlier this year.
The study, conducted by Irene M. Ghobrial, MD, Director, Clinical Investigator Research Program and Lavine Family Chair for Preventive Cancer Therapies at Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, and colleagues, evaluated the prevalence and clinical implications of monoclonal gammopathies in 7,622 participants in the PROMISE study and the Mass General Brigham Biobank screened by quantitative mass spectrometry to measure abnormal proteins in their blood.
The study, which included 2,439 Black individuals and 4,986 White individuals, reported a total prevalence of monoclonal gammopathies of 43% in Black individuals or individuals with a first-degree family history of blood cancers older than age 50 using mass spectrometry, compared with a prevalence of MGUS of 6% using serum protein electrophoresis, a less sensitive technology. Dr. Ghobrial and colleagues termed monoclonal gammopathies below the clinical immunofixation electrophoresis detection level (< 0.2 g/L) monoclonal gammopathy of indeterminate potential (MGIP).3
“The results are very interesting because the prevalence was beyond what we expected,” said Dr. Ghobrial. “We found a new entity [MGIP] that is below the current cutoff of what we call monoclonal gammopathy of undetermined significance. We didn’t want to confuse it with typical MGUS in patients with very low levels of monoclonal gammopathies. We don’t know the significance of MGIP, and it may not have the same rate of progression as MGUS. We did find worse overall survival in patients with MGUS, especially those with an MGIP score in 4.5 years of follow-up and patients with cardiovascular disease, so our results open the door to many more questions.”
In an interview with The ASCO Post, Dr. Ghobrial discussed the benefit of screening for MGUS and the potential to prevent multiple myeloma from ever developing in high-risk individuals.
Creating an Early Warning System for Myeloma
Based on your study results, should all high-risk individuals for multiple myeloma be screened for MGUS or smaller concentrations of abnormal proteins (now called MGIP)? And what should these individuals do with that information?
Even if you remove the level of MGIP we found in our study cohort, the prevalence of MGUS via mass spectrometry was between 13% and 15% of the population older than age 50, and that is a very high percentage of people who may be at risk for developing myeloma and may want to consider early interception. We are researching what the next steps should be to create for the first time a screening method for a blood cancer like myeloma and whether we should start thinking of the implications of that for high-risk individuals for other types of cancer as well.
Another interesting finding is that 43% of Black individuals or people with a first-degree family history of myeloma harbored either MGUS or MGIP, and it was discovered using mass spectrometry, a more sensitive technology than serum protein electrophoresis. What is the significance of MGIP?
We do not want to say that MGIP is going to cause myeloma, because these slight spikes could be abnormalities related to an older immune disease or something that is transient, and that is why we need longer follow-up of the PROMISE study. We do not want to alarm a large population of people, because we do not know the long-term clinical significance. However, biologically, it is very interesting to find so many people with M-protein concentrations at the MGIP level.
Searching for a Genetic Link to Myeloma
The prevalence of MGUS via mass spectrometry increased with age (13% for those older than age 50 and 18% for those older than age 70); was higher in men (12%) than in women (10%); and was significantly higher in Black individuals (17%) than in the controls but not in those with a family history (13%) compared with the controls. Still, those with a family history of myeloma have between a twofold and fourfold increased risk of developing the disease. Is myeloma an inherited genetic disease?
This is a good question. We are doing germline sequencing in all family members in the PROMISE study to try to identify a risk allele that increases the development of myeloma. Right now, it is difficult to know definitively.
“We do not know if it is one step or several steps to myeloma, but we think a germline variant is likely a contributor to disease development.”— Irene M. Ghobrial, MD
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It is not likely we will find a common gene variant, but it could be a rare variant that increases a person’s risk of MGUS, for example. Such a person might then need some other risk factor, such as aging or obesity, to trigger the further development of myeloma. We do not know if it is one step or several steps to myeloma, but we think a germline variant is likely a contributor to disease development.
We are looking at the same genetic component for Black Americans. Why is race a risk factor for myeloma? What is the risk allele for people of African descent? We just do not know yet. We must understand at a single-cell level what is the first early mutation that happened to cause the development of MGUS and then what else triggers further clonal expansion leading to myeloma. We are doing that research as we speak.
Likely, there is a germline variant contributing to the environmental factors and immune aging. We know that aging and race can show differences in the immune system and how it regulates cancer. Understanding how the immune system contributes to cancer development or progression is important. We know that inflammation can trigger further clonal expansion, so we are investigating all these factors as well as inherited genetic abnormalities.
We need to identify the genetic signature that leads to that early event of clonal expansion and then what happens later to cause some individuals with a genetic predisposition to progress to myeloma and not others. There are many open questions rather than answers at this point.
Detecting Myeloma at Earlier Stages
Some researchers have questioned whether the small concentrations of abnormal protein (MGIP) that mass spectrometry can detect represent true monoclonal gammopathy. Is it accurate to use the label MGIP to describe the stage before MGUS?
I agree. Some researchers say MGIP has no clinical significance, but I say this newer name correctly describes the small spikes of abnormal proteins we are seeing, which could represent true abnormal proteins. We do not have to understand all of the clinical significance of MGIP yet. We are describing what we are seeing and trying to understand what it means in the development of MGUS and potentially myeloma.
Researching a Genetic Signature for Myeloma
Some individuals diagnosed with MGUS may never go on to develop myeloma. Is there a danger of overdiagnosing MGUS when it might never lead to myeloma? And what should be the clinical strategy to possibly prevent myeloma for these individuals?
These questions are good because a diagnosis of MGUS could cause anxiety for people. The biggest discussion in cancer care today is how much diagnosing is too much? A diagnosis of MGUS is like receiving a diagnosis of high cholesterol. Having high cholesterol can lead to a heart attack, but there are interventions to prevent that from happening.
We have a clinic devoted to the early detection of myeloma, and we are developing many clinical trials for patients with smoldering myeloma. If our data look good, we will continue to research a genetic signature that will help us predict which individuals will go on to develop myeloma and how to eliminate those abnormal cells. Perhaps, we can develop a vaccine or a bispecific antibody that could completely eradicate the disease at its earliest stages.
We must be careful; we may not need to treat everyone. Some carriers of MGUS may have a mutation that is a normal phenotype cell and may never go on to progress to myeloma. We still need to do a lot of work to understand who is truly at risk of disease progression, and then we may be able to intervene and prevent myeloma.
Our hope is that in the future, no one will have to experience anemia or a bone fracture from myeloma. That is the potential benefit of this type of early myeloma screening. Yes, there is a risk of overdiagnosing people who may never go on to develop the cancer, but if we can prevent every case of myeloma, the risk will be worth it.
We do not yet know the full clinical significance of identifying MGUS in high-risk individuals. However, isn’t it amazing to research potential discoveries that may have biological and clinical significance of this disease in the future?
DISCLOSURE: Dr. Ghobrial has received honoraria from Celgene, Bristol Myers Squibb, Takeda, Amgen, Janssen, and Vor Biopharma; and has served as a consultant or advisor to Bristol Myers Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar Biosciences, Sanofi, Janssen, Pfizer, Menarini Silicon Biosystems, Oncopeptides, The Binding Site, GlaxoSmithKline, AbbVie, Adaptive, and 10xGenomics. Dr. Ghobrial’s spouse, William Savage, MD, PhD, is Chief Medical Officer at Disc Medicine and holds equity in the company.
REFERENCES
1. American Cancer Society: Key Statistics About Multiple Myeloma. Available at www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html. Accessed August 2, 2022.
2. Manier S, Salem KZ, Liu D, et al: Future directions in the evaluation and treatment of precursor plasma cell disorders. Am Soc Clin Oncol Educ Book 35:e400-e406, 2016.
3. El-Khoury H, Lee DJ, Alberge JB, et al: Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: A multicentre cohort study. Lancet Haematol 9:e340-e349, 2022.
