Understanding Risk Stratification in Monoclonal Gammopathy of Undetermined Significance

A Conversation With Irene M. Ghobrial, MD

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About 4 years ago, I [Jo Cavallo] wrote about the death of my brother Dom from multiple myeloma in 2011 and my subsequent enrollment in the PROMISE trial ( identifier NCT03689595). My goal for enrolling in the study was twofold: to honor Dom and others with the cancer and to make a contribution toward understanding why some high-risk individuals for myeloma develop the cancer and others do not. (See “I Do Not Have a Multiple Myeloma Precursor Condition. Why Not?” in the December 10, 2019, issue of The ASCO Post.)

The study is recruiting first-degree relatives of people diagnosed with multiple myeloma—who have between a twofold and fourfold increased risk of developing the cancer1—or one of its precursor conditions, including monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, and Waldenström’s macroglobulinemia, as well as persons of African or African American descent with or without a family history of the disease. Black Americans have a threefold increased prevalence of the cancer compared with White individuals, even after adjusting for socioeconomic and other risk factors,1 and a higher mortality rate than White individuals.2

Becoming a Patient-in-Waiting?

After qualifying for the PROMISE study, I was sent a blood collection kit, which I took to a nearby lab as directed to have three vials of blood drawn and sent to the study investigators for analysis. Within days, I was e-mailed the good news: I tested negative for myeloma precursor conditions and was accepted into the “screen-negative” cohort of the study.

However, when I repeated the blood test 3 years later, a requirement of the study, a research assistant from PROMISE called to tell me that a highly sensitive research level analysis using mass spectrometry detected a small amount of M protein, 0.23 g/L, in my blood sample. In this study, any M protein level greater than or equal to 0.2 g/L is considered positive for MGUS. Fortunately, all the other values, including my levels of free-light chains and IgA, IgG, and IgM immunoglobulins, were in the normal range. Even though the research assistant assured me the spike in my M protein level could be transitory, and even if it did signify MGUS, my risk of transforming to multiple myeloma was extremely low—less than 1% per year—I immediately became alarmed and wasn’t sure how to process this information.

With advances in diagnostics like mass spectrometry, was I now a “patient-in-waiting” for the development of myeloma? New research findings showed that MGUS, even low-risk MGUS, can change over time, progressing to high- or intermediate-risk monoclonal gammopathies to smoldering myeloma and then to multiple myeloma within just 5 years.3

Because the mass spectrometry analysis used in PROMISE is new, and not yet approved by the U.S. Food and Drug Administration for use in the clinical setting, I was instructed to get a clinical validation blood test, which was negative for any signs of MGUS. I will be retested through the PROMISE study in a year.

“Mass spectrometry is a very, very sensitive test, and you just crossed the border of having a negative result, so we had to tell you the finding,” explained Irene M. Ghobrial, MD, principal investigator of the PROMISE study; Director, Clinical Investigator Research Program, Lavine Family Chair for Preventive Cancer Therapies at Dana-Farber Cancer Institute; and Professor of Medicine at Harvard Medical School. In December, Dr. Ghobrial was named Co-Director of Dana-Farber’s Centers for Early Detection and Interception, which are designed to prevent cancer and find the disease before symptoms appear, when it is most curable.

Irene M. Ghobrial, MD

Irene M. Ghobrial, MD

“The clinical serum protein electrophoresis validation test you had to confirm the research finding is much less sensitive and would not detect the very low level of M protein we found in your blood,” she told me. “Still, it is likely that when we repeat the test in a year, your level of M protein could be normal.”

Despite the uncertainty of whether I do or do not have MGUS and what the diagnosis could mean in the long term, after talking with Dr. Ghobrial, I realized I would rather know if I do have the benign condition than not know. But the diagnosis raised another question for me: When do the benefits of screening healthy people for the possibility of cancer outweigh the harms that overscreening can cause, especially for conditions like low-risk MGUS, for which there is currently no intervention to prevent progression to higher-risk MGUS, smoldering myeloma, and multiple myeloma?

Recently, I talked with Dr. Ghobrial about how the development of increasingly sensitive screening technologies are raising concern for patients and physicians about the benefits and risks of cancer screenings; how to manage patients’ fears after a diagnosis of MGUS; and differentiating among precursor conditions, cancers that will never develop to aggressive disease, and those that will.

Weighing the Benefits and Risks of Screening

Getting a positive diagnosis of MGUS, even though I was told the risk of it transforming to high-risk disease and myeloma is small, was anxiety-provoking. How shouldpeople diagnosed with low-risk MGUS be monitored; and how should they think about the condition, as patients-in-waiting for the potential transformation to myeloma?

Once we are confident of a positive finding of MGUS, we are obligated to inform patients. Then we have a discussion with them to provide information and to understand how the diagnosis affects them long term. This is an important question, because the diagnosis can cause anxiety.

We do struggle with whether there is any benefit to telling patients with low-risk MGUS about the diagnosis if we do not have potential therapeutics to prevent disease progression. But it is unethical for us to know a research result and not inform the patient. That said, for conditions such as monoclonal gammopathy of indeterminate potential (MGIP), a monoclonal gammopathy below the clinical immunofixation electrophoresis detection level (< 0.2 g/L), we are currently not informing patients of the finding, because the level of M protein is so low, and we do not know the clinical long-term outcome of MGIP.

“For patients with very low–risk MGUS who will probably never develop cancer in their lifetime, the question is, what is the benefit of screening?”

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Hopefully, we are improving our risk stratification for all monoclonal gammopathies, including smoldering myeloma. In our PROMISE patient cohort, we are finding some patients with very high–risk MGUS who are likely to develop multiple myeloma within 1 or 2 years. These patients are the ones we want to capture now, before they go on to develop active disease and suffer bone pain, pathologic fractures, infection, and anemia.

I have a patient in PROMISE who had very high–risk MGUS numbers. When we repeated the test 6 months later, her numbers were much higher, and we have enrolled her in a clinical trial for high-risk smoldering myeloma to try to prevent overt disease. We recommended another patient in the study with very high levels of monoclonal gammopathy to immediately see her local physician for additional tests for myeloma, and within a week, she was diagnosed with active disease and started on therapy. So, we are seeing people across the monoclonal gammopathy spectrum from very low to very high risk of transforming to myeloma.

For patients with very low–risk MGUS, who will probably never develop cancer in their lifetime, the question is, what is the benefit of screening? My hope is that as we improve on risk stratification to include, in addition to the clinical markers of MGUS, genomic markers and immune markers, we will be able to more precisely stratify an individual’s risk for transforming to active myeloma.

In addition, once we have effective interventions to prevent myeloma—for example, a vaccine that could eliminate a small clone of MGUS that has a chance of developing into cancer in 10 or 20 years—patients may opt for that vaccine or another intervention. For some cancers, such as colorectal cancer, it is possible to prevent the disease from ever developing by removing polyps during a colonoscopy. Interventions we are researching for MGUS come with some side effects, so should we offer them to people with very low–risk MGUS, whose disease may never transform to active myeloma? If the benefit outweighs the risk, then the answer is “yes.”

There are a lot of data showing that people diagnosed with MGUS may also have other comorbidities such as a higher risk of developing blood clots and cardiovascular disease. If we understand the full impact of MGUS, we may start to screen for these other diseases and not just for the development of cancer.

Transforming to Active Myeloma

Who are the people with a diagnosis of monoclonal gammopathy most likely to transform to active multiple myeloma?

Currently, we use clinical immune marker characteristics such as an abnormal serum free-light chains ratio, non-IgG MGUS status, and high serum M protein level (≥ 1.5 g/dL), as well as how fast the numbers are increasing at each repeated test. We are researching to see whether it is possible to perform genomic testing on patients to determine the mutations they have and whether liquid biopsy can be used to detect circulating tumor cells in their blood.

Preventing Multiple Myeloma

Please talk about the potential interventions you are researching for people with high-risk MGUS and smoldering myeloma, who are most likely to transform to active disease.

We are doing a lot of research on interventions for patients with smoldering myeloma, because we know the risk of progression to myeloma is over 50% within 2 years,4 and in this circumstance, the benefit of treatment outweighs any risks. For example, we are investigating chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers in patients with high-risk smoldering myeloma, which is great, because these therapies use a patient’s own immune system to kill myeloma cells.

In general, I think the future for interventions in high-risk MGUS and in smoldering myeloma will include immunotherapies, including CAR T-cell and bispecific antibodies that engage the T cells, as well as vaccines, which we are also investigating. In addition, we are studying prevention strategies, such as lifestyle modifications in patients with obesity, which is a risk factor for multiple myeloma progression. But if we can better understand how to use the immune system to kill precursor cells, that would be the best way to prevent myeloma.

Managing Patients’ Fears

How can oncologists help their patients with low– and low-intermediate–risk MGUS manage their fears that the condition may transform to myeloma?

Most oncologists are busy seeing and caring for patients with high-risk MGUS and those with active disease and are likely to tell patients with low- and low-intermediate–risk MGUS to go back to their primary care physician to monitor the condition.

Very few oncologists specialize in what we are doing in the Dana-Farber Centers for Early Detection and Interception, which focuses on early detection and specializes in understanding the risk of disease progression and the value of early detection of MGUS. If you look at where we are in reducing cancer incidence and mortality, the trend is in prevention and early detection. But we do not have all the tools yet to achieve those goals.

Determining Whether Myeloma Is an Inherited Genetic Disease

In 2022, you published the first results from the PROMISE study, which showed the prevalence of MGUS via mass spectrometry increased with age 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.5 Still, those with a family history of myeloma have between a twofold and fourfold increased risk of developing the disease. Is myeloma beginning to look like an inherited genetic disease?

We are doing a lot of germline sequencing now, especially in those with a strong family history of MGUS, myeloma, and lymphoma, and I do not have an answer yet about whether myeloma is an inherited genetic disease. This is a huge area of interest for us, but we need large numbers of people to conduct this type of study, and we do yet not have enough data needed to answer this question.

Defining Benign Conditions That Will Never Turn Into Malignancies

Screenings for cancer can feel empowering to people as a way to find and treat cancer early, improving the potential for cure, and advances in cancer screening technologies make it possible to find cancers earlier and earlier. However, many of these cancers, including low-grade ductal carcinoma in situ (DCIS), for example, may never turn into aggressive disease. Yet the use of bilateral mastectomy has increased over the past 2 decades for women diagnosed with DCIS, in whom the rate of bilateral mastectomy nearly tripled from 2005 to 2013.6

Currently, screenings for MGUS are limited to the research setting for high-risk individuals. Is there a potential danger of overdiagnosis and overtreatment if screening for MGUS becomes available to the general public?

Yes, absolutely. This is why we need to differentiate between precursor conditions and the cancers that will never develop to active disease and those that will in a person’s lifetime—for example, DCIS that will never go on to develop aggressive breast cancer from the DCIS that will go on to advanced disease—and predict when that development is likely to happen; is it in 5, 10, or 15 years?

Once we have that understanding and have confirmed the data, we can be confident about informing a patient it is not necessary to do anything about the finding and the mutation we found in a normal cell is common as we age. All of us get precancerous conditions that may never develop into cancer. We want to be able to differentiate between those conditions and a mutation that is a cancer we need to detect early to prevent it from becoming aggressive.

There is a lot of research underway to see whether we can detect good biomarkers to tell us which patients will develop cancer over their lifetime. Once we can do that, we can truly say we are not overdiagnosing, underdiagnosing, overtreating, or undertreating patients.

Perhaps what we need to do—in the case of MGUS, which is a benign condition—is to more specifically define which types of MGUS are likely to change to active myeloma, rather than give everyone the same diagnosis. If we could just treat myeloma a little bit earlier to prevent end-organ damage, bone lesions, and bone fractures, it would make a huge difference in the quality of life for patients. But defining the people diagnosed with monoclonal gammopathies who will need treatment 1 or 2 years before they experience these issues is critical, and we will not get this information unless we screen for it.

We are currently stuck with diagnosing a lot of people with a condition we should call benign gammopathy, so we do not make patients overly anxious. But we cannot define who those patients are until we understand the ramifications of MGUS better. 

DISCLOSURE: Dr. Ghobrial has received honoraria from Bristol Myers Squibb, Takeda, Amgen, Janssen, Vor Biopharma, and AbbVie; has served as a consultant to Bristol Myers Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar, Sanofi, Janssen, Pfizer, Menarini Silicon Biosystems, Oncopeptides, The Binding Site, GlaxoSmithKline, AbbVie, Adaptive, and 10xGenomics; and has received reimbursement for travel, accommodations, and expenses from Bristol Myers Squibb, Novartis, Takeda, and Janssen Oncology. Dr. Ghobrial’s spouse, William Savage, MD, PhD, is Chief Medical Officer at Disc Medicine and holds equity in the company.


1. Manier S, Salem KZ, Liu D, et al: Future directions in the evaluation and treatment of precursor plasma cell disorders. ASCO Educational Book 36:e400-e406, 2018.

2. Marinac CR, Ghobrial IM, Birmann BM, et al: Dissecting racial disparities in multiple myeloma. Blood Cancer J 10:44, 2020.

3. Landgren O, Hofmann JN, McShane CM, et al: Association of immune marker changes with progression of monoclonal gammopathy of undetermined significance to multiple myeloma. JAMA Oncol 5:1293-1301, 2019.

4. Mateos MV, Kumar S, Dimopoulos MA, et al: International Myeloma Working Group risk stratification model for smoldering multiple myeloma. Blood Cancer J 10:102, 2020.

5. El-Khoury H, Lee DJ, Alberge JB, et al: Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screen by mass spectrometry: A multicenter cohort study. Lancet Haematol 9:e340-e349, 2022.

6. Miller ME, Muhsen S, Olcese C, et al: Contralateral breast cancer risk in women with ductal carcinoma in situ: Is it high enough to justify bilateral mastectomy? Ann Surg Oncol 24:2889-2897, 2017.