In 2018, researchers from Dana-Farber Cancer Institute launched a large, ambitious screening study called (PROMISE; ClinicalTrials.gov identifier NCT03689595) to identify people with premalignant precursor conditions of multiple myeloma, to understand the molecular signs of progression to myeloma and develop therapies to thwart that progression. Funded as part of the Stand Up to Cancer Multiple Myeloma Dream Team, PROMISE’s goal is to enroll 50,000 individuals between the ages of 40 and 75 in the United States and Canada who are at high risk of developing multiple myeloma, including those with a first-degree relative diagnosed with multiple myeloma or one of its precursor conditions (monoclonal gammopathy of undetermined significance, smoldering myeloma, or Waldenström’s macroglobulinemia) and African American individuals with or without a family history of multiple myeloma.
High-risk individuals enrolling in PROMISE must complete an online health questionnaire and submit a blood sample for genetic testing. Patients who test positive for a myeloma precursor condition will be referred to a hematologist or oncologist for follow-up and may have the opportunity to participate in a clinical trial investigating new therapies to prevent progression to myeloma.
Although age is a critical risk factor in the development of multiple myeloma—most of the approximately 32,000 people diagnosed each year with the cancer are older than age 651—persons of African and African American descent have a threefold increased prevalence of the cancer than 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 which suggests a potential genetic predisposition among these populations, although the genetic basis of inherited myeloma susceptibility is not well understood.2
Predicting Who Will Develop Myeloma
Studies show that all patients diagnosed with multiple myeloma had prior monoclonal gammopathy of undetermined significance or smoldering myeloma precursor conditions, which most likely went undiagnosed because they are often asymptomatic and there are no routine screenings for these conditions. Not every patient with myeloma precursors goes on to develop active disease, although the risk is higher for those with smoldering myeloma.
Irene Ghobrial, MD
“Although the chance of patients with monoclonal gammopathy of undetermined significance or smoldering myeloma developing myeloma may be low, we should be looking for these precursor conditions with the goal of preventing myeloma. That is the hope of the PROMISE study. We should not be waiting for people to develop myeloma,” said Irene Ghobrial, MD, Director of the Michele & Steven Kirsch Laboratory; Director, Clinical Investigator Research Program at Dana-Farber Cancer Institute; Professor of Medicine at Harvard Medical School; and Principal Investigator of the PROMISE study.
The ASCO Post talked with Dr. Ghobrial about the launch of the PROMISE study and how its findings could lead to the conversion of multiple myeloma from an almost-always fatal disease to a preventable one.
Risk Factors for Myeloma
In addition to aging, the development of multiple myeloma has been linked to environmental exposures. Do you expect PROMISE to definitively answer whether myeloma is a genetic disease?
Aging, environmental factors, and family history are very important in the development of multiple myeloma. All participants enrolling in PROMISE, whether they test positive or negative for precursor conditions, will answer an epidemiology survey that asks about their diet, environmental exposures, and body weight, among other data. We are also looking at patients’ immune microenvironment to see how well the immune system is working to kill cancer cells, as well as their macroenvironment and how they both interact with the patients’ genetics and genomics. So, our study is all-inclusive and a truly holistic approach to try to understand all the factors that lead to the development of myeloma.
Our goal is to enroll 50,000 participants into the study, because we calculate that we need 50,000 people to find 3,000 patients with precursor conditions. The most important questions we are trying to answer are: Can we detect myeloma early by screening? Can we define who will progress quickly or not at all to myeloma, because some people will never progress to active disease? Can we develop an intervention for those patients to prevent myeloma?
Understanding Why Myeloma Is Trending Younger
More than one-third of patients diagnosed with myeloma are younger than age 65,3 and studies suggest that the cancer is more aggressive in these patients. Why do you think younger adults are being diagnosed with this cancer?
We don’t know why younger adults are developing this cancer, because it is more commonly a disease that happens as we acquire more and more somatic mutations through aging. We are studying a subgroup of younger patients, up to age 40, to try to understand whether they have a different type of myeloma than older adults and whether they develop an aggressive myeloma because they have certain genetic or genomic markers that lead to quicker disease progression. So, instead of taking 20 years to go from precursor monoclonal gammopathy of undetermined significance to active myeloma by age 60 or 65, for example, some younger patients are developing precursor conditions and within a few months progressing to myeloma. We don’t know why this may be happening.
Moving Away From Watchful Waiting?
The PROMISE study may ultimately eliminate the approach of watchful waiting in patients with precursor conditions. What types of early therapeutic interventions do you envision to prevent disease progression?
We have a whole algorithm of potential ideas to stop progression to active myeloma, as well as some clinical trials that are already underway. We have divided the trials between patients with monoclonal gammopathy of undetermined significance and early smoldering myeloma to try to design a therapy specifically for each patient. We are not talking about using conventional chemotherapies in these patients. Instead, we are thinking about investigating immunotherapies, vaccines, or agents that change the glycolytic pathway, for example, metformin.
For patients with higher-risk smoldering myeloma, we are thinking of using more aggressive immunotherapies, including bispecific monoclonal antibodies or combinations of immunotherapies with targeted agents, to perhaps achieve a cure. We also have ideas for using other multiple drug combinations to treat these patients, with some trials already underway, and we are in the process of designing more clinical studies that may be able to prevent or cure myeloma in the future.
PROMISE of Preventing Multiple Myeloma
Can multiple myeloma really be transformed into a preventable cancer?
I believe so, absolutely, and it is my hope that we prove that. I really think we can prevent this cancer.
In the PROMISE study, we take three vials of blood from participants; we use them for serum protein electrophoresis to measure specific proteins in the blood, serum free light chain analysis to look for excessive production of antibodies, and mass spectrometry analysis to measure levels of monoclonal immunoglobulins, to diagnose all cases of monoclonal gammopathy of undetermined significance or smoldering myeloma. We are also conducting next-generation sequencing to determine each patient’s genetic markers to learn which mutations are predictive for progression to active disease. If we can prevent these patients from having bone fractures and anemia, we should not be diagnosing patients with myeloma in the future.
We encourage all high-risk individuals for myeloma to learn about the PROMISE study and enroll in the study at promisestudy.org. Knowledge is empowering. Some people may hesitate to participate in the study because they don’t want to know if they have a precursor condition, but there is something powerful about having that information. Learning that you have a precursor condition is not a guarantee you will develop active myeloma, and it is not a death sentence. Having this knowledge can give people the power to learn about early interventions that can prevent myeloma.
Preventing and curing more cancers are our ultimate goals. ■
DISCLOSURE: Dr. Ghobrial has consulted for Takeda, Janssen, Bristol-Myers Squibb, and Celgene.
REFERENCES
1. American Cancer Society: Key statistics about multiple myeloma. Available at http://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html. Accessed November 25, 2019.
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. Gandolfi S, Prada CP, Richardson PG: How I treat the young patient with multiple myeloma. Blood 132:1114-1124, 2018.
