What are the precursor conditions to multiple myeloma?

What are the precursor conditions to myeloma? How are MGUS and smoldering myeloma defined?

So what is MGUS and smoldering multiple myeloma? These are precursor conditions to multiple myeloma. Patients with these precursor conditions are asymptomatic and have a higher than average lifetime risk of progressing to overt multiple myeloma. They are characterized based on a continuum.

MGUS is the earliest stage, typically characterized as a patient having less than three grams per deciliter of an M-spike and less than 10% plasma cells or cancer cells in the bone marrow.

What is smoldering myeloma? Smoldering multiple myeloma is a slightly more advanced state prior to the development of overt multiple myeloma. It's characterized by an M-spike of greater than three grams per deciliter, as well as a bone marrow plasma cell percentage of 10 to 60%, with the absence of other features that might define myeloma, such as a very high serum free light chain ratio, a focal lesion on an MRI, or organ damage, which would be CRAB criteria for multiple myeloma.

What is high-risk smoldering myeloma? High-risk smoldering multiple myeloma is typically characterized based on an individual's likelihood of progressing to overt multiple myeloma in the near future. We use several key clinical metrics to understand a patient's risk, including how high their serum free light chain ratio is, how many plasma cells they have in the bone marrow, and their M-spike. Individuals with two or more of these features are considered at high risk for developing multiple myeloma and are often key candidates for clinical trials.

What is the PROMISE study? Dr. Marinac just described the Mayo 2018 20/20/2 model. The Mayo Clinic 2018 model includes serum biomarkers and a Bone Marrow Plasma Cell burden of more than 20% as risk factors. The IMWG validated the Mayo Clinic 2018 model with a cohort of 1996 patients, and the 2-year risk of progression to myeloma or amyloidosis in low-, intermediate-, and high-risk groups was 6%, 18%, and 44%, respectively. Risk factors in the older PETHEMA model include the presence of immunoparesis and the percentage of Plasma Cells with an aberrant immunophenotype. However, the requirement for multiparameter flow cytometry makes the PETHEMA model difficult to implement clinically.

Although the PETHEMA and Mayo Clinic 2018 models are used in clinical trials and practice, the classification of “high-risk” SMM is significantly discordant between the models. To further optimize risk stratification, the IMWG recently developed a risk stratification model incorporating high-risk cytogenetic markers, including translocation(4;14), translocation(14;16), a gain of 1q, monosomy 13 deletion, and more refined criteria for risk factors included in the Mayo Clinic 2018 model. Using the IMWG 2020 model, intermediate- and high-risk patients with SMM had a 2-year risk of progression to myeloma or amyloidosis of 51% and 73%, respectively.

The PROMISE study is a nationwide screening study for individuals at higher than average risk of developing multiple myeloma or its precursor condition within their lifetime. It's based on the premise that detecting multiple myeloma at its earliest stages, particularly at the precursor stages, is critical to preventing it and helping a person live a long, healthy life.

PROMISE enrolls individuals who are over the age of 40. Since the recording of this video, the age to qualify for the PROMISE study screening is now 30 or over, and participants must be either Black or African American, or have a strong family history of a blood cancer or blood cancer precursor condition like MGUS or smoldering multiple myeloma.

Individuals interested in the PROMISE study can enroll through the website, PROMISEstudy.org, by taking a brief eligibility survey or consenting to the study. We send them a kit to take to a Quest laboratory to collect their blood, which is sent back to us, and we share the results with patients.

If a patient enrolled in PROMISE screens negative, we will rescreen them in the future. If a patient screens positive for a precursor condition, they meet with a clinician as part of our study team, typically a research nurse or a nurse practitioner, who provides them with the education and resources they need for appropriate follow-up care. We also follow them over time because the more patient information we have about myeloma and its precursor conditions, the better we can design studies to help patients.

What are some initial findings from the PROMISE study? From the first 2000 patients in the PROMISE study, one striking finding is that precursor conditions for multiple myeloma are very common, particularly about twice as common among individuals who are Black or African American or have a family history of blood cancer or blood cancer precursor conditions. Many patients in the country, millions of individuals, have these precursor conditions to multiple myeloma but don’t know about it.

Dr. Robert Kyle has cataloged patient histories and archived blood samples, observing a vast number of people with plasma cell proliferative disorders for more than 60 years. One case he reviewed involved a patient named Mrs. Ahlstrom, who had been seen at the Mayo Clinic 19 years prior because she wasn't feeling well. She was found to have an increase in the globulins in her blood but was told to go home since her blood work was otherwise good. She returned 13 years later when serum protein electrophoresis was possible, showing a very large spike of about 2.9g per deciliter, yet remained asymptomatic and was again told to enjoy life.

Seven years later, she developed symptomatic multiple myeloma with bone pain and various problems. She was treated with two alkylating agents, the only two available at the time, which had minimal response, and unfortunately, she died about nine years later. We have followed a cohort of patients with monoclonal gammopathy of undetermined significance (MGUS) for 40 years, and over that period, we found that almost 1% of these individuals progressed to symptomatic multiple myeloma requiring therapy, Waldenstrom macroglobulinemia if they had an IgM monoclonal protein, or AL amyloidosis.