In this issue, Visram et al1 make a significant advancement in the controversy of screening of multiple myeloma (MM) by providing an initial answer to the question “Is monoclonal gammopathy the same entity when diagnosed through screening compared with incidental detection?” The study addresses this concern, demonstrating that after accounting for competing risks of death, the progression risk is similar for patients with screened vs clinically detected monoclonal gammopathy of undetermined significance (MGUS). They also found that progression risk factors, such as the size of the M spike, abnormal free light chain ratio, and immunoparesis, are consistent regardless of how MGUS is detected.
MM is a plasma cell neoplasm that is almost always preceded by precursor conditions, specifically MGUS and smoldering myeloma (SMM).2 Patients are diagnosed when they present with symptoms or signs of end-organ damage.3 However, many individuals are diagnosed with incidental MGUS when physicians order serum protein electrophoresis (SPEP) and immunofixation while investigating other conditions, such as neurological or rheumatological disorders.3 This study investigates whether risk stratification models developed for incidentally found MGUS or SMM can be applied to those detected through screening. If applicable, this could enable the swift implementation of enhanced risk stratification for screened cases, helping to identify individuals at the highest risk for progression. This would allow for closer monitoring, prevention, or early interventions for those at greater risk.
Over 50 years ago, Kyle and his colleagues characterized MGUS not merely as a benign gammopathy but as a condition of undetermined significance.4 The first screening study for MM demonstrated the prevalence of MGUS to be approximately 3% in the population over age 50. They also noted that MGUS progresses to MM in about 1% of cases per year. By comparison, SMM has a 10% annual risk of progression for the first 5 years. High-risk SMM is defined by 2 of the following factors: >20% plasma cells in the bone marrow, >2 g/dL M spike, or a serum free light chain ratio of 20; it has a 44% chance of progression in 2 years to overt MM.5 Subsequent studies indicated that MGUS is two- to threefold more prevalent among individuals of African descent, consistent with the higher incidence of MM in these populations.6
Two significant screening studies were initiated in the last decade. The Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study screened over 80 000 individuals aged 40 and older in Iceland, randomizing them into 3 arms: arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. The data comparing early intensive workup to no follow-up is maturing and will contribute to assessing whether MGUS screening improves overall survival in that population. The study also found that the prevalence of SMM is about 0.5% in the general population over age 40.7
The Predicting Progression of Developing Myeloma in a High Risk Screened Population (PROMISE) study focuses on screening high-risk individuals, specifically those of African descent or with a family history of myeloma, and continues to recruit 30 000 individuals. Early results indicated a prevalence of 13% in these high-risk groups, attributed to both the higher-risk population screened and the use of mass spectrometry, a more sensitive test compared with SPEP.8
The rationale for cancer screening is to identify diseases in their earliest stages, allowing for early intervention to improve survival outcomes. The Wilson and Jungner principles of screening outline essential requirements for effective screening tests.9 Applying these principles, we find that MM is indeed a significant health issue with accepted treatment options available. It has a recognizable early symptomatic phase and a cost-effective, sensitive, and specific blood test for diagnosis. Additionally, the natural progression of the disease is well understood, with clear policies for treating symptomatic patients.
However, despite that SPEP is a simple, sensitive, and specific blood test, the approach of MGUS screening has not gained widespread acceptance. If nearly all cases of MM begin with MGUS, could screening facilitate earlier identification and intervention before the onset of symptoms or end-organ damage? Could this improve survival and quality of life? Might myeloma be a preventable disease if detected and treated early?
Two main limitations prevent MGUS screening from becoming standard practice. First, we need to determine whether the natural history of a screened population differs from that of individuals incidentally diagnosed with MGUS. Can we apply the risk models and stratifications for MGUS and SMM progression to patients detected through screening, or do these patients exhibit different rates of disease progression? The study by Visram et al indicates that the progression rate of MGUS is similar for individuals diagnosed incidentally and those identified through screening. However, the study’s findings are primarily based on a population of European ancestry, highlighting the need for additional research to assess these results in more racially diverse populations.
Secondly, the most significant issue is that there is currently no accepted treatment to prevent or delay the progression from MGUS to MM, meaning that any MGUS diagnosis could lead to patient anxiety without tangible benefits. Recent studies indicate that early treatment of SMM can significantly improve progression-free survival.10 Nevertheless, differing definitions of risk and treatment approaches have resulted in a lack of consensus regarding the early treatment of SMM. Further randomized studies comparing therapy to observation, as well as other novel approaches aimed at achieving deep remissions to prolong the delay of progression, are currently underway. Additionally, more innovative strategies, such as vaccines for cancer prevention, are being developed.
Should a therapeutic intervention be approved and conclusively shown to improve survival for asymptomatic patients, it would warrant a mandate for early screening to identify those who could benefit most. The hope is that this could mirror the success story of the human papillomavirus (HPV) infections and cervical cancer. By screening for HPV and preventing infections with a vaccine, many cases of cervical cancer can be prevented. Can we envision a similar prevention strategy for MM?
If approved therapies for asymptomatic SMM are not paired with routine screening, we risk identifying patients by chance rather than ensuring access for all those at risk. This could exacerbate disparities in care among patients of different ethnic and racial backgrounds, who are already disadvantaged by delayed identification of MM. Implementing screening, especially for high-risk groups such as African Americans, could significantly improve early detection and intervention in a demographic that frequently faces delayed diagnoses and treatments. A systematic approach that benefits everyone, rather than just a select few, would result in a larger absolute number of patients receiving earlier therapeutic interventions.
Considering all these factors, the study by Visram et al initiates a crucial conversation about screening in MM. The next significant milestone would be the approval of therapeutic intervention in asymptomatic MM, which would strongly support the case for early screening of MGUS, as early intervention could greatly improve patient outcomes. The long-term follow-up of the ongoing iStopMM and PROMISE studies will help determine whether early screening improves survival outcomes for patients with MGUS and SMM.
Conflict-of-interest disclosure: I.M.G. reports consulting/advisory roles at AbbVie, Adaptive, Amgen, Aptitude Health, Bristol Myers Squibb, GlaxoSmithKline, Huron Consulting, Janssen, Menarini Silicon Biosystems, Oncopeptides, Pfizer, Sanofi, Sognef, Takeda, Binding Site a part of Thermo Fisher Scientific, Window Therapeutics, and 10× Genomics; speaker fees from Vor Biopharma and Veeva Systems, Inc., and is a cofounder and holds private equity in PreDICTA Bioscience. I.M.G.’s spouse is the Chief Medical Officer and holds private equity in Disc Medicine. F.C. declares no competing financial interests.
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