ultiple myeloma (MM) is a blood cancer that evolves from the early precursor conditions of monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to overt myeloma at a slow rate, and early diagnosis and treatment are critical to ease the personal and economic burden to patients. This article discusses why early detection matters, who should be screened, and the need for precise risk stratification.

What is multiple myeloma, and can we detect it early?

In multiple myeloma (MM), clonal plasma cells (white blood cells that produce antibodies) proliferate in the bone marrow. This results in overproduction of monoclonal immunoglobulin heavy and/or light chains, components of antibody proteins. Because of uncontrolled protein deposition, this increased circulating protein production can result in damage to various consequential end organs. Myeloma always evolves sequentially from the early precursor conditions of monoclonal gammopathy of undetermined significance (MGUS) and then to smoldering MM (SMM). Both conditions are often incidentally detected when a monoclonal gammopathy (MG), or abnormally augmented proteins called monoclonal (M) proteins, is found in the blood and/or urine. MGUS and SMM are distinguished by their annual risk of progression to myeloma. In general, MGUS progresses to overt myeloma at a slow rate of 1% per year, but the risk may be as high as 58% over 20 years in some patients. SMM has an annual risk of progression of 10%, but the risk is considerably higher in some patients. Patients with MGUS and SMM have a slightly decreased life expectancy compared to the general population, raising the possibility that other disorders are associated with MGUS and SMM that have not yet been identified. These considerations raise the important question of whether early detection can help prevent or at least delay later morbidity and mortality.

Why does early detection matter?

Although many patients are diagnosed at these early phases of disease, most do not receive treatment until they progress to overt myeloma (which is defined by end-organ damage, namely anemia, renal failure, lytic lesions and bone fractures, and hypercalcemia). The standard of care for these patients with early manifestations of disease like MGUS, or even SMM, is careful observation until end-organ damage occurs. This is analogous to treating a patient with breast cancer or colon cancer only after metastatic disease has occurred. It is no wonder that even with major advances in our treatment armamentarium for myeloma, we have not achieved a cure. Indeed, there could be great advantages to treating “precursor” myeloma before further acquisition of genomic aberrations, immune dysregulation, and clonal expansion. This hypothesis has been solidified by two norm-challenging phase III clinical trials that studied the effect of treating high-risk SMM patients with lenalidomide and dexamethasone (LenD; QUIREDEX, NCT00480363) or lenalidomide alone (NCT01169337) compared to observation, or so-called watchful waiting. They showed that early intervention indeed improves survival compared to observation. Both studies showed an improvement in progression-free survival (PFS), while one also demonstrated an improvement in overall survival. Several studies have attempted to improve upon the benefit observed with lenalidomide in SMM. Some of these are evaluating achieving deep remission in SMM with overt myeloma therapy.

Another major advantage of early therapeutic intervention is the decrease in the personal and economic burden on the patients. Early detection and interception would significantly reduce the cost of hospitalizations due to renal failure, bone fractures, etc., as well as reduce the personal impact on socioeconomic factors for time away from work and burden on the family with a sudden interruption of life by an accidental diagnosis and treatment of cancer compared to a planned, proactive decision to intervene early . This is especially true if the interception is not toxic.

Who is at risk, and what is the prevalence in the high-risk population?

Screening for diseases such as breast and colon cancer has been shown to save lives. Currently, there is no routine screening for myeloma or other blood cancers in the general population, despite it being a simple blood test with better sensitivity and specificity of detection of a monoclonal protein compared to intrusive and potentially nonsensitive studies such as mammograms and colonoscopies. The traditional argument for many years has been that there is no benefit from early detection because we still observe patients until they develop symptoms, and that the progression rate is low at 1% per year. However, this argument is no longer valid with the current data demonstrating that early interception has a significant beneficial effect on survival and that within a given population some individuals may be at much higher risk compared to the average. The only way to identify early asymptomatic cases is to systematically screen healthy individuals at risk.

MGUS is quite prevalent in the general aging population, affecting an estimated 3% of Americans aged 50 and older. However, this statistic is based on a mostly white population tested with an old technology, serum protein electrophoresis, and does not account for people at risk because of race or family history. MGUS and myeloma exhibit one of the largest racial disparities of all cancer types: compared to Whites, Blacks/AA have a two- to three-fold higher prevalence of MGUS and are more likely to develop MGUS at younger ages. MGUS and myeloma prevalence are also two-fold higher in individuals who have a first-degree relative diagnosed with a myeloma-related disorder or other lymphoproliferative disease. Our best estimate is that 12 million to 15 million people in the US alone have MGUS.

Who should be screened, and will screening offer more benefit than harm?

To answer this question, two studies were launched in the last few years, the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM) in Iceland and the PROMISE study in the US. iStopMM has enrolled over 80,000 individuals, which represents over half the eligible Icelandic population. This huge sample size provides a unique opportunity to measure the impacts of screening and early diagnosis on the lives and health of patients. We eagerly await additional results from this study.

The PROMISE study only screened high-risk individuals, namely African Americans and those with a first- or second-degree relative with a blood cancer. The study screened 7,600 individuals by quantitative mass spectrometry (MS) and found monoclonal gammopathies (MGs) in 40% of high-risk individuals aged 50 and older, 13% of which were at high levels of MGs, termed MS-MGUS; a lower fraction of MGs were further defined as monoclonal gammopathy of indeterminate potential (MGIP). Patients with monoclonal gammopathies had worse overall survival. Moreover, MGs were associated with developing blood cancers, cardiovascular diseases, and autoimmune disorders. The results indicate that older adults in these populations could potentially benefit from regular, high-sensitivity screening to identify MGs and potentially consider further investigations into their risk not only for myeloma but for other co-morbidities.

Why is early intervention not adopted yet as standard of care, and what are the next steps?

Treatment of SMM remains highly controversial. On the one hand, early intervention with LenD may slow progression to myeloma, but not increase overall survival, and can cause clonal selection in some patients who may need more aggressive therapy when their disease does advance. On the other hand, early intervention with optimal therapy may prevent end-organ damage, prolong time to disease progression, and induce deeper remission. Therefore, well-designed studies to define the population that would benefit from specific therapeutic interventions based on more precise risk stratification may help to advance the myeloma field toward a cure. Precision interception in high-risk SMM would help identify the subgroups of SMM patients who would benefit from more intensive therapy than LenD, such as those with 17p or p53 mutations, complex high-risk genomic alterations, or whose pace of disease progression can be quantitatively demonstrated to be more rapid than average. For these patients, four-drug regimens such as daratumumab/carfilzomib/lenalidomide and dexamethasone or daratumumab/bortezomib/lenalidomide and dexamethasone are being investigated. More interestingly, new studies using immunotherapies in high-risk SMM are being designed, including the use of bispecific antibodies or cellular therapies, such as CAR-T. These therapies may prove efficacious in high-risk disease without the need of using the conventional treatment options that are standard of care for overt myeloma. Other precision intervention options include the use of venetoclax in patients with translocation (11:14), who could benefit from therapy that targets this early cancer-causing event before additional genomic events lead to drug resistance.

Precise risk stratification of high-risk SMM patients would help healthcare providers identify those who would most benefit from specific therapeutic interventions.

Based on the above overview, it has been suggested that there are likely to be genomic, genetic, and epigenetic factors that govern the process of progression from MGUS to SMM to overt myeloma that are not fully understood. Patients with SMM have an annual risk of progression of 10% for the first 5 years, which drops to 3% for the following 5 years and down to 1% per year after that, similar to patients with MGUS. As such, SMM is thought to represent a mixture of high-risk patients, who could perhaps benefit from early therapeutic intervention before irreversible organ damage and symptoms appear, and low-risk MGUS-like patients, who may never progress and for whom treatment may represent more of a risk. However, as prediction models improve and newer, less toxic treatments become available, the optimal timing and patient group for initiation of therapy becomes a subject of debate. In 2014, the International Myeloma Working Group updated the diagnostic criteria for overt MM to include certain laboratory and imaging markers to identify patients who would benefit from therapy despite being asymptomatic. These myeloma-defining events (MDE) comprise a bone marrow plasma cell infiltration ≥60%, a serum involved free-light-chain ratio ≥100, or two or more focal lesions on cross-sectional imaging. Further studies are needed to develop insights into the kinetics of clonal progression as well as genomic and immune scoring systems to identify patients likely to progress to myeloma so that therapy can be initiated early with more precision.