1. May, Brandon

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Monoclonal gammopathy of undetermined significance (MGUS), a premalignant precursor of multiple myeloma, is present in approximately 3.2 percent and 5.3 percent of the population aged >=50 and >=70 years, respectively. Considering the rate of MGUS-particularly its rate of progression to multiple myeloma-persists throughout time, patients require close follow-up each year.

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According to previous research, MGUS may be the result of an event cascade following abnormal responses to antigenic stimulation, which may be primarily mediated by overexpression of IL-6 receptors and aberrant Toll-like receptor expression (Leukemia 2006;20(6):1130-1137). The risk of progression from MGUS to multiple myeloma has been described in previous research (Oncology (Williston Park) 2011;25(7):578-586).


Mechanisms that fuel this progression, however, remain less clear, and few studies have determined conclusive drivers behind this transition. Certain pathogenetic abnormalities, such as p53 and Ras mutations, myc abnormalities, secondary translocations, and p16 methylation may be implicated in this progression (Clin Cancer Res 2009;15(18):5606-5608). The type and size of serum monoclonal (M) protein, as well as an abnormal serum free light chain (FLC) ratio presence, represent two of the key risk factors associated with progression (Blood 2005;106(3):812-817).


Previous studies have also demonstrated that there may be certain genetic and environmental factors associated with the development of MGUS. For instance, African-Americans have an approximately twofold to threefold higher MGUS risk versus white Americans (Blood 2006;107(3):904-906, Mayo Clin Proc 2007;82(12):1468-1473). In contrast, the risk for MGUS is lower in Asians from Japan (Mayo Clin Proc 2007;82(12):1474-1479). There's hope that understanding MGUS risk factors may provide future insight into strategies that prevent or delay the progression of MGUS to multiple myeloma; however, this insight is on the very distant horizon.


MGUS Mayo Clinic Study

The Mayo Clinic in Rochester, Minn., has been one of the leaders in researching MGUS and its rate of progression into myeloma. Findings of an extension study from Mayo Clinic researchers have recently found that the risk for the progression of MGUS to multiple myeloma or a related blood cancer persists at 1 percent per year and up to 30 years after receiving the initial MGUS diagnosis (N Engl J Med 2018;378(3):241-249).


"Our study showed significant differences in the mode and risk of progression between patients with IgM MGUS and those with non-IgM MGUS," according to study investigator Robert Kyle, MD, a hematologist at the Mayo Clinic. "We also found that the current risk-stratification model according to the M protein level and serum FLC assay was valid in these two forms of MGUS."


In this study, investigators evaluated patients who received an MGUS diagnosis at the Mayo Clinic between the years 1960-1994 (n=1384). At median follow-up of 34.1 years (range, 0.0-43.6), the investigators assessed the participants' progression to multiple myeloma or a plasma-cell or lymphoid disorder. In addition, the investigators evaluated differences in disease progression among patients featuring either immunoglobulin M (IgM) (n=210) or non-IGM (n=1129) MGUS biologic subtypes. Additionally, the researchers compared event risks with age-, sex-, and calendar year-matched control patients who participated in the Iowa Surveillance, Epidemiology, and End Results (SEER) program.


S. Vincent Rajkumar, MD, Mayo Clinic researcher and senior author of this study, stated that Mayo Clinic currently does not recommend MGUS screening. "If MGUS is detected incidentally during workup for other conditions, risk stratification will help with how much testing is needed at baseline and the type of follow-up that is needed," he noted. "It is possible that appropriate follow-up of higher-risk MGUS patients can enable early diagnosis and improve survival in myeloma; however, this needs to be proven first."


Risk for Multiple Myeloma Persists

Progression of MGUS to multiple myeloma or similar blood disorder occurred in 11 percent (n=147) of patients during the follow-up of 14,130 person-years, translating to a 6.5-times higher rate than the control group (95% CI, 5.5-7.7). At 10, 20, 30, and 35 years, the risk of MGUS progression to a blood disorder was 10 percent, 18 percent, 28 percent, and 36 percent, respectively. A significantly higher risk of progression was observed among IgM MGUS versus non-IgM MGUS patients (1.1 events per 100 person-years vs. 0.8 events per 100 person-years, respectively; p<0.001). Also, in the first 10 years, the risk of progression was 2 percent per year versus 1 percent per year after 10 years.


Compared with the SEER patient population, IgM MGUS (relative risk [RR], 10.8; 95% CI, 7.5-15.0) was associated with a higher risk for progression than those in the non-IgM MGUS group (RR, 5.7; 95% CI, 4.7-6.9). A high serum M protein level (>=1.5 g per dL) and an abnormal serum FLC ratio (kappa/lambda FLCs) were two adverse risk factors associated with a 20-year progression risk of 55 percent compared with 41 percent and 19 percent in patients with just one risk factor or no risk factors, respectively.


Conversely, a low M protein level (<1.5 g per dL) and a normal serum FLC ratio were associated with an average of 1.1 events (95% CI, 0.6-2.0) per 100 person-years versus 3.6 events (95% CI, 1.8-7.2) per 100 person-years in those with high serum M protein levels and an abnormal serum FLC ratio.


Plasma-cell disorders and non-plasma-cell disorders (e.g., non-plasma-cell cancers, cardiovascular disease, and cerebrovascular disease) accounted for 11 percent and 87 percent, respectively, of deaths at 40 years. Patients with a MGUS diagnosis had a significantly shorter median survival rate compared with the matched control population (8.1 years vs. 12.4 years, respectively; p<0.001). At 30-year follow-up, the overall survival among patients with IgM MGUS was 4 percent (95% CI, 2-9) versus 7 percent (95% CI, 6-9) in non-IgM MGUS patients (p=0.12).


Clinical Care Implications

"This study demonstrates that the risk of progression to multiple myeloma [from MGUS] persists," said Daniel Auclair, PhD, Senior Vice President of Research at the Multiple Myeloma Research Foundation in Norwalk, Conn. "Even if you haven't developed multiple myeloma at 20 or 30 years, you're still not out of the woods."


According to Auclair, this study demonstrates the clinical utility of certain parameters, including high serum M protein level and an abnormal serum FLC ratio, but further research is needed to examine the granular aspects of progression risk. "If you can start to get a handle on a very precise biomarker on the risk of progression, you could maybe see if someone is on the path to progression. Still, we need to dig more deeply into the fine predictors of progression."


He also added that similar findings in future research may help identify better treatment strategies, particularly early in the start of multiple myeloma. "Current standard of care is observation. There are differences in patients' biology, but maybe we'll find some immune differences in this disease, and maybe we can decide if there should be greater interventions."


Although the study from Kyle and colleagues provides important insight into MGUS and its risk factors associated with progression to blood cancer, there were some important limitations that were addressed by the team at the Mayo Clinic. The small number of patients taken from a specific geographic location (Minnesota), for example, reduces the findings' generalizability across the entire MGUS population.


According to Auclair, future research may want to include a greater number of high-risk patients. The Multiple Myeloma Research Foundation is seeking to accomplish this soon and is currently developing a national myeloma registry that includes multiple myeloma patients all over the world. "You want to be able to have more certainty, and this comes from greater diversity," noted Auclair. "You need about 3,000-5,000 individuals screened to make sure you've accomplished this diversity."


Auclair mentioned that awareness of a precursor to disease may help slow or prevent progression to that disease. Whether this can help in terms of slowing progression of MGUS to multiple myeloma remains uncertain. According to Kyle and his research team, "Despite MGUS being a prevalent disorder that is associated with a modest but persistent lifetime risk of progression to incurable cancer, there are limited data at present to indicate that screening for MGUS or monitoring improves outcomes in patients."


While the risk for progression to multiple myeloma is small, Rajkumar emphasized that this risk persists indefinitely. Practicing oncologists "should also know that MGUS patients are far more likely to die of causes other than myeloma or related disorders and, therefore, they need the usual screening and care for other conditions as any other patient in that age group."


Brandon May is a contributing writer.