March-April 2018, Volume 15, Issue 2
When Does Monoclonal Gammopathy Acquire Significance?
Published on: February 08, 2018
Kyle RA, Larson DR, Therneau TM, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med. 2018;378:241-249.
Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition of multiple myeloma (MM) and lymphoid malignancies such as Waldenström macroglobulinemia (WM). It is defined by the presence of serum monoclonal protein (M protein) of 3.0 g/dL or less, in the presence of 10 percent or fewer monoclonal plasma cells in the bone marrow of asymptomatic patients.1 Individuals with IgG or IgA MGUS progress to MM, while those with IgM MGUS progress to WM or non-Hodgkin lymphoma.1 It is clear that our understanding of MGUS has improved tremendously throughout the years, but were it not for Dr. Robert Kyle, we would not know as much today.
Recently, Dr. Kyle published a seminal study on the longest follow-up to date of 1,384 patients with MGUS — a lifelong effort he initiated more than 50 years ago to identify risk factors of progression in MGUS. In fact, it was he who coined the term “MGUS.” He advocated in support of this term over earlier nomenclature including “benign monoclonal gammopathy” and Jan Waldenström’s 1952 description of “essential hyperglobulinemia.” Dr. Kyle’s rationale behind “undetermined significance” was based on the observation that this precursor condition could either remain unchanged or evolve into MM or WM.2
Dr. Kyle has since spearheaded efforts to study the long-term outcome of patients with MGUS. He initiated a large study evaluating patients with MGUS who resided in the 11 counties of southeastern Minnesota from 1960 through 1994. By way of this pioneering work, not only did he shape our understanding of MM and other hematologic malignancies, but he also laid the groundwork for future efforts in understanding cancer evolution from precursor conditions in general.
In 2002, Dr. Kyle and colleagues reported the first long-term follow-up study of this cohort, whereby the overall risk of progression of MGUS to MM, WM, amyloidosis, or lymphoma was approximately 1 percent per year.3 Naturally, that statistic has been extensively quoted in clinical practice ever since. A second report was published in 2003 showing a correlation between baseline M protein level in IgM MGUS patients and disease progression to lymphoma or WM.4 In 2005, the very same group showed that serum-free light chain (FLC) ratio had a clinically significant impact on MGUS disease progression.5
In 2006, Dr. Kyle and colleagues reported the prevalence of MGUS based on a population-based cohort study among all living residents of Olmsted County, MN, as of January 1, 1995. They found that MGUS was present in 3.2 and 5.3 percent of individuals aged 50 and 70 years or older, respectively, while it was 1.5 times more common in men than women.6 In 2010, in another study from that cohort, the authors introduced a new clinical entity, light-chain MGUS, defined by the presence of an abnormal free light-chain ratio and increased concentration of the involved light chain, in the absence of heavy-chain expression. Its prevalence was 0.8 percent in individuals aged 50 years and older.7
Now, with their recent article in The New England Journal of Medicine, published in January 2018, Dr. Kyle and his coauthors report the updated long-term follow-up data of the MGUS cohort, comprising patients diagnosed between 1960 and 1994, with a whopping median follow-up of 34.1 years. In this study, for the first time, they report shorter overall survival for MGUS patients compared with a matched control population. Furthermore, they report a higher risk of progression for IgM MGUS patients compared with non-IgM MGUS individuals. More specifically, in patients with IgM MGUS, the presence of two adverse risk factors (abnormal FLC ratio and M-protein ≥1.5 g/dL) is associated with a 55 percent risk of progression at 20 years, compared with 41 percent in patients who had one risk factor and 19 percent in patients who had none. Meanwhile, in patients with non-IgM MGUS the risk of progression at 20 years is 30 percent among those who had two risk factors, 20 percent among those who had one, and 7 percent among patients who had none.
At almost 90 years of age, Dr. Kyle has uniquely characterized the progression risk of MGUS — the very entity he helped define more than 50 years ago. His monumental studies have transformed the landscape of precursor conditions in plasma cell malignancies and cancer in general. So perhaps, as suggested by many of his colleagues in the field, MGUS should be called “Kyle gammopathy” in recognition of the colossal contributions of the man who described it.
Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113:5412-5417.
Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med. 1978;64:814-826.
Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564-569.
Kyle RA, Therneau TM, Rajkumar SV, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. 2003;102:3759-3764.
Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ration is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106:812-817.
Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-1369.
Dispenzieri A, Katzmann JA, Kyle RA, et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet. 2010;375:1721-1728.
Conflict of Interests
Drs. Bustoros, Liu, Sklavenitis-Pistofidis, and Ghobrial indicated no relevant conflicts of interest.
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