IgA or IgM MGUS less than 1.0 g/dL is at low risk of progression to neoplasm Open Access

TO THE EDITOR:

Individuals with serum monoclonal immunoglobulin (MIG) are at risk of progressing to a lymphoplasmacytic neoplasm (LPN) defined as multiple myeloma (MM), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or light chain amyloidosis. Most patients with MIG are found to have <10% bone marrow plasma cells and are categorized as monoclonal gammopathy of undetermined significance (MGUS).

There are limited data on the risk of progression to LPN in non–immunoglobulin G (non-IgG) MGUS with very small M-bands. Kaiser Permanente Northern California (KPNC), an integrated health care system caring for >4.6 million members with several decades of computerized health records, gave us the opportunity to identify a large group of patients with MGUS followed up for up to 20 years, and to address this knowledge gap.

KPNC electronic databases were queried to identify all patients aged ≥18 years with ≥1 serum protein electrophoresis (SPEP) assays performed between 1 January 1997 and 31 December 2006. Patients were categorized as having MGUS if the M-band was <3.0 g/dL, the presence of a serum immunofixation electrophoresis (IFE) confirmed MIG, and there was no history of LPN before, or within 3 months after, the detection of MIG.

Patients were followed up through the administrative end point of 31 December 2016, with censoring at membership disenrollment or death.

Outcomes of interest included MM, NHL, CLL, and light chain amyloidosis. A composite outcome of LPN was defined as the first instance of any of these outcomes. They were identified by querying diagnostic codes and the KPNC tumor registry.

Patient gammopathies were further categorized as IgA of <1.0 g/dL, IgA of ≥1.0 g/dL, IgG of <1.5 g/dL, IgG of ≥1.5 g/dL, IgM of <1.0 g/dL, and IgM of ≥1.0 g/dL. Demographics included age on the index date, and sex (male or female). Follow-up duration (in years) was calculated from the index date to end point.

Crude incidence rates (per 100 person-years; 95% confidence interval [95% CI]) of LPN were calculated by “new LPN cases divided by total time of the study patients at risk” for all patients in the exposure group and by its subgroups (M-band size, IFE type, M-band size stratified by IFE type, and sex). Statistical analyses were performed using Statistical Analysis System (SAS) version 9.4 (SAS, Cary, NC), with the threshold of significance set at the 2-sided P < .05.

The Kaiser Foundation Research Institute’s institutional review board approved the oversight and conduct of this study, with waiver of patient consent.

A total of 195 178 individuals had at least 1 SPEP; of these, 3303 individuals met our definition of MGUS. The median age of the cohort was 73 years (interquartile range, 63-79), and 54.1% were male. Nearly two-thirds of the patients had an IgG gammopathy (66%), and 72.7% of all patients with MGUS had a gammopathy of <1.0 g/dL.

The incidence of a new LPN was 2.14 (95% CI, 1.95-2.32) per 100 person-years and was correlated with M-band size of 1.5 to 3.0 g/dL, incidence of 6.60 (95% CI, 5.46-7.73); 1.0 to <1.5 g/dL, incidence of 3.47 (95% CI, 2.88-4.05); and <1.0 g/dL, incidence of 1.38 (95% CI, 1.21-1.55).

When comparing incidence rates of LPN by M-band size stratified by IFE type, subgroups IgA ≥1.0 g/dL (7.75 [95% CI, 5.32-10.19]) and IgG ≥1.5 g/dL (7.49 [95% CI, 6.00-8.97]) were higher than IgA <1.0 g/dl (2.09 [95% CI, 1.59-2.60]; P < .001), IgG < 1.5 g/dL (1.61 [95% CI, 1.41-1.82]), IgM ≥1.0 g/dL (2.22 [95% CI, 1.38-3.05]), and IgM <1.0 g/dL (1.51 [95% CI, 1.07-1.94]; P < .001). The subtypes clustered into 2 distinct groups with IgG ≥1.5 g/dL and IgA ≥1.0 g/dL representing the higher-risk groups and the remainder were lower risk (Figure 1).

Free light chain measurements were rarely used during the period from which this cohort was accrued, January 1997 to December 2006, and light chain values were not available for analysis.

In this series, progression of IgM MGUS is similar or less than that of IgG or IgA MGUS. This is different from the observations of Kyle et al,¹ who reported that the risk of progression for IgM MGUS was greater than that for IgG or IgA MGUS. However, Kyle et al¹ included Waldenström macroglobulinemia (WM) as an outcome in addition to NHL. We found, by chart review, that the diagnosis of WM was assigned very inconsistently in the period from which our patients were accrued and included patients with asymptomatic IgM MIG. This is not surprising because proposed consensus panel recommendations for the clinicopathologic definition of WM published in 2003, began with the statement, “There are currently no universally accepted criteria of the diagnosis of Waldenström’s Macroglobulinemia…”¹ Because subsequent definitions of WM required a pathologic diagnosis of World Health Organization–defined lymphoplasmacytic lymphoma, we chose to limit patients identified as having a LPN to those who had developed MM, NHL, CLL, or light chain amyloidosis (see the supplemental Appendix for further discussion).

Indirect evidence suggests that annual screening for LPN in patients with MGUS improves outcomes,^2,3 but questions have been raised about the practice,⁴ particularly in patients with MGUS at lower risk of progression.⁵ In fact, a large prospective randomized study of patients with MGUS, testing whether any follow-up at all improves outcomes, has been initiated.⁵ It has been pointed out that following up a patient with MGUS indefinitely is not only a financial burden but also creates substantial psychologic stress.^4,6,7 

Guidelines from the International Myeloma Working Group (IMWG) recommend that patients with MGUS “should be followed with serum protein electrophoresis and a complete blood count in 6 months and then annually for life.” However, those with MGUS belonging to the IgG subclass, with an M-protein of <1.5 g/dL, and a normal serum free light chain ratio were at a low risk of progression to LPN and needed less frequent surveillance monitoring.⁸ 

We found that patients with either IgA or IgM MGUS whose M-protein level was <1.0 g/dL were at close to the same risk of progression as patients with an IgG MGUS of <1.5 g/dL. We hypothesize that patients in these categories who have a normal free light chain kappa lambda ratio will have a risk of progression that would allow them to be added to the IMWG low-risk category.

The presence in blood of MIG is common and can be detected in 3.2% of individuals aged >50 years.¹ In this series, almost 3 quarters had an M-protein of <1.0 g/dL. As new detection technologies enter practice, patients with small quantities of MIG will become even more prevalent.^9-12 

The strength of our study rests with the biologic plausibility of the finding, the large size of the study group, the length of follow-up, and the thorough access to follow-up data owing to a universal electronic record with use spanning almost 3 decades. The Kaiser Permanente health membership has been demonstrated to be highly representative of the general population.¹³ Study limitations include the retrospective nature of the study and the absence of light chain values, which affects the ability to assess the independent prognostic value of M-protein size.

We propose including patients with MGUS in the low-risk category so long as the M-band is <1.0 g/dL and the free light chain ratio is normal even if the immunoglobulin class is IgA or IgM. For patients with an IgM MGUS of ≥1.0 g/dL, we would propose waiting for confirmation by others of our finding of a low risk of progression. If confirmed, this would also indicate that although IgM MGUS is at low risk of progression, that risk does not correlate with the size of the IgM M-protein.

Acknowledgments: This work was supported by a grant from the Kaiser Permanente Northern California Community Health Program (grant number RNG209160).

Contribution: A.P.P. and D.M.B. designed the study, contributed to data analysis, and wrote and edited the manuscript; and L.-Y.T. provided data analysis and statistical support.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Ashok Pai, Department of Hematology-Oncology, Kaiser Permanente, Oakland, CA 94611; email: ashok.p.pai@kp.org.