image
Chapter 13

At present, the IMWG [27] recommends the use of monoclonal protein type, and baseline monoclonal protein concentration and κ/λ sFLC ratio to risk stratify MGUS patients (Section 25.3.2). However, the risk of progression to MM may not remain the same throughout the course of MGUS.

Langren et al. [1219] investigated changes in immunological biomarkers in MGUS patients who progressed to MM and those who did not, using samples from the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The authors identified 685 MGUS patients, of which 187 patients progressed to MM, and 498 who showed no evidence of progression in the follow up period (up to 16 years). The study identified the following as risk factors for progression to MM: IgA isotype, a monoclonal protein concentration ≥15 g/L, a sFLC κ/λ ratio <0.1 or >10 and the presence of immunoparesis (uninvolved immunoglobulins below the lower level of normal). Freelite was used to measure FLCs.

The identified risk factors were used to develop a scoring system for samples, with a sample scoring 1 point for each risk factor present (with 1 point for each uninvolved immunoglobulin below the lower level of normal). This scoring system was used to monitor changes in patient’s risk of progression over time.

For non-IgM intact immunoglobulin MGUS patients, changes over time were examined in 159 patients who progressed, and 156 matched non-progressing MGUS controls. Increases in monoclonal protein concentration (p=0.02), involved sFLC levels (p=0.01) and number of suppressed uninvolved immunoglobulins (p<0.001) were associated with a higher risk of progression to multiple myeloma. These patterns were investigated further in samples from patients with at least 1 pre-diagnostic sample within 2 years of diagnosis or being selected as a control and at least 3 serial samples. The controls were also required to have at least 8 years of follow-up without progression. Forty-three progressing patients and 108 controls were included in these analyses. Progressors were more likely than non-progressors to have a sample scored as high-risk during their disease course (53% vs 1%, p<0.001). It is also important to note that 70% of the progressors had a sample scored at low or intermediate risk before progression, which indicates that risk may not remain stable over time, that it may increase and that annual blood testing for all MGUS patients may be helpful [1219].

Similar analyses were performed on light chain MGUS patients (28 progressors, 56 non-progressors) and again, increases in involved sFLC concentration (p<0.001) and number of suppressed immunoglobulins (p<0.001) were associated with a higher risk of progression. Progressors were more likely than non-progressors to have a sample scored as high-risk during their disease course (70% vs 1%, p<0.001). In the light chain MGUS cohort, 71% of the progressors had a sample scored at low or intermediate risk before progression, again indicating that risk of progression may alter over time and that monitoring MGUS patients annually may provide value [1219].

Landgren et al. [1219] have shown that the risk of progression of MGUS to MM is not constant, and may change during disease course, therefore these patients should be followed-up. This data “… supports annual blood testing for all individuals diagnosed with MGUS or light-chain MGUS, as well as yearly assessment of a patient’s clinical risk status.” Monitoring of MGUS patients may enable early detection of progression to MM and early treatment of those patients who do progress (Section 13.3.3).