Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance

Abstract

We hypothesized that the presence of monoclonal free kappa or lambda immunoglobulin light chains in monoclonal gammopathy of undetermined significance (MGUS), as detected by the serum free light chain (FLC) assay increases the risk of progression to malignancy. Of 1384 patients with MGUS from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 1148. At a median follow-up of 15 years, malignant progression had occurred in 87 (7.6%) patients. An abnormal FLC ratio (kappa-lambda ratio < 0.26 or > 1.65) was detected in 379 (33%) patients. The risk of progression in patients with an abnormal FLC ratio was significantly higher compared with patients with a normal ratio (hazard ratio, 3.5; 95% confidence interval [CI], 2.3-5.5; P < .001) and was independent of the size and type of the serum monoclonal (M) protein. Patients with an abnormal serum FLC ratio, non-immunoglobulin G (non-IgG) MGUS, and a high serum M protein level (> or = 15 g/L) had a risk of progression at 20 years of 58% (high-risk MGUS) versus 37% with any 2 of these risk factors (high-intermediate risk), 21% with one risk factor (low-intermediate risk), and 5% when none of the risk factors were present (low risk).

Figure 1.

Risk of progression to myeloma or related disorder in 1148 patients with monoclonal gammopathy of undetermined significance. (A) The upper curve illustrates risk of progression of all patients without taking into account competing causes of death. The lower curve illustrates risk of progression after accounting for other competing causes of death. (B) The upper curve illustrates risk of progression of monoclonal gammopathy of undetermined significance in patients with an abnormal serum kappa-lambda FLC ratio (< 0.26 or > 1.65). The lower curve illustrates the risk of progression in patients with a normal ratio.

Figure 2.

Effect of increasingly abnormal FLC ratio on the relative risk of progression of monoclonal gammopathy of undetermined significance to multiple myeloma or related disorder. This figure illustrates that as the serum kappa-lambda FLC ratio becomes increasingly abnormal, the risk of progression increases (A) and that this effect is present even after adjusting for differences in the serum monoclonal protein spike among patients (B). The middle curve in both figures represents relative risk; upper and lower curves represent 95% confidence intervals.

Figure 3.

Risk of progression of MGUS to myeloma or related disorder using a risk-stratification model that incorporates the FLC ratio and the size and type of the serum monoclonal protein. The top curve illustrates risk of progression with time in patients with all 3 risk factors, namely an abnormal serum kappa-lambda FLC ratio (< 0.26 or > 1.65), a high serum monoclonal protein level (≥ 15 g/L), and non–IgG MGUS; the second gives the risk of progression in patients with any 2 of these risk factors; the third curve illustrates the risk of progression with one of these risk factors; the bottom curve is the risk of progression for patients with none of the risk factors.