Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma

Abstract

We hypothesized that increased monoclonal free kappa or lambda immunoglobulin light chains in smoldering multiple myeloma (SMM), as detected by the serum free light chain (FLC) assay, indicates an increased risk of progression to active myeloma. Baseline serum samples obtained within 30 days of diagnosis were available in 273 patients with SMM seen from 1970 to 1995. At a median follow-up of surviving patients of 12.4 years, transformation to active disease has occurred in 59%. The best breakpoint for predicting risk of progression was an FLC ratio of 0.125 or less, or 8 or more (hazard ratio, 2.3; 95% CI, 1.6-3.2). The extent of abnormality of FLC ratio was independent of SMM risk categories defined by number of bone marrow plasma cells (BMPCs) and size of serum M proteins (BMPC>or=10% and serum M protein>or=3 g/dL; BMPC>or=10% but serum M protein<3 g/dL; and serum M protein>or=3 g/dL but BMPC<10%). Incorporating the FLC ratio into the risk model, the 5-year progression rates in high-, intermediate-, and low-risk groups were 76%, 51%, and 25%, respectively. The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients with SMM.

Figure 1

Effect of increasingly abnormal FLC ratio on the relative risk of progression of SMM to MM or related disorder. As the serum kappa/lambda FLC ratio becomes increasingly abnormal, the risk of progression increases. The middle curve in represents relative risk; upper and lower curves represent 95% confidence intervals. Vertical bars represent the normal range for kappa to lambda ratio. (A) Unadjusted. (B) Adjusted for BMPC count and M protein.

Figure 2

Risk of progression to myeloma or related disorder in 273 patients with SMM. Risk of progression of SMM to active myeloma using serum κ to λ FLC ratio of less than 0.125 (< 1:8) or more than 8 (top curve) versus 0.125 to 8 (bottom curve).

Figure 3

Risk stratification based on bone marrow plasmacytosis, serum M protein, and serum immunoglobulin FLC ratio. Patients are assigned 1 point for meeting each of the following criteria: BMPCs greater than or equal to 10%; serum M protein greater than or equal to 3 g/dL; and serum immunoglobulin FLC ratio either less than 0.125 or more than 8. The median times to progression for 1, 2, or 3 risk factors are 10, 5.1, and 1.9 years, respectively.