14.2. Monoclonal sFLCs and SMM progression

Chapter 14

IMWG guidelines [27] recommend that sFLCs are measured at baseline for all SMM patients to allow risk stratification (Section 25.3.2) [27]. A number of studies that demonstrate the prognostic utility of sFLC measurements in SMM are described below.

In an analysis of 43 SMM patients recruited to the UK MRC multiple myeloma (MM) trials between 1980 and 2000, Augustson et al. [297] observed that 84% of the patients had an abnormal κ/λ sFLC ratio at diagnosis, and that patients with normal sFLC ratios tended to progress more slowly than those with abnormal ratios. The difference was not significant, however, probably due to the small number of patients in the study.

Dispenzieri et al. [256] subsequently confirmed this finding in a larger study of sera obtained within 30 days of diagnosis from 273 SMM patients attending the Mayo clinic, Rochester, USA. At a median follow-up time of 12.4 years, transformation to active disease had occurred in 59% of patients. Abnormal κ/λ sFLC ratios were present in 90% of patients at baseline and were associated with adverse outcomes. The degree of ratio abnormality was independent of other SMM risk factors, including the number of BMPCs and the concentration of monoclonal immunoglobulin. The study concluded that an abnormal κ/λ sFLC ratio was an important additional determinant of clinical outcome; furthermore, an increasingly abnormal ratio was associated with a higher risk of progression to active MM. Patients with a normal (0.26 - 1.65) or near normal (0.25 - 4) ratio had a rate of progression of 5% per year, while patients with markedly abnormal ratios (either ≤0.0312 [1/32] or >32) had a rate of progression of 8.1% per year (Figure 14.1). This increased progression persisted after adjusting for competing causes of death. The best cut-off point for predicting risk of progression was a κ/λ sFLC ratio of <0.125 or >8, giving a hazard ratio for progression to active MM of 2.3 times that of patients with sFLC ratios between 0.125 and 8 (Figure 14.2).

Combining κ/λ sFLC ratios with the percentage of BMPCs and monoclonal protein concentration produced a highly significant risk model (Table 14.1) [256]. The three risk factors were defined as: 1) an abnormal κ/λ sFLC ratio (<0.125 or >8); 2) BMPC ≥10%; and 3) serum monoclonal protein ≥30 g/L. The cumulative probability of progression at 10 years was 50% in patients with one risk factor; 65% for those with two risk factors; and 84% for those with three risk factors (Figure 14.3). Correcting for death as a competing risk, the 10-year rates of progression were 35%, 54%, and 75%, respectively (p<0.001). Detection of a urinary monoclonal protein (>50 mg/24 hours) could not substitute for the κ/λ sFLC ratio in this model, indicating the value of using serum rather than urine for FLC analysis (Chapter 24).

The authors noted that unlike MGUS, in which the rate of progression remains constant over time (Chapter 13), the overall risk of progression in SMM was greatly influenced by the length of time from diagnosis, with the highest rates of progression occurring in the first few years. The risk of SMM progression to MM or a related condition was 10% per year for the first 5 years, 3% per year for the next 5 years and 1 - 2% per year for the next 10 years. This was most notable in the high-risk group, in whom the probability of progression was 26% per year for the first 2 years but reduced to 8% per year for the next 3 years (Figure 14.3). In contrast, the rate of progression in the low-risk group was 6% per year for the first 2 years, and approximately 4% per year subsequently. It is possible that some patients classified as SMM are biologically identical to those with MGUS, and with increasing follow-up the cohort becomes enriched with such patients, resulting in progressively decreasing rates of progression. Why abnormal κ/λ sFLC ratios should predict a worse outcome in SMM is unclear, but the authors speculated that these patients might have immunoglobulin heavy chain translocations or other genetic disruptions associated with disease progression [298].

Number of risk factors* Proportion of patients (%) 5-year progression (%)
1 28 25
2 42 51
3 30 76
*Risk factors: bone marrow plasma cells ≥10%; monoclonal protein ≥30 g/L; κ/λ sFLC ratio <0.125 or >8.

Table 14.1.Mayo Clinic risk stratification model to predict progression of SMM [299].

In a very large follow-on study from the Mayo clinic (Larsen et al. [299]), baseline sFLC results were analysed retrospectively in 586 patients with newly diagnosed SMM. The κ/λ sFLC ratio was abnormal in 74% of patients. Receiver Operating Characteristic (ROC) analysis identified the optimal diagnostic cut-off for the sFLC ratio to identify patients at highest risk of progression to symptomatic disease within 2 years of diagnosis. A serum involved/uninvolved sFLC ratio ≥100 was used to define high-risk SMM (now considered one of the diagnostic criteria for MM; Section 25.2.1), and included 15% of the total cohort. This resulted in a specificity of 97% and a sensitivity of 16%. The risk of progression to MM within 2 years of diagnosis was 72% for SMM patients with an involved/uninvolved sFLC ratio ≥100 (Figure 14.4). This risk increased to 79% when progression to AL amyloidosis was included as an endpoint in addition to MM. In univariate analysis, BMPC content, serum monoclonal protein concentration and involved/uninvolved sFLC ratio ≥100 were all significant prognostic factors, and all remained significant on multivariate analysis. The prognostic value of extreme sFLC ratios (≥100) for progression from SMM was recently confirmed by two subsequent studies [300][926]. Kastritis et al. [300] also identified extensive bone marrow infiltration (BMPCs ≥60%) as an additional risk factor. Both risk factors (extreme sFLC ratios, and BMPCs ≥60%) are now included in the revised definition of MM (Section 25.2.1) [42]. Moreau et al. [926] also compared the performance of Freelite polyclonal antisera-based assays and N Latex FLC monoclonal antibody-based assays. The authors concluded that the two assays are not interchangeable, and that cut-offs based on Freelite assays for SMM risk stratification cannot be applied to N Latex FLC assays (Section 8.5.3).

An alternative SMM risk stratification model developed by the Spanish PETHEMA study group incorporates the proportion of aberrant plasma cells (determined by multiparametric flow cytometry) and immunoparesis (suppression of uninvolved polyclonal immunoglobulins, i.e. suppression of IgA and/or IgM in an IgG patient) as risk factors for progression [271]. However, these criteria are limited by the requirement for fresh bone marrow aspirates from all patients and flow cytometry reagents that may not be available in all laboratories [301]. The prognostic significance of immunoparesis in SMM patients at baseline was confirmed by Fernandez de Larrea et al. [302]. Sandecka et al. [303] recently confirmed the validity of both the Mayo Clinic and PETHEMA models in a study of 287 SMM patients in the Czech Republic.

It is important to note that significant differences exist between the SMM risk stratification models of the Mayo Clinic and the Spanish PETHEMA group; a prospective study by Cherry et al. [305] identified only 28.6% overall concordance between the two models in defining low-, medium- and high-risk patients. A number of alternate SMM risk models have been suggested and are discussed in two recent review articles [306][307].