13.2.1. Prognostic value of serum FLCs in MGUS

Chapter 13

Rajkumar et al. [31] measured sFLCs in serum samples from 1148 MGUS patients at diagnosis by using archived (frozen) sera that had been collected from the original Kyle et al. cohort of 1384 MGUS patients [249]. An abnormal κ/λ sFLC ratio (<0.26 or >1.65) was detected in 379 (33%) cases at diagnosis. At a median follow-up of 15 years, malignant progression to MM or a related condition had occurred in 87 (7.6%) patients. The risk of progression in patients with abnormal sFLC κ/λ ratios was significantly higher (hazard ratio 2.6) than in patients with normal ratios, and was independent of the size and type of the monoclonal protein (Figure 13.1. ). Furthermore, the risk of progression increased as κ/λ ratios became more extreme Figure 13.2.

The prognostic value of baseline sFLC measurements has been validated in a number of other studies [32][881]. For example, in a retrospective study Turesson et al. [32] monitored 728 Swedish MGUS patients for up to 30 years (median 10 years). During which time, 84 patients developed a lymphoid disorder, with MM accounting for the majority (53/84) of cases. The κ/λ sFLC ratio was abnormal in 47% of the study population at baseline. Three risk factors were significantly associated with progression: an abnormal κ/λ sFLC ratio, monoclonal protein concentration (>15 g/L) and a reduction of one or two uninvolved immunoglobulin isotypes (immunoparesis). No association was found between the monoclonal protein isotype and risk of progression, which is in contrast to some previous reports [249][268][31], but in keeping with those of the Spanish PETHEMA group [271]. This Spanish group also previously identified immunoparesis as a significant risk factor for MGUS progression in univariate but not multivariate analysis [271].

Rajkumar et al. [31] constructed an MGUS risk stratification model based on the size and type of monoclonal protein, and the presence of an abnormal κ/λ sFLC ratio at diagnosis (Table 13.2 and Figure 13.3. Using this model, low-risk patients were characterised as those with a small (<15 g/L) IgG monoclonal protein and a normal sFLC ratio. Such patients had a 2% absolute risk of disease progression at 20 years when competing causes of death were taken into account. Importantly, this low-risk group accounted for approximately 40% of the cohort. A smaller group of high-risk patients were identified as those with a large (>15 g/L) IgA or IgM monoclonal protein and an abnormal sFLC ratio. These patients had a 27% absolute risk of progression at 20 years.

Risk of progression No. of abnormal risk factors No. of patients Absolute risk of progression at 20 years*
Low 0 449 2%
Low-intermediate 1 420 10%
High-intermediate 2 226 18%
High 3 53 27%
* Accounting for death as a competing risk.

The three risk factors are defined as an abnormal κ/λ sFLC ratio (<0.26 or >1.65), a high serum monoclonal protein concentration (>15 g/L), and a non–IgG subtype (IgA or IgM).

Table 13.2. Risk stratification model to predict progression of MGUS [31].

International Myeloma Working Group (IMWG) guidelines [260] recommend that patients with MGUS should be risk stratified at diagnosis to optimise counselling and follow-up, using the risk-stratification model outlined in Table 13.2 (see Chapter 25, Table 25.3). For patients with low-risk MGUS, follow-up is recommended at 6 months initially and, if stable, every 2 - 3 years or when symptoms suggest evidence of a plasma cell malignancy. For these patients, a baseline bone marrow examination or skeletal radiography is not routinely indicated. For patients with intermediate- and high-risk MGUS, follow-up is recommended at 6 months initially, then annually and/or upon any change in the patient's clinical condition. A bone marrow aspirate and biopsy should also be carried out at baseline to rule out any underlying plasma cell malignancy [260].

In future, additional markers may be added to risk stratification models to better define high-risk patients. Rawstron et al. [273] have recently showed that plasma cell phenotype (CD138/38/45 expression) and sFLCs provide independent and complementary prognostic information on the risk of progression. The use of additional genetic risk factors (including light chain gene rearrangements [274] and gene expression profiles [275]) are currently being investigated.