14.4. The prognostic value of changes in monoclonal protein concentration

Chapter 14

Several studies have evaluated the prognostic impact of an increasing monoclonal protein concentration during follow-up on risk of SMM progression. Many [964][1048][275][310], but not all studies [306], have reported a higher risk in patients who demonstrate a progressive rise in serum monoclonal protein. For example, Fernandez de Larrea et al. [1048] studied 206 SMM patients, and defined an "evolving" monoclonal protein type as either a 10% increase within the first year after diagnosis (for patients with an initial monoclonal protein ≥30 g/L) or a progressive increase in consecutive annual measurements during a period of 3 years (for patients with an initial monoclonal protein <30 g/L). A quarter of patients displayed an evolving type, and once recognised, patients had a median time to MM progression of only 1 year, and a five-fold increased risk of progression compared to non-evolving patients. On multivariate analysis, an evolving pattern was the strongest risk factor for progression, and for these patients the other known risk factors (such as the monoclonal protein size or percentage of BMPCs) failed to provide additional prognostic information. The authors concluded that SMM should be routinely monitored for an evolving type during follow-up.

International guidelines recommend that serum protein electrophoresis and 24-hour urine electrophoresis are performed at SMM diagnosis and at 2 - 3 months. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6 - 12 months (Section 25.3.2). Whilst there are no recommendations for the frequency of sFLC analysis during follow-up, in a recent review article, Rajkumar [306] suggested that sFLCs should be evaluated every 3 - 4 months. This information can then be used to identify SMM patients at the highest risk of disease evolution [955].

In a recent study, Wu et al. [1084] compared evolving biomarkers as risk factors to identify ultra-high-risk SMM in a cohort of 273 SMM patients. Baseline immunoparesis and evolving concentrations of M-protein (64% increase), haemoglobin (1.57g/dL decrease) and dFLC (169% increase) within one year from diagnosis were identified as predictors of ultra-high-risk progression to MM. The median time to progression in patients with ≥3 risk factors was 13 months.

An initial prospective study of the value of HLC measurements during SMM follow-up was reported by Fernandez de Larrea et al. [1208]. Of the 12/30 patients who demonstrated a progressive increase in involved HLC (iHLC) levels during follow up, 5 patients progressed to symptomatic MM. In one patient, the increase in iHLC preceded the increase in the M-protein measured by SPE by several months. Further study of the role of HLC analysis to monitor SMM is now warranted.


  1. How frequently are sFLC ratios abnormal in SMM?
  2. What is the recommended management for a patient with 20% BMPCs, Freelite κ sFLCs 250 mg/L, λ sFLCs 2 mg/L (κ/λ sFLC ratio 125) and no evidence of myeloma-related end organ damage?


  1. An abnormal sFLC ratio is found in 74 - 90% of SMM patients at diagnosis (Section 14.2).
  2. An involved/uninvolved Freelite sFLC ratio of ≥100 (with involved sFLCs ≥100 mg/L) is considered a biomarker of malignancy. This patient would be classified as having active MM requiring treatment, even in the absence of myeloma-related symptoms (Section 14.1).