1.3.1. Monoclonal FLC studies

Chapter 1

A recent study monitoring overall survival of MM patients after high dose melphalan and autologous stem cell transplant has substantiated the value of achieving a stringent complete response (sCR). The inclusion of sFLC analysis in the definition of sCR (i.e. requiring the presence of a normal κ/λ sFLC ratio in addition to other criteria) was first introduced into guidelines in response to observational studies which had demonstrated that a proportion of patients achieving a conventional CR still had abnormal sFLC ratios (Sections 15.2 and 18.2.2). In 2013, Kapoor et al. [29] published follow-up data, comparing patients who had achieved a sCR (n=109) with those who had only achieved a conventional CR (n=37) or near CR (n=91). Significantly improved long-term survival was seen for those achieving a sCR (compared to either lesser response), demonstrating the clinical relevance and desirability of attaining this degree of response (Section 20.3.1).

There has been much interest in recent years in the clonal heterogeneity of MM and how the dominant clone(s) may change during the course of a patient's disease, a concept referred to as clonal evolution (Chapter 19). Many of the studies have utilised genetic analysis of the tumour cells but there has also been some interest in identifying how changes in the monoclonal proteins produced can give an insight into clonal evolution. This concept was explored by Brioli et al. [30], who analysed changes in protein production at relapse amongst 520 MM patients. It was found that just over 10% (54 patients) relapsed with light chain escape and had a significantly shorter survival. The authors considered this represented the outgrowth of a more aggressive tumour clone and commented on the importance of using sFLC analysis for monitoring patients with IIMM in order to ensure that light chain escape was not missed (Section 18.2.1).

The first publication identifying abnormal sFLC ratios as a risk factor for MGUS progression (by Rajkumar and colleagues from the Mayo Clinic in 2005) [31] was, arguably, definitive; not least due to the size of the study population (n=1148) and length of follow-up (median 15 years). Few other research groups would be able to access a comparable study population. However, in 2013, Turesson and colleagues [32] published data from 728 Swedish people with MGUS who had been followed for up to 30 years (median 10 years). They confirmed the previous findings that an abnormal sFLC ratio and high monoclonal protein concentration predicted progression to lymphoid malignancies and differed only in their selection of general immunoparesis as a third risk factor, ahead of the immunoglobulin isotype (IgA and IgM indicating higher risk) (Chapter 13). It now seems unlikely that any future data will challenge the role of abnormal sFLC ratios as a risk factor in MGUS progression.