12.4. Improving our understanding of disease pathogenesis and response to therapy

Chapter 12

Data from measurement of sFLCs and HLCs has made a contribution to our understanding of monoclonal gammopathies. This includes aspects of: 1) clonal heterogeneity; 2) disease evolution, and 3) the bone marrow microenvironment.

Progression from MGUS to MM can involve a complicated branching transformation from benign to malignant clones, resulting in the presence of multiple clones at diagnosis (Chapter 19). Genetic transformations change the clonal composition during the course of disease and these changes may be reflected by changes in monoclonal protein production. Monitoring patients with a combination of HLC and FLC measurements provides information on tumour clones that may evolve over time. One such example is free light chain escape (FLC escape), first characterised in 1969, in which a patient with intact immunoglobulin MM relapsed with an increase in FLCs, but with no associated increase in intact immunoglobulins (Section 18.2.1) [261]. The importance of monitoring intact immunoglobulins and FLCs to survey these changes is discussed in Chapters 18 and 19.

More recently, quantitation of uninvolved polyclonal immunoglobulins of the same isotype as the monoclonal immunoglobulin (HLC pair) has offered insights into multiple myeloma tumour biology and the bone marrow microenvironment. Michallet et al. [942] report that patients treated with novel agents and autologous stem cell transplantation have increased recovery of the uninvolved HLC pair (e.g. recovery of IgGκ in an IgGλ patient), than patients treated with novel agents alone (p<0.001). Kumar et al. [905] suggest that normalisation of HLC ratios in patients who are MRD negative by standard criteria may indicate immune system recovery and a preliminary study by Campbell et al. [932] concluded that normalisation of both FLC and HLC assays provides a surrogate maker for MRD negativity by flow cytometry [932]. These studies are further discussed in Section 18.4.3. Several groups have also demonstrated the prognostic value of HLC pair suppression in MGUS (Section 13.2.2) and MM (Sections 20.4 and 20.5).