12.2. Multiple myeloma and related malignant disorders

Chapter 12

MM is the second most common form of haematological malignancy after non-Hodgkin lymphoma, and accounts for around 1% of all cancers. In Caucasian populations the annual incidence is approximately 60 per million, and this increases with age [243][244]. The number of new cases diagnosed each year is around 4,800 in the UK and almost 40,000 across Europe [243]. Worldwide, this figure rises to around 114,000, and a large variation in the incidence rates between different populations is observed (Figure 12.2) [243]. Furthermore, the incidence is slowly rising. In Europe, the incidence of MM has risen by approximately 10% in the last decade [244]. Similarly, a 13% increase in MM incidence has been observed in Taiwan between 2007 and 2012 [1095]. Survival rates for patients with MM are continually improving as a result of new treatments [245]. For example, 5-year survival in England has increased from around 10% in the early 1970s to almost 50% in 2010 - 2011 (Figure 12.3) [1054]. However MM deaths are higher in older adults, with a 5-year survival of approximately 30% for patients aged ≥75 years [1055].

According to international guidelines, serum electrophoresis and sFLC analysis constitute an effective screen for monoclonal plasmaproliferative disorders (other than AL amyloidosis, Chapters 23 and 25). Until recently, the diagnosis of MM was solely based on the presence of excess monoclonal plasma cells in the bone marrow alongside related organ or tissue impairment (i.e. hypercalcaemia, renal insufficiency, anaemia or bone lesions ], collectively known as the CRAB criteria). However, guidelines now define additional "biomarkers of malignancy (also known as SLiM criteria)", which include highly abnormal sFLCs (defined as an involved/uninvolved Freelite® sFLC ratio ≥100), to form part of the diagnostic criteria for MM (Section 25.2) [42].

Torti et al. [879] performed a retrospective analysis of 180 newly diagnosed MM patients and compared the use of traditional CRAB markers with the updated IMWG criteria at diagnosis. The majority of cases had a previous history of MGUS and SMM. A total of 21% of patients had at least one detectable SLiM biomarker before the clear manifestation of CRAB criteria; a highly abnormal sFLC ratio was the most common finding, being present in two-thirds of cases. Patients with SLiM features were at a very high risk of progression, with 92% developing CRAB features and progressing to active MM in less than one year. This study confirms the ability of the new MM diagnostic criteria to identify patients who are likely to benefit from early treatment before the development of end-organ damage.

MM patients can be subdivided into secretory and non-secretory types based on the presence or absence of a detectable monoclonal protein, with nonsecretory patients representing only 2% of cases [42]. The majority (85%) of patients with MM secrete an intact immunoglobulin monoclonal protein. The relative frequency of the classes of immunoglobulin secreted by the plasma cell clones reflect the frequencies normally observed in the body. Light chain MM (LCMM) and nonsecretory MM (NSMM) represent a further 13% and 2% of MM patients, respectively. A summary of MM monoclonal protein types is shown in Figure 12.5; this data is from more than 2500 patients entered into the UK Medical Research Council MM trials [247].

Over the past 15 years, there have been publications covering many aspects of sFLC analysis in the diagnosis, monitoring and prognosis of MM; these are reviewed in individual Chapters covering LCMM (Chapter 15), NSMM (Chapter 16) and intact immunoglobulin MM (IIMM; Chapters 17 and 18). Additionally, clinical applications of sFLC testing have been described in other malignant conditions that are related to MM, including plasmacytoma (Chapter 21) and plasma cell leukaemia (Chapter 22). The inclusion of sFLCs for routine monoclonal gammopathy screening and the relative merits of serum versus urine FLC measurements are also discussed (Chapter 23 and Chapter 24). It is well established that sFLC measurements provide valuable information in patients with diseases with monoclonal light chain deposition, such as cast nephropathy, AL amyloidosis and light chain deposition disease. These clinical applications are addressed in the succeeding section (Section 5).

Following the introduction of Hevylite assays, there is accumulating evidence showing that HLC analysis provides an additional tool for the management of patients with MM, by giving a quantitative and non-subjective indication of clonality. This evidence is presented in Chapters 17 and 18.