The outcome for patients with multiple myeloma (MM) is highly variable, and understanding the prognosis for a particular patient can help when selecting the intensity of treatment to be used and the frequency of review, as well as being necessary for stratifying patients before entry into trials.
The international staging system (ISS), first defined in 2005 , is a simple and inexpensive prognostic system based on serum albumin and β2-microglobulin (β2M) measurements. Multiple myeloma (MM) patients are grouped into stages I, II or III, with significantly different outcomes (Table 20.1, p<0.001) .
|Stage||Criteria||Median Overall Survival|
|I||Serum β2M <3.5 mg/L and serum albumin ≥35 g/L||62 months|
|II||Neither ISS stage I or III||44 months|
|III||Serum β2M ≥5.5 mg/L||29 months|
Table 20.1. International Staging System . β2M: β2-microglobulin.
In 2014, the International Myeloma Working Group (IMWG) proposed a new model for MM staging  based on the data from 2,642 newly diagnosed MM patients . The IMWG-2014 staging system combines the ISS prognostic model with chromosomal abnormalities (detected by interphase fluorescent in situ hybridisation [iFISH]). Using this system MM patients are grouped into low-risk, standard-risk and high-risk stages with different overall survival (Table 20.2).
|Stage||Criteria||Median Overall Survival|
Table 20.2. The IMWG-2014 risk stratisfaction system .
One year later, the IMWG published a revised ISS (R-ISS), based on data from 3,060 newly diagnosed MM patients enrolled onto 11 international trials. The R-ISS is based on the ISS with the addition of chromosomal abnormalities and the assessment of serum lactate dehydrogenase (LDH) levels . After a median follow-up of 46 months, the R-ISS stratified patients into three groups (Table 20.3), and the IMWG recommend use of the R-ISS to stratify patients in future clinical studies.
|R-ISS stage||Criteria||Median Overall Survival||5-year Overall Survival|
|I||ISS stage I and no high-risk cytogenetics and normal LDH||NR||82%|
|II||Neither R-ISS stage I or III||83 months||62%|
|III||ISS stage III and either high-risk cytogenetics or high LDH||43 months||40%|
Table 20.3. Revised international Staging System . High-risk cytogenetics: del(17p) and/or t(4;14) and/or t(14:16); NR: not reached.
Using the data from 555 MM patients included in the Czech Myeloma Group Registry of Monoclonal Gammopathies, Radocha et al.  validated the IMWG-2014 and R-ISS prognostic systems in clinical practice. Furthermore, Scott and colleagues  compared the performance of ISS, IMWG-2014 and R-ISS staging systems in a study of 628 newly diagnosed MM patients undergoing autologous hematopoietic stem cell transplant. The R-ISS provided the best prediction of progression free survival, but the performance of all three systems to predict overall survival was similar. The authors concluded that the R-ISS is the optimal prognostic tool, and recommended that LDH and cytogenetic analysis are performed on every MM patient at diagnosis .
The monoclonal protein size and type has frequently been investigated as a potential predictor of patient outcome in MM. Before the development of the ISS, the most widely used staging system was that devised by Durie and Salmon  and this incorporated the size of the monoclonal protein as one of the prognostic variables. In an analysis of data from 2592 patients who had participated in UK myeloma trials, Drayson and colleagues  corroborated results from earlier studies  by demonstrating that patients with light chain MM (LCMM) had shorter survival than those with intact immunoglobulin MM (IIMM). The authors’ concluded that this was a result of the increased incidence of renal failure in LCMM patients, which could be attributed to the higher levels of urinary FLC excretion in this group. Increased renal failure and shortened survival times were also seen in IIMM patients who had elevated urine FLC concentrations similar to those in LCMM. Similar findings were reported by Yadav et al. , who confirmed that high levels of sFLCs (>800 mg/L) was one of the strongest predictors of renal function in newly diagnosed MM patients.
Immunoparesis, the reduction of an uninvolved immunoglobulin below the lower limit of normal, has been investigated as a possible prognostic factor in MM. In the largest study to date, Heaney et al.  examined the impact of immunoparesis at MM diagnosis in 5826 patients recruited to UK myeloma trials. Polyclonal IgG, IgA or IgM levels were below normal in 80.6%, 80.2% and 88.9% of patients, respectively. Patients with immunoparesis had significantly reduced overall survival (OS) compared with patients for whom polyclonal immunoglobulins were within the normal range (p≤0.003). The authors comment that immunoparesis had a greater impact in recent trials employing modern therapies. The depth of IgM suppression, but not the depth of IgG or IgA suppression, was prognostic for survival, although the mechanism is not well understood. A number of other large studies have confirmed the prognostic value of qualitative  and quantitative  immunoparesis at MM diagnosis.
As previous studies have found that levels of both serum monoclonal immunoglobulin and urine FLCs are related to MM patient survival, serum HLC and sFLC analysis may provide better predictions. The purpose of this chapter is to present the studies that have investigated sFLC and HLC analysis as prognostic markers at each stage of MM development.