Asymptomatic (smouldering) multiple myeloma (ASMM)

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Figure 14.1 Kaplan-Meier plot of survival in 43 patients with SMM with (blue) and without (green) abnormal κ/λ ratios.

Figure 14.2 Effect of increasing abnormal sFLC ratios on the relative risk of progression of SMM to MM or related disorders. BMPC: bone marrow plasma cells. (This research was originally published in Blood ^[1] © the American Society of Hematology).

Figure 14.3 Risk of SMM progressing to MM using 2 different levels of sFLC κ/λ ratios. (This research was originally published in Blood ^[1] © the American Society of Hematology).

Figure 14.4 Risk of SMM progressing to MM with 1, 2 or 3 risk factors comprising; abnormal sFLC κ/λ ratios (<0.125 or >8), BMPC ≥10% and serum M-protein ≥30 g/L. (This research was originally published in Blood ^[1] © the American Society of Hematology)

Smouldering (asymptomatic) multiple myeloma (SMM) is an asymptomatic plasma cell disorder that carries a high risk of progression to symptomatic disease (10% per year for the first 5 years), which is far higher than the risk of progression of monoclonal gammopathy of undetermined significance (MGUS, 1% per year). Indeed, SMM represents the quintessential model for studying multiple myeloma precursor disease, and for developing early intervention strategies ^[2]. For a diagnosis of SMM to be made, two criteria must be met: the presence of a serum monoclonal protein (IgG or IgA) at concentration of ≥30g/L and/or clonal bone marrow plasma cells (BMPC) ≥10%, and the absence of end-organ damage such as lytic bone lesions, anaemia, hypercalcaemia, or renal failure that can be attributed to the plasma cell proliferative disorder ^[3] (see Chapter 25.1). Time to disease progression (TTP) in SMM patients is typically 2-4 years so whilst there is no need for immediate treatment, patients should be monitored on a regular basis ^[4][5]. Since the presence of urine free light chains (uFLCs) is an adverse prognostic indicator in SMM ^[6], serum free light chain (sFLC) levels may also relate to outcome. Furthermore, an abnormal sFLC ratio has been shown to identify monoclonal gammopathy of undetermined significance (MGUS) patients who are at increased risk of progression ^[7], suggesting that sFLCs may have a similar utility in SMM.

Augustson et al. ^[8] studied 43 patients with SMM who had been recruited to the UK, MRC multiple myeloma (MM) trials between 1980 and 2000. They found that abnormal FLC κ/λ ratios were present in 36 (84%) of the patients while 7 (16%) were normal. In the 26/36 patients with abnormal κ/λ ratios whose disease had progressed, the median time to progression was 713 days. This compared with a median time to progression of 1,323 days in the 6/7 patients with normal κ/λ ratios whose disease subsequently progressed. There was no significant difference in survival between the two groups (p<0.13) but patient numbers were inadequate for reliable statistical power (Figure 14.1).

A large study of sFLCs in patients with SMM ^[1] clearly demonstrated that abnormal sFLCs indicated an increased risk of progression to MM. Baseline serum samples obtained within 30 days of diagnosis were available from 273 patients. At a median follow-up time of 12.4 years, transformation to active disease had occurred in 59% of patients. Abnormal sFLC ratios were present in 90% at baseline and were associated with adverse outcome. The degree of ratio abnormality was independent of other SMM risk factors including the number of BMPCs and quantity of serum intact monoclonal immunoglobulin (M-protein). The study concluded that an abnormal sFLC ratio was another important additional determinant of clinical outcome. An increasingly abnormal sFLC ratio was associated with a higher risk of progression to active MM. Patients with a normal (0.26 to 1.65) or near normal ratio (0.25 to 4) had a rate of progression of 5% per year, while patients with markedly abnormal ratios (either <0.0312 (1/32) or >32) had a rate of progression of 8.1% per year (Figure 14.2). This increase persisted after adjusting for the competing causes of death. The best cut-off point for predicting risk of progression was a sFLC ratio of 0.125 or less, or 8 or more, giving a hazard ratio for progression to active MM of 2.3 times that of patients with sFLC ratios between 0.125 to 8 (Figure 14.3).

Incorporation of sFLC κ/λ ratios with the two factors of BMPC and M-protein concentration produced a highly significant risk model ^[1] (Table 14.1). The three risk factors were defined as: abnormal sFLC ratio (<0.125 or >8), BMPC ≥10%, and serum M-protein ≥30 g/L. The cumulative probability of progression at 10 years was 50% in patients with 1 risk factor; 65% for those with 2 risk factors; and 84% for those with 3 risk factors (Figure 14.4). Correcting for death as a competing risk, the 10-year rates of progression were 35%, 54%, and 75%, respectively (P<0.001). Use of urinary M-protein of 50 mg/24h could not substitute for the sFLC ratio in this model indicating the value of using serum rather than urine for FLC analysis.

The authors noted that unlike MGUS, in which the rate of progression remains constant over time (Chapter 19), the overall risk of progression in SMM was greatly influenced by the length of time from diagnosis, with the highest rates of progression occurring in the first few years. The risk of SMM progression to MM or a related condition was 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. This was most notable in the high-risk group, in whom the probability of progression was about 26% per year for the first 2 years but slowed to 8% per year for the next 3 years (Figure 14.4). In contrast, the rates of progression in the low-risk group were 6% per year for the first 2 years and about 4% per year subsequently. It is possible that some patients classified as SMM are biologically identical to those with MGUS, and with increasing follow-up the cohort becomes enriched with such patients, resulting in progressively decreasing rates of progression. Why abnormal FLC κ/λ ratios should predict a worse outcome in SMM is unclear, but the authors speculated that these patients might have immunoglobulin heavy chain translocations or other genetic disruptions associated with disease progression ^[9].

In a very large follow-on study from the same group ^[10], baseline sFLC results were retrospectively analysed in 586 patients with newly diagnosed SMM. Receiver Operating Characteristic (ROC) analysis identified the optimal diagnostic cut-offs for the FLC ratio, to identify patients at highest risk of progression to symptomatic disease. A sFLC ratio of <0.01 or >100 was highly specific for the future development of active MM, with 76% of patients progressing within 2 years of diagnosis. The authors concluded that these patients should be monitored especially closely.

An alternative SMM risk stratification model developed by the Spanish PETHEMA study group incorporates the proportion of aberrant plasma cells (aPC, determined by multiparametric flow cytometry) and immunoparesis as risk factors for progression ^[11]. However, these criteria are limited by the requirement of a fresh bone marrow aspirate for all patients and flow cytometry panels that may not be available in all laboratories ^[12].

International guidelines (Chapter 25.3) now recommend that sFLCs should assessed at baseline in SMM ^[3][13], that patients should be risk stratified to optimise counselling and follow up, and that participation in clinical trials should be considered for patients at high risk. It is hoped that gaining further insights into SMM disease will have a dramatic impact on clinical managment in the future.

Table 14.1. Mayo Clinic risk stratification model to predict progression of SMM ^[1].
* Risk factors: bone marrow plasma cells ≥10%; M-protein ≥30 g/L; sFLC κ/λ ratio <0.125 or >8.

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