Asymptomatic (smouldering) multiple myeloma (ASMM)

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Figure 14.1 Kaplan-Meier plot of survival in 43 patients with ASMM 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 ASMM 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 ASMM 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 ASMM progressing to MM with 1, 2 or 3 high risk factors comprising; abnormal sFLC κ/λ ratios, BMPC >10% and serum M-protein >30g/L. (This research was originally published in Blood ^[1] © the American Society of Hematology)

Patients with asymptomatic MM (ASMM) satisfy two of the criteria for MM:- monoclonal protein concentrations greater than 30g/L and/or 10% or more monoclonal plasma cells in the bone marrow, but no features of end-organ damage such as bone fractures (CRAB criteria). Such patients were classified in the Durie and Salmon staging system as Grade 1 (Chapter 25.1). The time to disease progression is typically 2-4 years so there is no need for immediate treatment but patients should be monitored on a regular basis ^[2][3]. Since the presence of urine FLCs is an adverse prognostic indicator ^[4], sFLC levels may also relate to outcome. Extrapolation from the data of Rajkumar et al.^[5], showing the prognostic importance of monoclonal FLCs in MGUS, would further suggest their utility in ASMM.

Augustson et al. ^[6], studied 43 patients with ASMM who had been registered on the UK, MRC multiple myeloma 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 patients with abnormal ratios who progressed, the median time period was 713 days. This compared with 1,323 days in the 6 patients who progressed who had normal κ/λ ratios. 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).

The largest study of sFLCs in patients with ASMM has recently been reported from the Mayo Clinic. Dispenzieri et al.^[1], showed clearly 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 of 12.4 years, transformation to active disease had occurred in 59%. Abnormal sFLC ratios were present in 90% at baseline and were associated with adverse outcome. The degree of ratio abnormality was independent of other ASMM risk factors including the number of bone marrow plasma cells (BMPC) and quantity of serum intact monoclonal immunoglobulins (M-protein).

The study concluded that abnormal sFLC ratios were an important additional determinant of clinical outcome. An increasingly abnormal sFLC ratio was associated with a higher risk for 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-point for progression was sFLC ratios of <0.125 or greater than 8, 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. 5 year progression rates in high- (BMPC>10% and serum M-protein >30g/L), intermediate- (BMPC>10% and serum Mprotein <30g/L), and low-risk groups (BMPC<10% and serum M-protein >30g/L) were 76%, 51%, and 25%, respectively. The cumulative probability of progression at 10 years was 50% in patients with 1 risk factor; 65% for 2 risk factors; and 84% for 3 risk factors (Figure 14.4). Corrected for death as a competing risk, the 10 year rates 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 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 ASMM was greatly influenced by the length of time from diagnosis, with the highest rates in the first few years (Figure 14.3 and 14.4). 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. In contrast, the low-risk group progression rates were 6% per year for the the first 2 years and about 4%, per year, subsequently. Maybe, some patients classified as ASMM are biologically identical to 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 ASMM is unclear, but the authors speculated that these patients might have immunoglobulin heavy chain translocations or other genetic disruptions associated with disease progression ^[7]. The importance of finding adverse risk factors for ASMM was discussed in an accompanying editorial ^[8].

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