Background

Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM). According to 2003 classification, the IMWG (International Myeloma Working Group) recommended only to treat patients with end organ damage - often referred as CRAB criteria (hypercalcemia, renal failure, anemia and radiological bone lesions). The standard of care for SMM was to postpone treatment until progression to symptomatic disease occurred. The average annual risk of progression of SMM to MM was 10%/year. In 2014 IMWG proposed a revised classification including 3 new criteria that enable early diagnosis of MM before organ damage. The new criteria of MM needs the presence of more than 10% clonal bone marrow plasma cells combined with either the presence of end organ damage (CRAB criteria) or one of following new biomarkers of malignancy: bone marrow plasma cells ≥60%, serum free light chains (FLC) ratio ≥100 and ≥2 focal lesions on MRI. The FLC criteria were established with Freelite™ assay (The Binding Site Company) and have not been validated with other available assays. Freelite™ assay which used polyclonal antibodies was available since 2001. More recently N Latex assay (Siemens Healthyneers) using monoclonal antibodies has been commercialized in Europe. It is now well know that there is a good correlation between the 2 assays even though results in absolute values are not numerically identical. In this context, the aim of this study was to evaluate the concordance between the two assays to identify high risk SMM, when considering the biomarker of malignancy FLC ratio ≥100.

Methods

This is a retrospective study including 185 patients with SMM according to 2003 IMWG criteria. FLC concentration and ratio were evaluated in frozen sera with both assays in a BN Prospec and evolution status was collected.

Results

The average age was 62.5 (± 10.2) years old. Results revealed poor correlation between the 2 assays with a Slope Passing-Bablok value of 0.63 (0.57-0.67) for the FLC κ and of 0.44 (0.35-0.62) for the κ/ λ ratio ≥ 100, and concordance in determining the level of FLC λ with a Slope Passing-Bablok 1.16 (0.99-1.40). A Freelite™ratio ≥ 100 was found in 27 patients (14.3%), and a N Latex ratio ≥ 100 was found in 10 patients (5.3%). All but one patients with an N Latex ratio ≥ 100 had also a Freelite™ ratio ≥ 100. Mean of follow up was 2.4 years. A progression toward MM was observed in 77 (40.7%) patients. Among the 27 patients with Freelite™ ratio ≥ 100, 14 patients (55.5%) have evolved toward MM (figure 1A). Specificity and sensitivity for a Freelite™ ratio ≥ 100 were respectively 88.7% (95% CI 81.8 to 94.0%) and 20.3% (95% CI 11.8 to 31.2%). With the N Latex Assay, only 10 patients had a FLC ratio ≥ 100, in which 7 patients have evolved towards MM. Specificity and sensitivity for a N-Latex ratio ≥ 100 were respectively be 67.0% (95% CI 57.4 to 75.6%) and 53.2% (95% CI 41.5 to 64.7%). Given the poor predictive performance of a N-Latex ratio ≥ 100 we determined that a N-Latex ratio ≥ 70 have adequate specificity of 95.5% (95% CI 89.9 to 98.5%) and a sensitivity of 13.0% (95% CI 6.4 to 22.6%) (figure 1B). 15 patients (8.1%) patients had a N-Latex ratio ≥ 70. Among these, 10 patients (66.6%) have evolved toward MM.

Conclusion

Our study shows poor correlation between the two FLC assays in SMM patients. A Freelite™ ratio ≥ 100 had a lesser specificity than previously described (specificity 95% in Larsen study [1]). The 100 cut-off value was not performant enough for N-Latex assay. A new ratio is thus needed and was found to be 70 to have sufficient specificity and sensitivity. This result need to be validated in an independent cohort. However, with a Freelite™ ratio ≥ 100 or an N Latex ratio ≥ 70, a significant number of patients would have been overtreated. Physicians should be aware of the limits of both assays.

1.Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;27:941-6.

Figure 1

probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70)

Figure 1

probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70)

Disclosures

Moreau:The Binding Site: Other: supply of free light chain assays ; SIEMENS: Other: supply of free light chain assays , Research Funding. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.