Normalization of the Serum Free Light Chain Ratio in Patients with Intact Immunoglobulin Multiple Myeloma Who Achieve Less Than Complete Response

Background

Normalization of the serum free light chain ratio (rFLC) following achievement of complete response (CR) denotes stringent CR in multiple myeloma (MM) and is associated with favorable prognosis. In contrast, the clinical significance of this phenomenon in patients not achieving CR has not been energetically studied. Only a few studies have reported better progression free survival (PFS) and overall survival (OS) in patients who achieved normalization of the rFLC at their best response than in those who did not. As monoclonal intact immunoglobulin (Ig) and monoclonal FLC are independent biomarkers for the neoplastic plasma cell burden in intact immunoglobulin MM (IIMM), it is not clear whether patients who failed to achieve CR but normalized the rFLC also had improved outcomes. Here, we retrospectively analyzed the prognostic significance of normalization of the rFLC in IIMM patients who did not achieve CR.

Patients and methods

Consecutive patients with IIMM diagnosed and treated at the Kameda Medical Center from Jun 2007 to April 2017 were identified. IMWG response criteria were used to assess response. We excluded patients with negative immunofixation for monoclonal M-protein in the serum or urine at diagnosis and those who achieved CR. The FLC assay (FREELITE, The Binding Site, Birmingham, UK) was performed at least monthly as a part of routine clinical management. The following ranges were used for normal FLC values: κ FLC, 0.33-1.94 mg/dL; λ FLC, 0.57-2.63 mg/dL; and rFLC, 0.26-1.65.

Results

There were 239 patients diagnosed with symptomatic MM, including 191 patients with IIMM and 48 patients with light chain MM (LCMM). Among 191 patients with IIMM, 78 achieved CR by chemotherapy; the remaining 113 patients were included in this analysis. No patient with LCMM achieving less than CR (n = 15) obtained normalization of rFLC during the whole treatment. The median observation period was 21.9 months (m) [range, 0.2-118.9 m] and the median age was 77.0 yr (range, 43.8-90.7 yr). Sixty-four of the 113 patients (56.6%) obtained a normal rFLC during the course of treatment. Patients who achieved a normal rFLC were significantly younger (median age, 75.3 vs 79.2 yr, P = 0.014), more frequently received autologous stem cell transplantation (15.6% vs 0%, P = 0.005), and had better response [very good partial response (VGPR) rate: 57.8% vs 22.4%, P < 0.001] than those who did not. No significant difference was seen between patients with and without normalization of the rFLC with regard to sex, heavy- or light-chain type, ISS category, revised ISS category, albumin, β2 microglobulin, or creatinine levels, hemoglobin concentration, lactate dehydrogenase abnormality, induction regimen, or administration of maintenance therapy. Patients with a normal rFLC had significantly longer PFS and OS than those without on univariate analysis (median PFS, 24.2 vs 6.6 m, P = 0.001; median OS, 59.6 vs 20.2 m, P < 0.001). Normalization of the rFLC retained its prognostic significance for both PFS and OS on multivariate analysis (both P < 0.001). We further examined the impact of achievement of a normal rFLC on PFS and OS in patients with a high or low baseline rFLC. Using receiver operating characteristic curve analysis, the optimal cutoff was 69.8; patients were divided into two groups based on the cutoff. As expected, patients with a higher baseline rFLC who achieved a normal rFLC had longer PFS and OS (median PFS, 29.7 vs 4.3 m, P < 0.001; median OS, 93.6 vs 15.8 m, P < 0.001), but those with a lower baseline rFLC did not (median PFS, 21.4 vs 7.1 m, P = 0.484; median OS, 53.9 vs 34.9 m, P = 0.120). In addition, patients with a lower baseline rFLC were more likely to achieve normal rFLC than those with a higher baseline rFLC, although the difference was not statistically significant (P = 0.074).

Conclusion

This study demonstrated that achieving normalization of the rFLC during the course of treatment is robustly predictive for both PFS and OS in patients with IIMM who do not achieve CR. As monoclonal FLC is secreted independently of monoclonal intact Ig from neoplastic plasma cells, normalization of the rFLC also confers improved prognosis of patients with IIMM who had high levels of rFLC. These data indicate that serial measurement of FLC at all levels of response may be a valuable tool for accurate prognostication in IIMM even when achieving only VGPR or worse response to therapy.

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