Abnormal Heavy/Light Chain Ratio after Treatment Is a Robust Predictor of Shorter Survival in Patients with IgA Myeloma
Authors: Abe Yoshiaki , Suehara Yasuhito , Takamatsu Hiroyuki , Usui Yoshiaki , Narita Kentaro , Takeuchi Masami , Endean Kelly , Matsue Kosei 
Published: October 2019

Accurate quantification of monoclonal protein (M-protein) is essential for response assessment, management, and prediction of prognosis in patients with multiple myeloma (MM). Serum protein electrophoresis (SPEP) is commonly used to determine the degree of M-protein reduction in intact immunoglobulin (Ig) MM. However, SPEP has limitations when M-protein comigrates into the beta-fraction or M-protein fails to show a distinct sharp spike on densitometry. Ig heavy/light chain (HLC) assay enables separate quantification of the different light chain types of each Ig class. Although HLC assay quantifies different light chain subtypes of Ig classes, the sensitivity for detecting M-protein clonality and its impact on outcome may differ between IgA and IgG myeloma.

To investigate the clinical and prognostic impact of HLC assay, we retrospectively analyzed the correlation of heavy/light chain ratio (HLCR) with clinical status and its impact on outcome. A total of 402 frozen serum samples from 120 patients with MM (41 for IgA and 79 for IgG) treated at Kameda Medical Center (Kamogawa-shi, Chiba, Japan) and Kanazawa University Hospital (Kanazawa-shi, Ishikawa, Japan) at the times of various IMWG responses were collected. Samples were analyzed using the HLC assay, and the results were compared with serum protein electrophoresis (SPEP), free light chain ratio (FLCR), immunofixation, total IgG, IgA, and overall survival (OS).

Percentages of samples with normal HLCR at presentation, PR, VGPR, CR, and sCR were 0%, 0%, 27.6%, 100%, and 88.9%, respectively, for IgA MM and 0%, 12.5%, 64.3%, 100%, and 84.3%, respectively, for IgG MM. Normalization of HLCR at VGPR was more frequent in IgG MM compared to IgA MM (PR; 12.5% vs. 0%, respectively, P = 0.169, VGPR; 64.3% vs. 27.6%, respectively, P = 0.004), which suggests the lower sensitivity of detecting clonality in patients with IgG MM than those with IgA MM. Abnormal HLCR was seen more frequently in patients with poorer myeloma response, and it appeared to be more sensitive for detecting clonality in IgA myeloma compared to IgG myeloma after treatment. No significant difference in OS was observed between patients with or without uninvolved Ig suppression and OS if they obtained ≥ VGPR. Among the 85 patients that achieved ≥ VGPR, those that remained HLCR abnormal showed significantly shorter overall survival (OS) compared to those achieving normal HLCR (not reached vs. 55.5 months, P = 0.032). This correlation was seen in IgA myeloma patients (not reached vs. 30.1 months, P = 0.014), but not in IgG myeloma patients when analyzed separately. Univariate and multivariate analyses of factors that may affect survival identified abnormal HLCR at the best response as the only independent risk factor (hazard ratio, 4.7; 95% confidence interval, 1.4 - 15.26; P = 0.012) for shorter OS in this subset of patients.

In conclusion, HLC assay is useful for accurate monitoring of monoclonal protein in patients with myeloma. The results suggested that obtaining normal HLCR indicated a more favorable prognosis in patients with IgA myeloma, but not IgG myeloma, that achieved VGPR or better response.

Disclosures

Takamatsu: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria.