Academy of Diagnostics & Laboratory Medicine - Scientific Short
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Clinical laboratory specialists often face significant challenges when reporting test results for multiple myeloma (MM) patients using immunofixation electrophoresis (IFE). This technique is particularly problematic when the disease cannot be measured by quantitative protein electrophoresis methods. Typically, IFE detects a distinct band above the polyclonal background, indicating monoclonal protein (MP) secreted by tumor plasma cells. This band and its migration pattern are used to monitor treatment response and disease progression. The International Myeloma Working Group (IMWG) classifies patients with positive IFE results but negative serum protein electrophoresis (SPE) as having a very good partial response (VGPR).1 If IFE results turn negative, along with negative urine IFE and less than 5% plasma cell infiltration, the classification is upgraded to a complete response (CR).1 However, IFE has significant limitations, including limited sensitivity (detection limit of approximately 0.1 g/L)2, subjective interpretation, and susceptibility to interferences such as monoclonal antibodies or post-treatment oligoclonal bands.3 To address these issues, we compared IFE results with a more sensitive and objective technique: mass-to-charge MP detection using MALDI-TOF Mass Spectrometry (QIP-MS) with the Exent® Analyzer (The Binding Site, Thermo Fisher).
We analyzed 430 serum samples from three clinical trials by the Spanish Myeloma Group: GEM12, GEM14, and GEM-CESAR.4–6 These samples were collected at specific times: post-induction, post-autologous stem cell transplant (ASCT), post-consolidation, and the 1st and 2nd years after maintenance treatment. Mass spectrometry (MS) detected MP in 45% of cases, compared to 32% with IFE. The negative predictive value (NPV) of MS, using IFE as a reference, was 0.8987. However, the positive predictive value (PPV) was lower at 0.5855, due to cases where IFE was positive but MS was negative (5.58%) and cases where MS was positive but IFE was negative (18.6%). Re-analysis of the IFE-/MS+ cases showed that the IFE gel displayed oligoclonal bands, confirming the higher sensitivity of MS in detecting MPs.
When evaluating the clinical impact of MS on median progression-free survival (mPFS) among 137 patients in VGPR (IFE+), we observed a trend where patients with positive MS results had shorter mPFS compared to those with negative MS results (5.96 years vs. not reached), though this was not statistically significant. More importantly, in patients achieving CR (IFE-), mPFS was significantly different based on MS results. Patients with IFE-/MS+ had an mPFS of 4.65 years, while those with IFE-/MS- had an mPFS that was not reached (p=0.0001). IFE alone could not distinguish between subgroups of patients with significantly different mPFS. These findings highlight the critical limitations of IFE in evaluating treatment response in MM patients, especially with faint or oligoclonal bands. The variability in IFE interpretation among different clinical laboratories in multicenter trials further compounds these issues, highlighting the superior sensitivity and reliability of MS to evaluate treatment response and monitor disease progression.
Given the heterogeneity in IFE interpretation and the era of highly effective MM treatments that induce rapid and deep responses, further studies comparing MS and IFE are warranted. Considering MS as a more accurate and sensitive alternative technique to evaluate complete response could meaningfully improve the response evaluation and management of MM patients.
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