Enhanced Detection of M-Protein in Non-Secretory and Oligo-Secretory Multiple Myeloma Using MALDI-TOF Mass Spectrometry

Background: Non-secretory myeloma, characterized by the absence of detectable paraprotein in the blood, poses a rare and complex challenge within the spectrum of multiple myeloma. Oligo-secretory myeloma, defined by the International Myeloma Working Group as having paraprotein levels below 10 g/L, Bence Jones protein below 200 mg/24h, and involved serum free light chain below 10 mg/dL, also presents diagnostic and monitoring difficulties due to its low paraprotein levels. Due to the limited ability of traditional methods like serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) to detect proteins in non-secretory and oligo-secretory multiple myeloma, monitoring these patients is challenging. Consequently, they are often excluded from clinical trials, restricting their access to novel treatments available for secretory myeloma. Current clinical practice for monitoring these conditions primarily relies on invasive bone marrow biopsies and expensive imaging techniques such as MRI and whole-body PET/CT scans. Advanced technologies such as mass spectrometry (MS) have demonstrated increased sensitivity in detecting low protein levels and offer a minimally invasive alternative to bone marrow biopsies, potentially serving as a superior tool for surveillance in these patients. In this study, we directly compared the results of SPEP and IFE with those of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) MS using samples from a cohort of oligo-secretory and non-secretory multiple myeloma patients. This technology can provide quantitative intact M protein results and qualitative results for the presence of light chains.

Methods: Serum was collected from 5 patients with oligo-secretory and 17 patients with non-secretory myeloma. Blood samples were collected at varying stages of disease, including both relapse and remission. MALDI-TOF MS was performed within a median time interval of 4 days (range: 0-7 days) between sample collection for SPEP and MS analysis.

Results: Among the 22 patients studied, 13 (59%) showed detectable disease by MS that was not identified by SPEP and/or IFE, whereas none (0%) had disease detectable only by SPEP and/or IFE and not by MS. Three (14%) samples showed detectable disease by both methods, and 5 (23%) patients had no detectable disease by either method. The 2 patients whoachieved minimal residual disease negativity had no detectable M protein on either SPEP or MS. MS demonstrated a sensitivity of 90% and specificity of 100%, while SPEP showed a sensitivity of 31% and specificity of 100%.

Conclusion: Non-secretory and oligo-secretory myeloma present a diagnostic and monitoring challenge due to their low or absent monoclonal protein production. Our study demonstrates the superior sensitivity of MALDI-TOF MS compared to standard SPEP in detecting M-protein in these patients. By identifying M-protein in 59% of patients where SPEP failed, MS offers a valuable tool for accurate disease surveillance and potentially earlier intervention. This increased sensitivity can also enhance risk stratification and improve therapeutic decision-making and may ultimately lead to better outcomes. Further research is warranted to explore the potential benefits of integrating MS into routine clinical practice for non-secretory and oligo-secretory myeloma patients, as it could significantly enhance our ability to monitor disease progression, response to therapy, and potentially facilitate their inclusion in clinical trials for novel therapies.

Hoffman:Syndax: Other: stock and other ownership interests. Landgren:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees. Diamond:Janssen: Honoraria. Kazandjian:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alphasights: Consultancy; MJH Life Sciences: Honoraria; Magnolia: Honoraria; BMS: Honoraria; Aptitude Health: Honoraria; MJH Life Sciences: Honoraria; Arcellx: Honoraria, Other: served on independent data monitoring committees (IDMC); Aperture Medical Technologies: Honoraria, Other: served on independent data monitoring committees (IDMC); Dedham Group: Consultancy; Curio Science: Honoraria; Karyopharm Therapeutics: Honoraria, Research Funding, Speakers Bureau; NCI/NIH, FDA, MMRF, DoD-PROMETHEUS (Murtha Cancer Center Research Program), Amgen, BMS/Celgene, Janssen,: Research Funding; Plexus: Honoraria; MMRF: Honoraria; Bridger Consulting Group: Consultancy.