A critical analysis of the IMWG multiple myeloma complete response criterion in the era of mass spectrometry

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In the context of multiple myeloma (MM), achieving a “Complete Response” (CR) is a clinically significant milestone, indicating a considerable reduction in disease burden. According to the International Myeloma Working Group (IMWG) criteria, CR is defined by four parameters: “negative immunofixation (IFE) on the serum and urine, disappearance of any soft tissue plasmacytomas, and the presence of less than 5% plasma cells (PC) in bone marrow (BM) aspirates.”1 The Spanish Myeloma Group and others have previously highlighted the limited clinical value of urine IF in defining CR, raising questions about this requisite in the definition of CR.2, 3 In this context, we aim to assess the value of the morphological PC count in BM examinations in patients in unconfirmed CR based on negative sIFE results. We will also explore the clinical value of mass spectrometry (MS) as a highly sensitive, non-invasive, single serological marker in this population, potentially allowing for a more accurate and less invasive assessment of disease status. We analyzed a total of 716 paired serum and BM samples obtained from 290 newly diagnosed transplant-eligible (NDTE) MM patients included in the GEM12MENOS65 (NCT01916252), and GEM14MAIN (NCT02406144) (Supporting Information S1: Table S1) clinical trials. Enrollment details and treatment schemas have been previously described.4-6 Samples were obtained at four predefined time points: post-induction, after autologous stem cell transplant (ASCT), post-consolidation, and after 2 years of maintenance. Serum samples were analyzed using Quantitative Immunoprecipitation Mass Spectrometry (MS) with anti-IgG/A/M, total κ, and total λ beads in the EXENT Analyzer (The Binding Site, part of Thermo Fisher Scientific), and serum protein electrophoresis (SPEP) and immunofixation (IFE) were carried out as per each center's protocol.7-9 First-pull BM aspirations were used for morphological assessment with May–Grümwald–Giemsa staining. Plasma cell (PC) counts were obtained from a 200-cell differential count, using conventional bright-field microscopy. Each study site's independent ethics committee reviewed and approved the protocols, amendments, and informed consent forms. If required, these data can be obtained via the corresponding author. First, we analyzed the individual clinical value of the two main factors defining CR (i.e., PC counting [<5% vs. ≥5%] and sIFE [positive vs. negative]) in all samples, including all time points, and independently of the conventional response achieved by the patients at each of those moments.1 As shown in Figure 1A,B, neither PC nor sIFE distinguished patient groups with different median progression-free survival (mPFS); in contrast, MS status clearly separated two cohorts with distinct mPFS (Figure 1C). Focusing on the 476 samples with unconfirmed CR based on negative sIFE results, we observed that PC counting did not differentiate two groups of patients with different mPFS (Figure 2A). However, a significant reduction in mPFS was noted among the 117 samples that were MS-positive (Figure 2B). We then combined the results of PC counting and sIFE, therefore dividing the global cohort into samples in CR (<5% PC and sIFE-negative) versus less than CR (≥5% PC and/or sIFE-positive). We have previously shown that, in this group of patients, the CR category only distinguished two groups with different PFS after induction and after ASCT, but no significant differences were observed after consolidation.10 In this study with longer follow-up, we confirmed the previous findings and additionally showed that the CR category did not discriminate two groups of patients with different PFS after two years of maintenance (Supporting Information S1: Figure 1). Accordingly, no significant differences in PFS between the ≥CR and <CR groups defined as above were found when analyzing all samples globally (Supporting Information S1: Figure 2). In contrast, as shown in Supporting Information S1: Figure 3, among cases in ≥CR, those found to be MS-positive (n = 91) displayed a significantly inferior PFS. Further, analysis of the combined results of PC counting and MS (among sIFE-negative cases) showed that only 36 out of the 476 cases were MS-negative and had ≥5% PC, the majority of them (31/36) with undetectable residual disease in the BM analyzed by flow cytometry and therefore corresponding to polyclonal PC. Therefore, among sIFE-negative cases, the NPV of MS using the results of PC counting as a reference was 90% (86%–93%; P = 0.0005). We have previously shown that, in this group of patients, MS identified two cohorts with significantly different mPFS at the four time points analyzed.11 Among sIFE-positive cases, MS showed a tendency to discriminate between two subgroups of patients with different mPFS, although statistical significance was not reached (P = 0.058; Supporting Information S1: Figure 4). These findings confirm the subjectivity of IFE interpretation and are likely explained by results falsely interpreted as positive. As shown in Supporting Information S1: Figure 5, all BM PC counts and sIFE results available were grouped into conventional CR versus non-CR and then combined with MS findings, resulting in four defined subgroups: (1) ≥CR and MS-negative, (2) ≥CR and MS-positive, (3)

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