Abstract
【Introduction】Urine and serum immunofixation electrophoresis (IFE) and free light chain (FLC) are used for measuring paraprotein levels produced by neoplastic plasma cells and are widely accepted as standard tests for diagnosis and monitoring of multiple myeloma (MM). Treatment response criteria defined by the International Myeloma Working Group (IMWG) largely relies on the decrease in paraprotein levels of intact immunoglobulin with or without serum FLC. However, the paraprotein levels vary widely between patients and even in the same patient during the course of the disease. Therefore, considerable discrepancy often exists between the extents of decrease in neoplastic tumour cell burden and paraprotein levels in response to chemotherapy. We retrospectively compared the bone marrow plasma cell (BM-PC) levels using 6- to 8-color flow cytometry (FCM) with various levels of IMWG-defined responses after treating patients with MM.
【Methods】We included patients with MM (light chain only multiple myeloma (LCMM), n =35 ; intact immunoglobulin multiple myeloma (IIMM), n =115 ) who were treated at Kameda Medical Center, Japan and Kanazawa University Hospital, Japan, between April 2007 and June 2017. Among them, 130 patients (LCMM; n=35 , IIMM; n=95 ) who achieved partial response (PR) or better response were selected on the basis of the co-availability of serum and urine test data, FLC data, and multicolor flow cytometry (MFC)-generated BM-PC quantitation data. MFC-mediated assessment of BM-PCs was performed during diagnosis and when each IMWG-defined treatment response was obtained. The residual BM-PC level was compared with the IMWG-defined responses using Kruskal-Wallis analysis. Oligosecretary and non-secretary myeloma were excluded from this study. This study conformed to the principles of the Declaration of Helsinki.
【Result】Complete data set of IFE, FLC, and MFC during diagnosis, PR, very good partial response (VGPR), complete response (CR), and stringent CR (sCR) were available in 37, 58, 10, and 50 samples in IIMM and in 4, 21, 15, and 21 samples in LCMM. Mean BM-PCs during diagnosis in IIMM and LCMM was 2.1 x 10-1 and 2.2 x 10-1, respectively. In patients with IIMM, mean residual BM-PCs at PR, VGPR, CR, and sCR in IIMM were 1.8 × 10-2 (range: 1.4 × 10-5-7.5 × 10-2), 2.0 × 10-3 (range: 1.4 × 10-5-2.9 × 10-2), 4.4 × 10-4 (range: 2.1 × 10-5-2.0 × 10-3), and 4.8 × 10-4 (range: 2.0 × 10-6-5.3 × 10-3), respectively. Although significant difference in residual BM-PC levels was observed between PR vs. VGPR (P < 0.01), there were no statistically significant difference between VGPR vs. CR (P = 0.08) and CR vs. sCR (P = 0.9). Of note, 58% patients had residual MM cells ≥ 10-4 even when they achieved sCR. The amount of involved intact immunoglobulin at diagnosis was significantly higher in these patients than those who achieved residual MM cells <10-4 (mean: 5206.1 vs. 3954.7 p = 0.04).
In patients with LCMM, mean residual BM-PCs cells at PR, VGPR, CR, and sCR were 3.5 × 10-2 (range: 5.1 × 10-3-7.7 × 10-2), 8.9 × 10-3 (range: 4.0 × 10-4-8.9 × 10-2), 2.0 × 10-3 (range: 4.0 × 10-5-1.0 × 10-2), and 1.1 × 10-4 (range: 2.0 × 10-6-7.0 × 10-4), respectively. Significant difference in the amount of residual BM-PC was only observed between CR and sCR, but not in PR vs. VGPR and VGPR vs. CR (PR vs. VGPR: p = 0.08, VGPR vs. CR: p = 0.08, CR vs. sCR: p = 0.03). Normal FLC ratio was highly predictive of lower residual BM-PCs (> 10-4) in LCMM. (Figure 1)
Figure 2 shows the proportion of residual BM-PCs at various IMWG responses. The percentages of samples with residual BM-PCs at the levels of ≥ 10-3, 10-3 > - ≥ 10-4 , and < 10-4 in IIMM were 86.8% (n = 32/37), 7.8% (n = 3/37), and 5.2% (n = 2/37) for PR, 31.0% (n = 18/58), 56.8% (n = 33/58), and 12.0% (n = 7/58) for VGPR, 20% (n = 2/10), 40% (n = 4/10), and 40% (n = 4/10) for CR, and 12% (n = 6/50), 46% (n = 23/50), and 42% (n = 21/50) for sCR, respectively. In the case of LCMM, these figures were 100% (n = 4/4), 0% (n = 0/4), and 0% (n = 0/4) for PR, 66.6% (n = 14/21), 33.3% (n = 7/21), and 0% (n = 0/21) for VGPR, 20% (n = 3/15), 66.6% (n = 10/15), and 13.3% (n = 2/15) for CR, and 0% (n = 0/21), 23.8% (n = 5/21), and 76.1% (n = 16/21) for sCR, respectively.【Conclusion】The depth of residual BM-PCs response did not parallel that of IMWG response, and ~20% patients with CR had high level of residual BM-PCs (≥ 10-3). Although paraprotein-based assessment is feasible for disease monitoring in MM, our data indicates that response to treatment could be better assessed by BM-PC.
No relevant conflicts of interest to declare.
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