Prognostic evaluation system for IgD-type multiple myeloma based on IgD quantitative detection

Abstract

The present invention discloses a prognosis evaluation system for IgD type multiple myeloma based on IgD quantitative detection, which includes a data acquisition module and a judgment module; the data acquisition module is used to obtain the qIgD of the sample serum and submit it to the judgment module; the judgment module is used to evaluate according to the principle that the progression-free survival of the subject with qIgD concentration in the preset range is greater than the progression-free survival of the subject with qIgD>preset range upper limit according to the acquired qIgD data; the preset range of qIgD is 7.7-132.1mg / L. The present invention quantitatively detects IgD by detecting the concentration of iFLC, and the detection sensitivity of qIgD can reach 0.1mg / L, which is significantly higher than the existing evaluation index serum M component, and the evaluation is more accurate.

Description

Technical Field

[0001] The invention belongs to the technical field of prognosis evaluation of IgD type multiple myeloma, and more specifically, relates to a prognosis evaluation system for IgD type multiple myeloma based on IgD quantitative detection. Background Art

[0002] Plasma cell myeloma (PCM) is a multifocal plasma cell tumor originating from the bone marrow, characterized by the malignant proliferation of clonal plasma cells in the bone marrow. In most cases, there is secretion of monoclonal immunoglobulin M or its fragments, leading to related organ or tissue damage. Among them, IgD multiple myeloma is a rare subtype of plasma cell myeloma, accounting for about 1%-2% according to foreign reports, with a poor prognosis. The median survival time of IgD multiple myeloma patients evaluated by the existing evaluation system is only 13-21 months.

[0003] There are five types of immunoglobulins in human blood, namely IgM, IgG, IgA, IgE, and IgD, among which IgD mainly appears on the surface of mature B lymphocytes. Existing studies have pointed out that IgD plays a role in the development of IgD-type multiple myeloma, but the mechanism is not clear at present. This is mainly because the content of IgD secreted in serum is extremely low, accounting for about 1% of the total Ig, and the individual content varies greatly. Generally, the IgD content in adult serum is 0-80 mg / L, which is difficult to detect; in addition, IgD performance is unstable, easy to aggregate during the separation process, and is easily cleaved by enzymes. The structure of IgD is extremely similar to IgG. Existing detection technology is difficult to accurately detect, and the sensitivity of quantitative IgD is low. Moreover, the clinical characteristics of IgD-type multiple myeloma are mostly from case reports. There is a lack of large-scale case studies, and its function and pathogenesis cannot be further studied. The current assessment of the prognosis of patients with IgD-type multiple myeloma uses the IMWG assessment criteria.

[0004] However, the existing IMWG evaluation criteria are usually based on the evaluation of serum M components. In most plasma cell myelomas, the quantification of serum M components is important for evaluating treatment response and predicting progression-free survival. Generally speaking, the quantitative evaluation of serum M components requires the subject's M protein to reach a level above the level of measurable lesions. However, in subjects with IgD multiple myeloma, due to the low concentration of serum M components, it is difficult to reach the level of measurable lesions. The accuracy of predicting progression-free survival of subjects with IgD multiple myeloma using the existing evaluation system is low. Therefore, the development of a prognostic evaluation system suitable for IgD multiple myeloma is conducive to more accurate prediction of progression-free survival of subjects with IgD multiple myeloma, which helps hematologists choose appropriate treatment methods and adjust treatment plans. Summary of the invention

[0005] In view of the above defects or improvement needs of the prior art, the present invention provides an IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection, the purpose of which is to find that qIgD is an effective parameter that is compatible with the existing prognosis evaluation system, and to establish an IgD type multiple myeloma prognosis evaluation system based on the qIgD evaluation index, especially an evaluation system established in combination with qIgD and IMWG standards, the qIgD detection sensitivity is 0.1 mg / L, which can significantly improve the accuracy of the existing evaluation system, thereby solving the technical problem of low accuracy of the existing evaluation system in evaluating IgD type multiple myeloma.

[0006] To achieve the above object, according to one aspect of the present invention, a prognosis evaluation system for IgD-type multiple myeloma based on IgD quantitative detection is provided, which includes a data acquisition module and a judgment module;

[0007] The data acquisition module is used to obtain qIgD of sample serum and submit it to the judgment module;

[0008] The judgment module is used to evaluate based on the acquired qIgD data according to the principle that the progression-free survival of subjects whose qIgD concentration is within a preset range is greater than the progression-free survival of subjects whose qIgD concentration is greater than the upper limit of the preset range; the preset range of qIgD is 7.7-132.1 mg / L.

[0009] Preferably, in the IgD-type multiple myeloma prognosis assessment system based on IgD quantitative detection, the detection sensitivity of qIgD is 0.1 mg / L.

[0010] Preferably, in the IgD-type multiple myeloma prognosis assessment system based on IgD quantitative detection, the qIgD is measured by turbidimetry using a SPA PLUS professional protein analyzer and a latex-enhanced immunoassay.

[0011] Preferably, in the IgD multiple myeloma prognosis assessment system based on IgD quantitative detection, the data acquisition module is also used to obtain the sample rFLC and serum FLC levels; the judgment module judges and evaluates according to the following principles:

[0012] (1) If qIgD and rFLC are normal, the progression-free survival of the subject is estimated to be [27, 51] months, and the median PFS is 39 months;

[0013] (2) If qIgD is abnormal and / or rFLC is abnormal, the progression-free survival of the subject is estimated to be [8, 13] months, and the median PFS is 10 months;

[0014] Normal qIgD refers to a qIgD concentration within the range of 7.7-132.1 mg / L, whereas a concentration above 7.7-132.1 mg / L refers to an abnormal qIgD concentration.

[0015] The normal rFLC refers to a ratio of affected to uninvolved FLC within the range of 0.26-1.65, whereas a ratio of affected to uninvolved FLC refers to an abnormal rFLC.

[0016] Preferably, in the IgD-type multiple myeloma prognosis assessment system based on IgD quantitative detection, if the qIgD concentration is greater than the upper limit of the preset range, the subject's progression-free survival is assessed to be [7, 12] months, and the median PFS is 10 months.

[0017] Preferably, the data acquisition module of the IgD multiple myeloma prognosis evaluation system based on IgD quantitative detection is also used to obtain the IMWG standard evaluation indicators of the sample; the IMWG standard evaluation indicators include serum and urine immunofixation electrophoresis results, bone marrow plasma cell ratio and 24-hour urine m-protein content.

[0018] Preferably, the judgment module of the IgD multiple myeloma prognosis assessment system based on IgD quantitative detection judges according to the following principles:

[0019] If the qIgD level is lower than the upper limit of the preset qIgD range, serum and urine immunofixation electrophoresis are negative, there is no soft tissue plasmacytoma, and bone marrow plasma cells are ≤5%, it is considered a complete remission;

[0020] If the qIgD level is reduced by ≥90% and the 24-hour urine protein level is <100 mg, it is considered a very good partial response;

[0021] If the qIgD level is lower than the upper limit of the preset range of qIgD, the rFLC is normal, and there is no clonal plasmacytoma in the immune biopsy, it is a strict complete response; the no clonal plasmacytoma refers to a κ / λ ratio of ≤4:1 for κ-type patients or a κ / λ ratio of ≥1:2 for λ-type patients;

[0022] The median PFS of the evaluated subjects was strict complete remission > complete remission > very good partial remission.

[0023] Preferably, the IgD-type multiple myeloma prognostic assessment system based on IgD quantitative detection assesses the progression-free survival of subjects in strict complete remission to be [27, 51] months, with a median PFS of 39 months.

[0024] Preferably, the IgD-type multiple myeloma prognostic assessment system based on IgD quantitative detection assesses the progression-free survival of subjects in complete remission to be [1, 58] months, with a median PFS of 29 months.

[0025] Preferably, the IgD-type multiple myeloma prognostic assessment system based on IgD quantitative detection assesses the progression-free survival of the subjects to be [8, 18] months in subjects with very good partial remission, with a median PFS of 13 months.

[0026] In general, compared with the prior art, the above technical solution conceived by the present invention adopts qIgD which is compatible with the existing evaluation system as an effective parameter for evaluation, and can achieve the following:

[0027] Beneficial effects:

[0028] The present invention establishes an IgD type multiple myeloma prognosis evaluation system based on an effective evaluation parameter qIgD, and judges the length of a subject's progression-free survival period according to whether the qIgD concentration falls within a preset range, wherein the preset range of qIgD is 7.7-132.1 mg / L, and a subject falling within the range has a longer progression-free survival period; in particular, a SPA PLUS professional protein analyzer is used, a latex enhanced immunoassay method is used, and IgD is measured by turbidimetry, wherein the qIgD detection sensitivity in the present invention can reach 0.1 mg / L, and the detection sensitivity of the evaluation index qIgD of the system is extremely significantly higher than the detection sensitivity of the existing evaluation index serum M component of 100 mg / L, and the accuracy of the prognosis evaluation of IgD type multiple myeloma can be improved.

[0029] In particular, the present invention further combines qIgD and the existing IMWG standard for prognostic evaluation, confirming that qIgD is compatible with the existing evaluation system, and the evaluation system revised based on qIgD has a 2-year PFS AUROC of 0.94 (0.86, 0.96), while the IMWG standard evaluation system has a 2-year PFS AUROC of 0.86 (0.75, 0.93), P < 0.05; the evaluation system revised based on qIgD has a 3-year PFS AUROC of 0.92 (0.82, 0.95), while the IMWG standard evaluation system has a 3-year PFS AUROC of 0.85 (0.73, 0.94), P < 0.05. This shows that compared with the International Myeloma Working Group (IMWG) standard, adding qIgD data to the IMWG response standard can improve the accuracy of PFS prediction by the existing evaluation system, which is of great significance for the prognosis evaluation of IgD-type multiple myeloma subjects and may help hematologists choose appropriate treatment methods.

[0030] Moreover, using the evaluation system provided by the present invention, the median PFS of the subjects with complete remission and very good complete remission were 29 months and 13 months, respectively, which were significantly different. However, using the existing IMWG evaluation system, the median PFS of the subjects with complete remission and very good complete remission were both 11 months, which was indistinguishable. This indicates that the qIgD-based evaluation system provided by the present invention can better evaluate the prognosis of subjects with complete remission and very good complete remission. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the maximum reduction and response rate estimated by different indicators;

[0032] Figure 1 A is the estimated maximum reduction in qIgD (M≤10 g / L); Figure 1 B is the maximum reduction estimated by iFLC (M≤10 g / L); Figure 1 C is the maximum IgD reduction estimated by qIgD (M>10 g / L); Figure 1 D is the comparison of the response rates using the IMWG standard and qIgD, respectively; Figure 1 E is the comparison of the response rates using iFLC and qIgD, respectively;

[0033] Figure 2 is the correlation analysis between iFLC and qIgD;

[0034] Figure 3 PFS was assessed based on qIgD;

[0035] Figure 3 A is the combination of rFLC and qIgD to evaluate PFS; Figure 3 B is the assessment of PFS of sCR subjects based on qIgD; Figure 3 C is the assessment of PFS of CR subjects based on qIgD;

[0036] Figure 4 The PFS was evaluated by combining the IMWG criteria and the qIgD-based criteria;

[0037] Figure 4 A is the use of IMWG criteria to assess PFS; Figure 4 B is based on the combined assessment of PFS using qIgD criteria;

[0038] Figure 5 The 2-year and 3-year PFS AUROC curves were evaluated using the IMWG standard and qIgD and IMWG standards, respectively;

[0039] Figure 5 A is the use of IMWG criteria to assess PFS; Figure 5B is the 2-year PFS AUROC curve evaluated by IMWG standard and qIgD and IMWG standard respectively; Figure 5 C is the 3-year PFS AUROC curve evaluated by IMWG standard and qIgD and IMWG standard, respectively. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0041] Abbreviations of professional terms:

[0042] MM: multiple myeloma; PCM: plasma cell myeloma; IMWG: International Myeloma Working Group;

[0043] IgD: immunoglobulin D; qIgD: quantitative IgD;

[0044] DS: traditional staging system; ISS: international staging system; R-ISS: revised international staging system;

[0045] LDH: lactate dehydrogenase; IMiD: immunomodulatory drugs; PIs: proteasome inhibitors;

[0046] FISH: fluorescence in situ hybridization; IFE: immunofixation electrophoresis; ASCT: autologous hematopoietic stem cell transplantation;

[0047] sFLC: serum-free light chain, including κ light chain and λ light chain; rFLC: ratio of involved to uninvolved FLC; iFLC: involved FLC;

[0048] PFS: progression-free survival; ULN: upper limit of normal.

[0049] Serum M protein is an immunoglobulin molecule and its molecular fragments with the same structure and electrophoretic mobility produced by the proliferation of monoclonal B cells. It is an important parameter in the existing evaluation system, but its detection sensitivity is low (100 mg / L), and in the efficacy evaluation, serum M protein content above 10g / L is considered measurable, and below 10g / L is considered unmeasurable. Multiple myeloma can be divided into 8 types according to the characteristics of M protein in serum, including IgG, IgA, IgD, IgE, IgM, light chain type, biclonal type and non-secretory type, and further divided into κ type and λ type according to the light chain type of M protein.

[0050] Among them, IgG type is the most common, followed by IgA type, and IgD type multiple myeloma accounts for less than 2% of plasma cell myeloma PCM. However, compared with other PCM isotypes, IgD type has a worse prognosis. Moreover, the clinical characteristics of IgD type multiple myeloma are mostly from case reports. There is a lack of large-scale case studies, making it difficult to conduct further in-depth research, and the mechanism is currently unclear.

[0051] Although researchers have pointed out that IgD plays a role in the metabolic process of the development of IgD-type multiple myeloma, it is still unknown whether the content of IgD can be used to evaluate the prognosis of multiple IgD-type multiple myeloma. The possible reasons include two aspects: on the one hand, the content of IgD in IgD-type multiple myeloma is trace, the content of IgD in serum is very low, and the content of IgD in general adult serum is 0-80 mg / L, and the performance of IgD is unstable. It is currently difficult to accurately detect and quantify. Compared with its true content, the error of the test cannot be ignored. Therefore, due to the existence of test errors, the quantitative test data is likely to make the evaluation and prognosis results of IgD-type multiple myeloma more vague, that is, the accuracy is reduced. The current routine quantitative IgD content data cannot be used to evaluate IgD-type multiple myeloma; on the other hand, it is unknown whether the IgD content is a factor independent of the existing evaluation indicators. If the metabolic status of the patient represented by the IgD content has been reflected in the existing IgD-type multiple myeloma evaluation and prognosis system, then increasing the IgD content as an evaluation indicator will not improve the accuracy of the prognosis evaluation effect; on the contrary, if the IgD content as an evaluation indicator is not compatible with the existing prognosis evaluation system, then increasing the IgD content as an evaluation indicator will lead to a decrease in the overall performance of the evaluation system.

[0052] Therefore, including the content of IgD, there is currently no clear effective parameter that can be used to evaluate IgD multiple myeloma. In particular, it is helpful to improve the sensitivity of the prognosis evaluation of IgD multiple myeloma, and the evaluation indicators that are compatible with the existing evaluation system, as an improvement of the existing prognosis evaluation indicators of IgD multiple myeloma, are conducive to improving the accuracy of the existing evaluation system for the prognosis evaluation of IgD multiple myeloma, and a large amount of experimental exploration and data verification are needed.

[0053] The present invention is based on a multicenter retrospective study, and includes 356 IgD myeloma patients from 14 centers of the Asian Myeloma Working Group (AMN). We compared the qIgD and iFLC concentrations at baseline and after 4 treatment cycles in 78 subjects, and found that the change trend between qIgD and iFLC had a certain correlation. The qIgD was quantitatively detected by the method of detecting the iFLC concentration, and its detection sensitivity could reach 0.1 mg / L, which was significantly higher than the detection sensitivity of the existing evaluation indicator serum M protein of 100 mg / L.

[0054] Furthermore, by combining qIgD and the existing IMWG criteria for evaluating the prognosis of IgD multiple myeloma, it was confirmed that the combination of qIgD and the existing IMWG evaluation indicators can improve the accuracy of the existing evaluation system for the evaluation of progression-free survival of IgD multiple myeloma patients, indicating that qIgD is compatible with the existing evaluation system and can improve the accuracy of the evaluation, that is, qIgD can be used as an effective evaluation parameter. The progression-free survival is defined as the time interval from diagnosis to progression defined by the IMWG criteria or death caused by any cause.

[0055] The present invention provides an IgD multiple myeloma prognosis assessment system based on IgD quantitative detection, which includes a data acquisition module and a judgment module;

[0056] The data acquisition module is used to obtain qIgD of sample serum and submit it to the judgment module;

[0057] The judgment module is used to evaluate according to the acquired qIgD data, based on the principle that the longer the progression-free survival period of the subject is, the greater the qIgD concentration is within the preset range; the preset range of qIgD is 7.7-132.1 mg / L; the detection sensitivity of qIgD is 0.1 mg / L, and IgD is quantitatively detected by detecting the concentration of iFLC;

[0058] Furthermore, the data acquisition module is also used to obtain rFLC and serum FLC levels; and submit them to the judgment module; wherein the qIgD and serum-free light chain (sFLC) detection is as follows:

[0059] Serum sample pretreatment: Fasting venous blood samples were collected into vacuum coagulation tubes, and serum was aspirated after centrifugation at 3000 g for 10 min;

[0060] IgD and sFLC detection: IgD and sFLC were measured by turbidimetry using a latex-enhanced immunoassay using a SPA PLUS professional protein analyzer. The sFLC assay measures the absolute free κ and λ light chain concentrations and reports them as the κ / λ ratio, and the involved / uninvolved FLC ratio (rFLC) is calculated using the monoclonal light chain as the numerator.

[0061] The judgment module makes judgments according to the following principles:

[0062] (1) If qIgD and rFLC are normal, the progression-free survival of the subject is estimated to be [27, 51] months, and the median PFS is 39 months;

[0063] (2) If qIgD is abnormal and / or rFLC is abnormal, the progression-free survival of the subject is estimated to be [8, 13] months, and the median PFS is 10 months;

[0064] The normal qIgD refers to a qIgD concentration within the range of 7.7-132.1 mg / L, otherwise it is an abnormal qIgD concentration.

[0065] The normal rFLC refers to a ratio of affected to uninvolved FLC within the range of 0.26-1.65, whereas a ratio of affected to uninvolved FLC refers to an abnormal rFLC.

[0066] In the case of abnormal qIgD, if the qIgD concentration is > the upper limit of the normal range, the estimated progression-free survival of the subject is [7, 12] months, and the median PFS is 10 months.

[0067] Furthermore, the data acquisition module is also used to obtain the sample IMWG standard evaluation indicators; the IMWG standard evaluation indicators include serum and urine immunofixation electrophoresis results, bone marrow plasma cell ratio and 24-hour urine m-protein content, and submit them to the judgment module;

[0068] The judgment module performs judgment and evaluation according to the following principles:

[0069] (1) If the qIgD level is lower than the upper limit of the preset qIgD range, serum and urine immunofixation electrophoresis are negative, there is no soft tissue plasmacytoma, and bone marrow plasma cells are ≤5%, it is considered a complete remission;

[0070] (2) If the qIgD level is reduced by ≥90% and the 24-hour urine protein level is <100 mg, it is considered a very good partial response;

[0071] (3) If the qIgD level is lower than the upper limit of the preset range of qIgD, rFLC is normal, and there are no clonal cells in the immune biopsy, it is a strict complete remission; the non-clonal plasmacytoma refers to a κ / λ ratio of ≤4:1 for κ patients or a κ / λ ratio of ≥1:2 for λ patients;

[0072] The median PFS of the evaluated subjects was strict complete remission > complete remission > very good partial remission.

[0073] Using the combined criteria of qIgD and IMWG, the progression-free survival of subjects with strict complete remission was [27, 51] months, with a median PFS of 39 months; the progression-free survival of subjects with complete remission was [1, 58] months, with a median PFS of 29 months; the progression-free survival of subjects with very good partial remission was [8, 18] months, with a median PFS of 13 months.

[0074] The following are examples:

[0075] Example 1

[0076] This study was approved by the Ethics Committee of Shanghai Changzheng Hospital, and all subjects signed written informed consent in accordance with the provisions of the Declaration of Helsinki. Clinical and laboratory covariates were collected from hospital medical records and checked by two independent observers, and any discrepancies were adjudicated by a third observer.

[0077] The sample data of this example are derived from the data of 100 consecutive IgD PCM subjects who visited Shanghai Changzheng Hospital from September 2013 to December 2021, including 74 males and 26 females, with a median age of 58 years (interquartile range [IQR], 52-64 years) at diagnosis. The specific indicators tested are as follows:

[0078] (1) Fluorescence in situ hybridization (FISH) analysis

[0079] After Ficoll-Hypaque gradient separation, plasma cells in pre-treated bone marrow aspirates were isolated using magnetic beads coated with anti-human CD138 antibodies (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany), and cytogenetics were analyzed by fluorescence in situ hybridization (FISH) according to standard methods using commercially available probes (MetaSystems FISH Probes, Altlussheim, Germany). Two hundred interphase nuclei were analyzed using fluorescence microscopy.

[0080] (2) qIgD, serum-free light chain (sFLC) and serum M component detection

[0081] Serum sample pretreatment: Fasting venous blood samples were collected into vacuum coagulation tubes and serum was aspirated after centrifugation at 3000 g for 10 min.

[0082] IgD and sFLC detection: IgD and sFLC were measured by turbidimetry using a latex-enhanced immunoassay using a SPA PLUS professional protein analyzer. The sFLC assay measures the absolute free κ and λ light chain concentrations and reports them as the κ / λ ratio, and the involved / uninvolved FLC ratio (rFLC) is calculated using the monoclonal light chain as the numerator.

[0083] Serum M component detection: immunofixation electrophoresis (IFE).

[0084] The information and test results of the above 100 subjects are summarized in Table 1:

[0085] Table 1 Subjects and clinical characteristics

[0086]

[0087]

[0088] (3) Statistical analysis

[0089] Continuous outcomes were compared using the Wilcoxon rank-sum test and dichotomous outcomes were compared using the chi-square test. Pearson correlation tests for continuous outcomes and spearman correlation tests for dichotomous outcomes were used to assess associations. Receiver-operator characteristic (ROC) curve analysis was performed using the pROC and survival ROC software packages to obtain time-dependent receiver operator area under the curve (AUROCs).

[0090] Kaplan-Meier was used for time-to-event analysis and log-rank test for comparison of survival curves, with a two-sided P value < 0.05 considered significant. Statistical analyses were performed using SAS 9.4 1 (SAS Institute, Cary, NC) and R 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria);

[0091] The correlation analysis of qIgD, M component and iFLC response is as follows:

[0092] Excluding 8 subjects with unmeasurable FLC (iFLC) or < upper limit of normal qIgD (<0.1 g / L or 0.132 g / L); and 1 subject who died early, 70 patients were analyzed to compare qIgD and iFLC quantification results with IMWG-defined response criteria.

[0093] According to IMWG criteria, 25 of 28 subjects with a stringent complete remission had normal qIgD concentrations, as did 6 of 13 subjects with a complete remission. Seven of 13 subjects with a very good partial remission had a qIgD reduction of ≥90% but greater than the upper limit of normal. Nine of 13 subjects with a partial remission had a qIgD reduction of ≥50% but less than 90%.

[0094] All 3 subjects with stable disease had a <50% reduction in qIgD response. Figure 1 A and Figure 1 B shows the maximum reduction estimated using qIgD and iFLC.

[0095] Twenty subjects with an M component ≥10 g / L (excluding 1 subject who died early) were analyzed to compare qIgD and M component concentrations. Of the 10 subjects with a strict complete remission by IMWG response criteria, 8 had normal qIgD, 3 of the 5 complete remissions had normal qIgD, 3 of the 3 very partial remissions had a qIgD reduction ≥90% but greater than the upper limit of normal, 1 subject with a partial remission had a qIgD reduction ≥50% but <90%, and 1 subject with stable disease had a qIgD reduction <50%. The maximum IgD reduction estimated using qIgD is shown in Figure 1 C.

[0096] Depend on Figure 1 D shows that for subjects with M component ≥10 g / L, there was no statistical difference in response time, with median PFS of 7 months [1, 10] months and 5 months [2, 10] months, respectively; P = 0.45;

[0097] Depend on Figure 1 E shows that for subjects with M component or <10g / L, there was no statistical difference in response time, with median PFS of 4 months [1, 10] months and 3 months [1, 10] months, respectively; P = 0.40.

[0098] Example 2 Combining qIgD and rFLC data to evaluate PFS in subjects with IgD multiple myeloma

[0099] Subjects who died before the second treatment cycle (n=2), progressed within 4 cycles of starting treatment (n=6), and subjects without serial qIgD and sFLC concentrations or measurable qIgD and sFLC levels (n=14) were excluded. Baseline and 4 treatment cycle qIgD and iFLC concentrations were compared in the remaining 78 subjects. Figure 2 As shown, there was a certain correlation between the changing trends of qIgD and iFLC; P < 0.001.

[0100] Using this evaluation system, 100 subjects in the embodiment were evaluated, and the evaluation results were as follows:

[0101] The PFS of the subjects was analyzed using qIgD and rFLC data. Figure 3A shows that subjects with normal qIgD concentration and normal rFLC had better survival rate compared with subjects with abnormal qIgD concentration or / and abnormal rFLC, among which the progression-free survival of subjects with normal qIgD concentration and normal rFLC was [27, 51] months, and the median PFS was 39 months; the progression-free survival of subjects with abnormal qIgD concentration or / and abnormal rFLC was [8, 13] months, and the median PFS was 10 months.

[0102] Example 3 Combining qIgD and IMWG evaluation criteria to evaluate PFS in subjects with IgD multiple myeloma

[0103] The qIgD concentration data were added to the IMWG criteria for evaluation as follows:

[0104] Complete remission (CR) is defined as a qIgD level lower than the upper limit of the preset range (ULN) of qIgD, negative serum and urine immunofixation electrophoresis, absence of any soft tissue plasmacytoma, and bone marrow plasma cells ≤5%. The preset range of qIgD is 7.7-132.1 mg / L.

[0105] A strict complete remission (sCR) is defined as a qIgD level below the upper limit of the preset range (ULN) of qIgD, a normal rFLC ratio, and the absence of bone marrow clonal plasma cells in the immune biopsy, i.e., a κ / λ ratio of ≤4:1 for κ-type patients or a κ / λ ratio of ≥1:2 for λ-type patients;

[0106] like Figure 3 In the stringent complete remission cohort, qIgD concentrations were normal (IgD - The median PFS of subjects with qIgD concentration > upper limit of normal (IgD + ) had a median PFS of 21 months (18, 23 months; P = 0.006;);

[0107] like Figure 3 As shown in C, in the complete remission cohort, the median PFS of subjects with normal qIgD concentration was 29 months (4, 55 months), and the median PFS of subjects with qIgD concentration > upper limit of normal was 11 months (2, 20 months);

[0108] Example 4 Response rate of IgD-type multiple myeloma prognostic evaluation system based on IgD quantitative detection

[0109] The comprehensive standard described in the present invention is adopted, which is as follows:

[0110] (1) Strict complete remission (sCR) according to the qIgD level below the upper limit of the preset range (ULN) of qIgD, normal serum FLC ratio, and no bone marrow clonal plasma cells in the immune biopsy, that is, the κ / λ ratio of patients with κ type is ≤4:1 or the κ / λ ratio of patients with λ type is ≥1:2;

[0111] (2) qIgD level is lower than the upper limit of the preset range (ULN) of qIgD, serum and urine immunofixation electrophoresis is negative, there is no soft tissue plasmacytoma, bone marrow plasma cells ≤5%, if the only measurable disease is FLC, normal FLC ratio (0.26-1.65), complete remission (CR); the preset range of qIgD is 7.7-132.1 mg / L;

[0112] (3) serum and urine m-protein can be detected by immunofixation but not by electrophoresis, or the qIgD level is reduced by ≥90% and the urine m-protein level is <100 mg / 24 h; if the only measurable disease is FLC, the difference between the affected and unaffected FLC levels is reduced by ≥90%, which is a very good partial response (VGPR);

[0113] (4) According to the qIgD level reduction of 50-89%, the 24-hour urine m-protein reduction of ≥90% or to <200mg; if the only measurable disease is FLC, the difference between the involved and uninvolved FLC levels is reduced by 50-89%. In addition to the above criteria, if the size of the soft tissue plasmacytoma is reduced by ≥50% at baseline, it is a partial response (PR);

[0114] (5) not meeting the criteria for CR, VGPR, PR, or PD and having stable disease (SD);

[0115] (6) If any one or more of the following conditions are met (relative to the lowest response value), it is considered as progressive disease (PD). The specific conditions are as follows:

[0116] (1) qIgD level increased by ≥25% and serum immunofixation was positive;

[0117] (2) the difference between affected and unaffected FLC levels increased by ≥25% (absolute increase >100 mg / L);

[0118] (3) bone marrow plasma cell percentage increased by ≥25% (absolute percentage increased by ≥10%);

[0119] (4) an increase of ≥25% in existing bone lesions or soft tissue plasmacytomas, or the appearance of new osteolytic bone lesions or soft tissue plasmacytomas;

[0120] (5) Hypercalcemia occurs (corrected serum calcium > 2.8 mmol / L or 11.5 mg / dL).

[0121] Using the evaluation system provided by the present invention, each reaction rate is:

[0122] ① Strict complete remission accounted for 37%;

[0123] ② Complete remission accounted for 13%;

[0124] ③ Very good partial response accounted for 27%;

[0125] ④Partial remission accounted for 17%.

[0126] Figure 4 PFS stratified by the IMWG response criteria system and PFS stratified by the combined response criteria system are shown.

[0127] Depend on Figure 4 As shown in A, the results of the existing IMWG response criteria system evaluation showed that the median PFS of subjects with complete remission was 11 months (6, 16 months), and the median PFS of subjects with very good partial remission was 11 months (6, 17 months; P = 0.42;), indicating that there was no significant difference in the median PFS of subjects with complete remission and subjects with very good partial remission when only the IMWG criteria were used to evaluate.

[0128] Depend on Figure 4 As shown in Figure B, the median PFS of subjects with complete remission evaluated by the qIgD provided by the present invention combined with the IMWG standard was significantly longer than that of subjects with very good partial remission, wherein the median PFS of subjects with complete remission was 29 months (1, 58 months), while the median PFS of subjects with very good partial remission was 13 months (8, 18 months; P = 0.01), and there was a significant difference in the evaluation results of the two, indicating that the evaluation system provided by the present invention is more accurate in predicting PFS, and qIgD stratification can distinguish whether the PFS curve of the subject reaches complete remission (CR) or very good partial remission (VGPR).

[0129] Example 6 Testing of the Accuracy of the IgD-Based Multiple Myeloma Prognosis Assessment System Based on IgD Quantitative Detection

[0130] This example tests the PFS prediction accuracy of IMWG and the IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection provided by the present invention by comparing AUROC, and the results are as follows:

[0131] Depend on Figure 5 A It can be seen that the median PFS evaluated for IgD multiple myeloma using the existing IMWG evaluation system is 15 months (11, 19 months).

[0132] The receiver-operator characteristic curves for 2-year and 3-year PFS were compared between this evaluation system and the IMWG response criteria. Figure 5 B. Figure 5 As shown in C;

[0133] Depend on Figure 5 B, The 2-year PFS AUROC using only the IMWG response criteria was 0.86 (0.75, 0.93), while the 2-year PFS AUROC using the revised criteria based on qIgD was 0.94 (0.86, 0.96), P < 0.05;

[0134] Depend on Figure 5 C shows that the 3-year PFS AUROC using only the IMWG response criteria was 0.85 (0.73, 0.94), while the 3-year PFS AUROC based on the revised criteria of qIgD was 0.92 (0.82, 0.95), P < 0.05. This indicates that adding qIgD data to the International Myeloma Working Group (IMWG) response criteria can improve the accuracy of PFS prediction compared with the IMWG criteria and may help hematologists choose appropriate treatments.

[0135] In summary, based on the compatibility of qIgD with existing evaluation systems, the IgD-type multiple myeloma prognosis evaluation system provided by the present invention combines qIgD and IMWG standards, and improves the PFS prediction accuracy of the existing evaluation system relative to the existing IMWG evaluation system, indicating that the use of this evaluation system can more accurately evaluate the prognosis of IgD-type multiple myeloma subjects. In addition, when the qIgD data is combined with the IMWG response criteria for evaluation, a considerable proportion of subjects are downgraded compared with the use of the IMWG response criteria, and the qIgD data is combined with the IMWG response criteria to evaluate the median PFS of complete remission and very good partial remission. There is a significant difference.

[0136] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A prognosis evaluation system for IgD-type multiple myeloma based on IgD quantitative detection, characterized in that: It includes a data acquisition module and a judgment module; The data acquisition module is used to acquire qIgD including sample serum and submit it to the judgment module; the judgment module is used to evaluate according to the acquired qIgD data, according to the principle that the progression-free survival period of the subjects whose qIgD concentration is within the preset range is greater than the progression-free survival period of the subjects whose qIgD concentration is greater than the upper limit of the preset range; the preset range of qIgD is 7.7-132.1 mg / L; Specifically: If the qIgD concentration is > the upper limit of the preset range, the subject's progression-free survival is assessed to be [7, 12] months, and the median PFS is 10 months.

2. The IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection according to claim 1, characterized in that: The detection sensitivity of the qIgD is 0.1 mg / L.

3. The IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection according to claim 2, characterized in that: The qIgD was measured by turbidimetry using a SPAPLUS professional protein analyzer and a latex-enhanced immunoassay.

4. The IgD multiple myeloma prognosis evaluation system based on IgD quantitative detection according to any one of claims 1 to 3, characterized in that: The data acquisition module is also used to obtain the rFLC level of the sample and the serum FLC level; the judgment module is used to judge and evaluate according to the following principles: (1) If qIgD and rFLC are normal, the progression-free survival of the subject is estimated to be [27, 51] months, and the median PFS is 39 months; (2) If qIgD is abnormal and / or rFLC is abnormal, the progression-free survival of the subject is estimated to be [8, 13] months, and the median PFS is 10 months; The normal qIgD refers to a qIgD concentration within the range of 7.7-132.1 mg / L, otherwise it is an abnormal qIgD concentration. The normal rFLC refers to the ratio of affected to uninvolved FLC being within the range of 0.26-1.65; if it is λ type, <0.26 is abnormal, and if it is κ type, >1.65 is abnormal.

5. The IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection according to claim 4, characterized in that: The data acquisition module is also used to obtain the IMWG standard evaluation indicators of the sample; the IMWG standard evaluation indicators include serum and urine immunofixation electrophoresis results, bone marrow plasma cell ratio and 24-hour urine m-protein content.

6. The IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection according to claim 5, characterized in that: The judgment module judges and evaluates according to the following principles: If the qIgD level is lower than the upper limit of the preset qIgD range, serum and urine immunofixation electrophoresis are negative, there is no soft tissue plasmacytoma, and bone marrow plasma cells are ≤5%, it is considered a complete remission; If the qIgD level is reduced by ≥90% and the 24-hour urine protein level is <100 mg, it is considered a very good partial response; If the qIgD level is lower than the upper limit of the preset range of qIgD, the rFLC is normal, and there is no clonal plasmacytoma in the immune biopsy, it is a strict complete response; the no clonal plasmacytoma refers to a κ / λ ratio of ≤4:1 for κ-type patients or a κ / λ ratio of ≥1:2 for λ-type patients; The median PFS of the evaluated subjects was strict complete remission > complete remission > very good partial remission.

7. The IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection according to claim 6, characterized in that: Among subjects with strict complete remission, the assessed progression-free survival was [27, 51] months, and the median PFS was 39 months.

8. The IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection according to claim 6, characterized in that: Among subjects with complete remission, the assessed progression-free survival was [1, 58] months, with a median PFS of 29 months.

9. The IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection according to claim 8, characterized in that: Among subjects with very good partial response, the evaluable progression-free survival was [8, 18] months and the median PFS was 13 months.

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