CN115754294A

CN115754294A - IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection

Info

Publication number: CN115754294A
Application number: CN202211396634.4A
Authority: CN
Inventors: 杜鹃; 刘进; 卢静; 强琬婷; 何海燕; 范晓强; 郭沛; 金丽娜; 石浪
Original assignee: Shanghai Changzheng Hospital
Current assignee: Shanghai Changzheng Hospital
Priority date: 2022-11-09
Filing date: 2022-11-09
Publication date: 2023-03-07

Abstract

The invention discloses an IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection, which comprises a data acquisition module and a judgment module; the data acquisition module is used for acquiring qIgD of the sample serum and submitting the qIgD to the judgment module; the judging module is used for evaluating the progression-free survival time of the subject with qIgD concentration in a preset range according to the acquired qIgD data and the principle that the progression-free survival time of the subject is greater than qIgD and is greater than the upper limit of the preset range; the preset range of qIgD is 7.7-132.1mg/L. The invention quantitatively detects the IgD by a method for detecting the iFLC concentration, the detection sensitivity of qIgD can reach 0.1mg/L, and is remarkably higher than the existing evaluation index serum M component, and the evaluation is more accurate. Particularly, qIgD is combined with an IMWG standard for evaluation, and compared with the conventional evaluation system, the evaluation system provided by the invention can obviously improve the accuracy of the conventional evaluation system in predicting the PFS of the IgD type multiple myeloma.

Description

IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection

Technical Field

The invention belongs to the technical field of IgD type multiple myeloma prognosis evaluation, and particularly relates to an IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection.

Background

Plasma Cell Myeloma (PCM) is a multifocal Plasma cell tumor that originates in the bone marrow and is characterized by a malignant proliferation of clonal Plasma cells in the bone marrow, with the secretion of monoclonal immunoglobulin M or fragments thereof in most cases, resulting in damage to the relevant organs or tissues. Among them, igD-type multiple myeloma is a rare subtype in plasma cell myeloma, accounting for about 1% -2% according to foreign reports, and has poor prognosis, and the median survival time of IgD-type multiple myeloma patients evaluated by the existing evaluation system is only 13-21 months.

There are 5 immunoglobulins in human blood, igM, igG, igA, igE, igD, wherein IgD is mainly present on the surface of mature B lymphocytes. The prior research indicates that IgD plays a certain role in the development process of IgD type multiple myeloma, but the mechanism is not clear at present. The main reason is that the content of IgD secreted in serum is very low, which accounts for about 1% of total Ig, and the individual content difference is large, and the content of IgD in serum of an adult is generally 0-80 mg/l, which is difficult to detect; in addition, the IgD has unstable performance, is easy to polymerize in the separation process and is easy to be cracked by enzyme, the structure of the IgD is extremely similar to that of IgG, the existing detection technology is difficult to accurately detect, the sensitivity of the quantitative IgD is low, and the clinical characteristics of the IgD type multiple myeloma are mostly reported by one case at present, and the function and pathogenesis of the IgD type multiple myeloma cannot be further researched due to the lack of the research of a large number of cases. The current assessment of the prognosis of patients with IgD-type multiple myeloma uses the IMWG assessment criteria.

However, existing IMWG evaluation criteria are typically based on the evaluation of serum M components, the quantification of which is important for assessing therapeutic response and predicting progression-free survival in most plasma cell myelomas. Generally, quantitative evaluation of serum M components requires that the subject's M protein reach levels above measurable lesions, but in IgD-type multiple myeloma subjects, due to the low serum M component concentrations, measurable lesion levels are difficult to achieve, and the accuracy of predicting progression-free survival in IgD-type multiple myeloma subjects using existing evaluation systems is low. Therefore, the development of a prognostic evaluation system suitable for IgD-type multiple myeloma facilitates more accurate prediction of progression-free survival of IgD-type multiple myeloma subjects, and helps a hematologist select a suitable treatment method and adjust a treatment scheme.

Disclosure of Invention

Aiming at the defects or improvement requirements of the prior art, the invention provides an IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection, aiming at finding that qIgD is an effective parameter compatible with the prior prognosis evaluation system, establishing the IgD type multiple myeloma prognosis evaluation system based on qIgD evaluation indexes, particularly combining the evaluation system established by qIgD and IMWG standards, wherein the qIgD detection sensitivity is 0.1mg/L, and the accuracy of the prior evaluation system can be obviously improved, so that the technical problem that the prior evaluation system has lower accuracy in evaluating the IgD type multiple myeloma is solved.

In order to achieve the above object, according to one aspect of the present invention, there is provided an IgD-based multiple myeloma prognosis evaluation system based on IgD quantitative detection, comprising a data acquisition module and a judgment module;

the data acquisition module is used for acquiring qIgD containing sample serum and submitting the qIgD to the judgment module;

the judging module is used for evaluating the progression-free survival time of the subject with qIgD concentration in a preset range according to the acquired qIgD data and the principle that the progression-free survival time of the subject is greater than qIgD and is greater than the upper limit of the preset range; the preset range of qIgD is 7.7-132.1mg/L.

Preferably, the IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection has the qIgD detection sensitivity of 0.1mg/L.

Preferably, the IgD-based quantitative detection-based prognostic assessment system for IgD-type multiple myeloma, wherein the qIgD is measured turbidimetrically using a latex-enhanced immunoassay with a SPA PLUS professional protein analyzer.

Preferably, the data acquisition module of the system for prognosis evaluation of IgD-type multiple myeloma based on IgD quantitative detection is also used for acquiring the rFLC and serum FLC levels of a sample; the judgment module judges and evaluates according to the following principle:

(1) Assessing progression-free survival of the subject at [27, 51] months with median PFS of 39 months if qIgD is normal and rFLC is normal;

(2) Assessing progression-free survival of the subject at [8, 13] month with median PFS of 10 months if qIgD and/or rFLC are abnormal;

the qIgD is normal, namely the qIgD concentration is in the range of 7.7-132.1mg/L, otherwise, the qIgD is abnormal;

the rFLC is normal, namely the ratio of the affected FLC to the unaffected FLC is in the range of 0.26-1.65, otherwise, the rFLC is abnormal.

Preferably, the system for the prognosis evaluation of IgD-type multiple myeloma based on IgD quantitative detection evaluates that the progression-free survival of a subject is [7, 12] months and the median PFS is 10 months if qIgD concentration is greater than the upper limit of the preset range.

Preferably, the data acquisition module of the system for prognosis evaluation of IgD-type multiple myeloma based on IgD quantitative detection is further used for acquiring a sample IMWG standard evaluation index; the IMWG standard evaluation indexes comprise a serum and urine immune fixation electrophoresis result, a bone marrow plasma cell proportion and 24-hour urine m protein content.

Preferably, the IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection is characterized in that the judgment module judges according to the following principle:

if the qIgD level is lower than the upper limit of the preset range of qIgD, the immune fixation electrophoresis of serum and urine is negative, no soft tissue plasmacytoma exists, and the bone marrow plasmacytoma is less than or equal to 5 percent and is completely relieved;

if the qIgD level is reduced by more than or equal to 90 percent, the urinary m protein level in 24 hours is less than 100mg, and the partial remission is good;

if the qIgD level is lower than the upper limit of the qIgD preset range, the rFLC is normal and no clonal plasmacytoma exists in immune biopsy, the strict and complete relief is achieved; the non-clonal plasmacytomas refer to a kappa/lambda ratio of a kappa type patient of ≤ 4 or a kappa/lambda ratio of a lambda type patient of ≥ 1;

subjects were evaluated for median PFS with strict complete remission > very good partial remission.

Preferably, the system for the prognostic evaluation of IgD-type multiple myeloma based on the quantitative detection of IgD evaluates the progression-free survival of a subject at [27, 51] months with a median PFS of 39 months in a strictly complete remission subject.

Preferably, the system for the prognostic evaluation of IgD-type multiple myeloma based on the quantitative detection of IgD evaluates progression-free survival of a subject at [1, 58] months with a median PFS of 29 months in a subject with complete remission.

Preferably, the system for the prognostic evaluation of IgD-type multiple myeloma based on the quantitative detection of IgD evaluates progression-free survival of a subject at [8, 18] months with a median PFS of 13 months in very good partial remission subjects.

In general, compared with the prior art, the above technical solutions contemplated by the present invention can obtain the following results because qIgD compatible with the existing evaluation system is used as an effective parameter for evaluation

Has the beneficial effects that:

the invention establishes an IgD type multiple myeloma prognosis evaluation system based on an effective evaluation parameter qIgD, and judges the duration of the progression-free survival time of a subject according to whether the qIgD concentration falls into a preset range, wherein the preset range of the qIgD is 7.7-132.1mg/L, and the progression-free survival time of the subject falling into the range is longer; particularly, a SPA PLUS professional protein analyzer is adopted, a latex enhanced immunoassay method is used, and the IgD is measured by a turbidimetric method, wherein qIgD detection sensitivity can reach 0.1mg/L, the detection sensitivity of an evaluation index qIgD of the system is remarkably higher than the detection sensitivity of an existing evaluation index serum M component by 100mg/L, and the accuracy of the pre-evaluation of the IgD type multiple myeloma can be improved.

In particular, the invention further combines qIgD and the existing IMWG standard for prognosis evaluation, which proves that qIgD can be compatible with the existing evaluation system, the evaluation system modified based on qIgD is 0.94 (0.86, 0.96) for PFS AUROC of 2 years, while the IMWG standard evaluation system is 0.86 (0.75, 0.93) for PFS AUROC of 2 years, and P is less than 0.05; the qIgD revision based evaluation system was 0.92 (0.82, 0.95) for PFS AUROC 3 years, while the IMWG standard evaluation system was 0.85 (0.73, 0.94) for PFS AUROC 3 years, P < 0.05. It is demonstrated that the addition of qIgD data to the International Myeloma Working Group (IMWG) response standard can improve the accuracy of PFS prediction by existing evaluation systems, is of great significance for prognosis evaluation of IgD-type multiple myeloma subjects, and may help the hematologist to select appropriate treatment methods, compared to the IMWG response standard.

Moreover, the median PFS for evaluating a subject with complete remission and a very good subject with complete remission was 29 months and 13 months, respectively, with significant differences, while the median PFS for evaluating a subject with complete remission and a very good subject with complete remission was 11 months, with no difference, using the evaluation system provided by the present invention, indicates that the prognosis for a subject with complete remission and a very good subject with complete remission can be better evaluated using the evaluation system provided by the present invention based on qIgD.

Drawings

FIG. 1 is a graph of the maximum decrement and response rate estimated for different indicators;

FIG. 1A is the maximum reduction in qIgD (M.ltoreq.10 g/L); FIG. 1B is the maximum reduction estimated for iFLC (M ≦ 10 g/L); FIG. 1C is the maximum IgD reduction estimated for qIgD (M >10 g/L); FIG. 1D is a comparison of reactivity ratios using IMWG standards and qIgD, respectively; FIG. 1E is a comparison of reactivity ratios using iFLC and qIgD, respectively;

FIG. 2 is iFLC and qIgD correlation analysis;

figure 3 is an assessment of PFS based on qIgD;

FIG. 3A is a PFS assessed in combination with rFLC and qIgD; figure 3B is an assessment of PFS in sCR subjects based on qIgD; figure 3C is an assessment of PFS in CR subjects based on qIgD;

FIG. 4 is a PFS assessment using IMWG and qIgD-based standard binding, respectively;

FIG. 4A is a PFS evaluated using IMWG criteria; figure 4B is based on assessment of PFS with qIgD standard binding;

FIG. 5 is a 2-year, 3-year PFS AUROC curve evaluated using the IMWG standard and qIgD and IMWG standards, respectively;

FIG. 5A is a PFS evaluated using IMWG criteria; FIG. 5B is a 2-year PFS AUROC curve evaluated using the IMWG standard and qIgD and IMWG standards, respectively; figure 5C is a 3 year PFS AUROC curve evaluated using IMWG criteria and qIgD and IMWG criteria, respectively.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.

Description of the abbreviations for the terms:

MM: multiple myeloma; PCM: plasma cell myeloma; IMWG: the international myeloma working group;

IgD: an immunoglobulin D; qIgD: quantifying IgD;

and (2) DS: a conventional staging system; ISS: an international staging system; R-ISS: a revised international staging system;

LDH: a lactate dehydrogenase; IMiD: an immunomodulatory drug; and (3) PIs: a proteasome inhibitor;

FISH: fluorescence in situ hybridization; IFE: performing immune fixed electrophoresis; ASCT: transplanting autologous hematopoietic stem cells;

and (3) sFLC: serum-free light chains, including kappa-type light chains and lambda-type light chains; rFLC: (ii) an affected to unaffected FLC ratio; iFLC: an affected FLC;

PFS: progression-free survival; ULN: upper limit of normal value.

Serum M protein is an immunoglobulin molecule and a molecular fragment thereof which are generated by monoclonal B cell proliferation and have the same structure and electrophoretic mobility, is an important parameter in the existing evaluation system, but the detection sensitivity is low (100 mg/L), and the serum M protein content is considered to be measurable when the serum M protein content is higher than 10g/L and not measurable when the serum M protein content is lower than 10g/L in the curative effect evaluation. The multiple myeloma can be classified into 8 types such as IgG, igA, igD, igE, igM, light chain type, double-clone type and non-secretory type according to the characteristics of M protein in serum, and further classified into kappa type and lambda type according to the light chain type of M protein.

Among them, igG type is the most common, igA type is the second, and IgD type multiple myeloma accounts for less than 2% of plasma cell myeloma PCM, but compared with other PCM isoforms, igD type prognosis is worse, and most of the clinical features of IgD type multiple myeloma are reported from one case at present, and the research on a large number of cases is lacked, so that the further research is difficult, and the mechanism is not clear at present.

Although researchers have shown that IgD is involved in the metabolic processes involved in the development of IgD-type multiple myeloma, it is unknown whether the content of IgD can be used to assess the prognosis of multiple IgD-type multiple myeloma. The possible reasons include two aspects: on one hand, the content of IgD in the IgD type multiple myeloma is trace, the content of IgD in serum is very low, the content of IgD in the serum of a general adult is 0-80 mg/L, and the IgD performance is unstable. At present, accurate detection and quantification are difficult, and compared with the real content of the IgD, the error of the test is not negligible, so that the quantitative test data is very likely to make the prognosis result of the IgD-type multiple myeloma evaluation more vague due to the existence of the test error, namely the accuracy is reduced, and the content data of the IgD which is conventionally detected and quantified cannot be used for evaluating the IgD-type multiple myeloma; on the other hand, whether the content of IgD is a factor independent of the existing evaluation index is unknown, and if the influence of the content of IgD on the metabolic condition of the patient represented by the existing IgD-type multiple myeloma evaluation prognosis system is reflected, the accuracy of the prognosis evaluation effect cannot be improved by increasing the content of IgD as the evaluation index; conversely, if the content of IgD as an evaluation index is not compatible with existing prognostic evaluation systems, increasing the content of IgD as an evaluation index results in a decrease in the overall performance of the evaluation system.

Therefore, there is currently no clear parameter that can be used to assess IgD-type multiple myeloma, including the content of IgD. Particularly, the method is helpful for improving the sensitivity of IgD type multiple myeloma prognosis evaluation, is compatible with the evaluation index of the existing evaluation system, is used as the improvement of the existing IgD type multiple myeloma prognosis evaluation index, is favorable for improving the accuracy of the existing evaluation system on the IgD type multiple myeloma prognosis evaluation, and needs a large amount of experimental groping and data verification.

The present invention is based on a multicenter retrospective study, involving 356 patients with IgD myeloma from 14 centers of the asian myeloma working group (AMN). We compared qIgD and iFLC concentrations after baseline and 4 treatment cycles in 78 subjects, and found that there was a correlation between the trend of change between qIgD and iFLC, the qIgD, which was quantitatively detected by the method for detecting iFLC concentration, had a detection sensitivity of 0.1mg/L, which was significantly higher than the detection sensitivity of 100mg/L of serum M protein, which is an existing evaluation index.

Furthermore, qIgD and the existing IMWG standard are combined for evaluating the prognosis of IgD type multiple myeloma, and the fact that the qIgD and the existing IMWG evaluation index are combined for evaluation is proved to improve the accuracy of the existing evaluation system in evaluating the progression-free survival time of an IgD type multiple myeloma patient, so that the qIgD can be compatible with the existing evaluation system and the evaluation accuracy can be improved, namely, the qIgD can be used as an effective evaluation parameter. The progression-free survival is defined as the time interval from diagnosis to death due to progression or any cause as defined by the IMWG standard.

The invention provides an IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection, which comprises a data acquisition module and a judgment module;

the judging module is used for evaluating according to the acquired qIgD data and the principle that the non-progress lifetime of the subject is longer when the qIgD concentration is in a preset range; the preset range of qIgD is 7.7-132.1mg/L; the qIgD has the detection sensitivity of 0.1mg/L, and the IgD is quantitatively detected by a method for detecting the iFLC concentration;

further, the data acquisition module is also used for acquiring rFLC and serum FLC levels; and submitting to the judging module; wherein qIgD and serum-free light chain (sFLC) detection are as follows:

pretreatment of a serum sample: the fasting venous blood samples were collected in vacuum procoagulant tubes and serum was aspirated after centrifugation at 3000g for 10 min;

IgD and sFLC detection: igD and sFLC were measured turbidimetrically using a latex-enhanced immunoassay using a SPA PLUS professional protein analyzer. Where the sFLC assay measures absolute free kappa and lambda light chain concentrations and reports the kappa/lambda ratio, the affected/unaffected FLC ratio (rFLC) was calculated using monoclonal light chains as molecules.

The judgment module judges according to the following principle:

(1) Assessing progression-free survival of the subject at [27, 51] months with a median PFS of 39 months if qIgD is normal and rFLC is normal;

(2) Assessing progression-free survival of the subject for [8, 13] months with median PFS of 10 months if qIgD is abnormal and/or rFLC is abnormal;

In the case of qIgD abnormality, if qIgD concentration > upper limit of normal range, subjects were assessed for progression free survival at [7, 12] month with median PFS of 10 months.

Furthermore, the data acquisition module is further used for acquiring a sample IMWG standard evaluation index; the IMWG standard evaluation indexes comprise a serum and urine immune fixation electrophoresis result, a bone marrow plasma cell proportion and 24-hour urine m protein content, and are submitted to a judgment module;

the judgment module is used for judging and evaluating according to the following principle:

(1) If the qIgD level is lower than the upper limit of the preset range of qIgD, the immune fixation electrophoresis of serum and urine is negative, no soft tissue plasmacytoma exists, and the bone marrow plasmacytoma is less than or equal to 5 percent and is completely relieved;

(2) If the qIgD level is reduced by more than or equal to 90 percent, the urinary m protein level in 24 hours is less than 100mg, which is a very good partial remission;

(3) If the qIgD level is lower than the upper limit of the qIgD preset range, the rFLC is normal and no clone cells exist in immune biopsy, the strict and complete relief is realized; the non-clonal plasmacytomas refer to kappa/lambda ratios of kappa patients of ≤ 4 or kappa/lambda ratios of lambda patients of ≥ 1;

Assessed using qIgD in combination with IMWG criteria, wherein progression-free survival in strictly fully remitted subjects was [27, 51] months with a median PFS of 39 months; progression-free survival in complete remission subjects was at [1, 58] month with a median PFS of 29 months, and progression-free survival in very good partial remission subjects was at [8, 18] month with a median PFS of 13 months.

The following are examples:

example 1

The study was approved by the Shanghai Long Committee of Hospital ethics, and all subjects signed written informed consent in accordance with the declaration of Helsinki. Clinical and laboratory covariates were collected from hospital medical records and examined by two independent observers, with disagreement adjudicated by the third observer.

The sample data of the embodiment is derived from data of 100 continuous IgD PCM subjects who visit Shanghai Yangtze university Hospital from 9 months to 2021 months in 2013, including 74 males and 26 females, the median age at diagnosis is 58 years (quartering distance [ IQR ],52-64 years), and specific index detection is as follows:

(1) Fluorescence In Situ Hybridization (FISH) analysis

Following Ficoll-Hypaque gradient separation, plasma cells in pre-treated bone marrow aspirates were isolated using anti-human CD138 antibody-coated magnetic beads (Miltenyi Biotec GmbH, bergischGladbach, germany) and cytogenetics were analyzed by Fluorescence In Situ Hybridization (FISH) according to standard methods by using commercially available Probes (Metasystems FISH Probes, alllussheim, germany). 200 interphase nuclei were analyzed using fluorescence microscopy.

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

Pretreatment of a serum sample: fasting venous blood samples were collected in vacuum procoagulant tubes and serum was aspirated after centrifugation at 3000g for 10 minutes.

IgD and sFLC detection: igD and sFLC were measured turbidimetrically using a latex enhanced immunoassay using the SPA PLUS professional protein analyzer. Where the sFLC assay measures absolute free kappa and lambda light chain concentrations and reports the kappa/lambda ratio, the affected/unaffected FLC ratio (rFLC) was calculated using monoclonal light chains as molecules.

And (3) detecting a serum M component: immuno-fixation electrophoresis (IFE).

The information and the test results of the 100 subjects are summarized in table 1:

TABLE 1 Subjects and clinical characteristics

(3) Statistical analysis

The successive results were compared using Wilcoxon rank sum test and the dichotomous results were compared using chi-square test. The Pearson correlation test for sequential results and the spearman correlation test for binary results were used to evaluate the correlation. Receiver-operator characteristic (ROC) curve analysis was performed using the pROC and survival ROC software package to obtain time-dependent receiver operator area under the curve (aurcs).

Kaplan-Meier inertia was used for time of occurrence analysis and log rank test to compare survival curves, with P values <0.05 on both sides considered significant. Statistical analysis was performed using SAS 9.4 (SAS Institute, cary, NC) and R3.5.1 (R Foundation for Statistical Computing, vienna, austria);

correlation analysis of qIgD, M Components and iFLC reactions as follows:

removing 8 unmeasurable FLCs (iFLC) or < upper limit of normal qIgD (< 0.1g/L or 0.132 g/L); and 1 early-dead subject, 70 patients were analyzed to compare qIgD and iFLC quantification results to IMWG-defined response criteria.

According to the IMWG standard, 25 of 28 subjects with strict complete remission had normal qIgD concentrations, as did 6 of 13 subjects with complete remission. The 7 qIgD reduction in 13 patients with very good partial remission was > 90% but above the upper normal limit. The reduction of 9 qIgD was > 50%, but less than 90% in 13 subjects with partial remission.

qIgD response was reduced by <50% in all 3 patients with stable disease. Fig. 1A and 1B show the maximum reduction estimated using qIgD and iFLC.

20 subjects having M component.gtoreq.10 g/L (excluding 1 of the early departures) were analyzed to compare the concentrations of qIgD and M component. In 10 subjects with strict and complete remission of IMWG response criteria, 8 qIgD were normal, in 5 complete remission 3 qIgD were normal, in 3 very partial remission 3 qIgD decreased by more than or equal to 90% but greater than the upper limit of normal, in 1 partial remission subjects qIgD decreased by more than or equal to 50% but <90%, and in 1 stable disease subjects qIgD decreased by <50%. The maximum IgD reduction estimated using qIgD is shown in fig. 1C.

As can be seen from FIG. 1D, there was no statistical difference in response time for subjects with M component ≧ 10g/L, with median PFS of 7 months [1, 10] month and 5 months [2, 10] month, respectively; p =0.45;

as can be seen in FIG. 1E, there was no statistical difference in response time for subjects with M component or <10g/L, with a median PFS of 4 months [1, 10] month and 3 months [1, 10] month, respectively; p =0.40.

Example 2 assessment of PFS in IgD-type multiple myeloma subjects in conjunction with qIgD and rFLC data

Subjects who died before the 2 nd treatment cycle (n = 2), progressed within 4 cycles of starting treatment (n = 6) and had no continuous qIgD and sFLC concentrations or measurable qIgD and sFLC levels (n = 14) were excluded. qIgD and iFLC concentrations were compared after baseline and 4 treatment cycles in the remaining 78 subjects. As shown in fig. 2, the trend of change between qIgD and iFLC has a certain correlation; p <0.001.

With the evaluation system, 100 subjects in the example had the following evaluation results:

the subject PFS was analyzed using qIgD and rFLC data as shown in figure 3A, subjects with normal qIgD concentration and normal rFLC had better survival compared to subjects with abnormal qIgD concentration or/and abnormal rFLC, where progression-free survival for normal qIgD concentration and normal rFLC subjects was at [27, 51] months with median PFS of 39 months; abnormal qIgD concentrations or/and progression-free survival of abnormal rFLC subjects was [8, 13] months with a median PFS of 10 months.

Example 3 assessment of PFS in IgD-type multiple myeloma subjects in combination with qIgD and IMWG assessment criteria

qIgD concentration data were added to the IMWG standard for evaluation as follows:

according to the condition that the qIgD level is lower than the Upper Limit (ULN) of the preset range of qIgD, the immune fixed electrophoresis of serum and urine is negative, no soft tissue plasmacytoma exists, and the content of bone marrow plasmacytoma is less than or equal to 5 percent, so that the condition is Completely Relieved (CR); the qIgD is within a preset range of 7.7-132.1mg/L;

according to qIgD levels below the upper limit of the qIgD preset range (ULN), the rFLC ratio is normal, and the marrow-free clonal plasma cells in the immunobiopsy, i.e.the kappa/lambda ratio in kappa-type patients is < 4 or > 1;

as shown in fig. 3B, in the strict senseIn the cohort with complete remission, qIgD concentration is normal (IgD) ^- ) Has a median PFS of 39 months (27, 51 months) and a qIgD concentration>Upper limit of Normal (IgD) ⁺ ) The median PFS of subjects of (a) is 21 months (18, 23 months; p =0.006; ) (ii) a

As shown in fig. 3C, in the complete remission cohort, median PFS was 29 months (4, 55 months) for subjects with normal qIgD concentration, and 11 months (2, 20 months) for subjects with qIgD concentration > upper normal limit;

example 4 response rates of IgD-type multiple myeloma prognostic assessment systems based on IgD quantitative detection

The comprehensive standard adopted by the invention is as follows:

(1) According to qIgD levels below the upper limit of the qIgD preset range (ULN), the serum FLC ratio is normal, and the immune biopsy has no marrow clonal plasma cells, i.e. the kappa/lambda ratio of kappa type patient is less than or equal to 4 or the kappa/lambda ratio of lambda type patient is more than or equal to 1, and is strictly complete remission (sCR);

(2) qIgD levels below the upper limit of the qIgD preset range (ULN), serum and urine immobility electrophoresis negative, no soft tissue plasmacytomas, no more than 5% bone marrow plasma cells, normal FLC ratio (0.26-1.65) for Complete Remission (CR) if the only measurable disease is FLC; the qIgD is within a preset range of 7.7-132.1mg/L;

(3) Serum and urine m protein can be detected by immunological immobilization, but electrophoresis cannot be detected, or qIgD level is reduced by more than or equal to 90%, and urine m protein level is less than 100mg/24h; if the only measurable disorder is FLC, the difference in affected and unaffected FLC levels decreased by > 90%, which is a Very Good Partial Remission (VGPR);

(4) According to qIgD level is reduced by 50-89%, urinary m protein is reduced by more than or equal to 90% or reduced to less than 200mg in 24 hours; if the only measurable disorder is FLC, the difference in affected and unaffected FLC levels is reduced by 50-89%. In addition to the above criteria, the reduction in soft tissue plasmacytoma size by > 50% if present at baseline is a Partial Remission (PR);

(5) Non-compliance with CR, VGPR, PR or PD criteria, stable Disease (SD);

(6) Any one or more of the following conditions (relative to the lowest response value) are met for disease Progression (PD), as follows:

(1) qIgD level is increased by more than or equal to 25%, and serum immune fixation is positive;

(2) The difference between affected and unaffected FLC levels increased by > 25% (absolute increase >100 mg/L);

(3) The percentage of bone marrow plasma cells is increased by more than or equal to 25 percent (the absolute percentage is increased by more than or equal to 10 percent);

(4) The increase of the existing bone lesion or soft tissue plasmacytoma is more than or equal to 25 percent, or new osteolytic bone lesion or soft tissue plasmacytoma appears;

(5) Hypercalcemia occurred (> 2.8mmol/L or 11.5mg/dL corrected serum calcium).

By adopting the evaluation system provided by the invention, each reaction rate is as follows:

(1) strict complete remission accounts for 37%;

(2) complete remission accounted for 13%;

(3) very good partial remission accounted for 27%;

(4) partial remission accounted for 17%.

Figure 4 shows a PFS layered using an IMWG reaction standard system and a PFS layered with a combinatorial reaction standard system.

As shown in figure 4A, the median PFS in the complete remission subjects was 11 months (6, 16 months) and the median PFS in the very good partial remission subjects was 11 months (6, 17 months; P = 0.42;), as assessed by the current IMWG response standard system, indicating that there was no significant difference in the median PFS in the complete remission subjects and the very good partial remission subjects assessed using only the IMWG standard.

As shown in fig. 4B, the median PFS of subjects in complete remission (29 months, 58 months) was significantly longer than that of very good subjects in partial remission using the qIgD-IMWG standard assessment provided by the present invention, whereas the median PFS of subjects in complete remission was 29 months (8, 18 months; P = 0.01), with significant differences between the two assessments, indicating that the PFS prediction accuracy of subjects using the assessment system provided by the present invention is more accurate, and qIgD stratification enables differentiation of subjects' PFS curves to achieve Complete Remission (CR) or Very Good Partial Remission (VGPR).

Example 6 testing of IgD-type multiple myeloma prognostic assessment System accuracy based on IgD quantitative detection

In this example, the AUROC is compared to test the accuracy of PFS prediction of IMWG and the IgD-type multiple myeloma prognosis evaluation system based on IgD quantitative detection provided by the present invention, and the results are as follows:

as can be seen in fig. 5A, the median PFS for IgD-type multiple myeloma assessments using the existing IMWG assessment system was 15 months (11, 19 months).

Comparing the recipient-operator profiles of the present evaluation system with IMWG response criteria for 2-year and 3-year PFS, the results are shown in fig. 5B, 5C, respectively;

from FIG. 5B, the 2-year PFS AUROC using only the IMWG response criteria was 0.86 (0.75, 0.93), while the 2-year PFS AUROC based on the revised criteria of qIgD was 0.94 (0.86, 0.96), P < 0.05;

as can be seen in FIG. 5C, the 3 year PFS AUROC using only the IMWG response criteria is 0.85 (0.73, 0.94); whereas the 3-year PFS AUROC based on the revised standard for qIgD is 0.92 (0.82, 0.95), P < 0.05. It is demonstrated that the addition of qIgD data to the International Myeloma Working Group (IMWG) response standard may improve the accuracy of PFS prediction and may help the haematologist to select the appropriate treatment compared to the IMWG standard.

In conclusion, based on the fact that qIgD can be compatible with the existing evaluation system, the IgD-type multiple myeloma prognosis evaluation system provided by the invention combines qIgD and IMWG standards, improves the PFS prediction accuracy of the existing evaluation system compared with the existing IMWG evaluation system, and shows that the evaluation system can be used for more accurately evaluating the prognosis of an IgD-type multiple myeloma subject. In addition, combining qIgD data with IMWG response criteria, a significant proportion of subjects were degraded compared to using IMWG response criteria, and there was a significant difference in median PFS between complete and very good partial remission when assessed using qIgD data in combination with IMWG response criteria.

It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims

1. An IgD type multiple myeloma prognosis evaluation system based on IgD quantitative detection is characterized by comprising a data acquisition module and a judgment module;

the data acquisition module is used for acquiring qIgD comprising sample serum and submitting the qIgD to the judgment module; the judging module is used for evaluating the progression-free survival time of the subject with qIgD concentration in a preset range according to the acquired qIgD data and the principle that the progression-free survival time of the subject is greater than qIgD and is greater than the upper limit of the preset range; the preset range of qIgD is 7.7-132.1mg/L.

2. The IgD type multiple myeloma prognosis evaluation system based on the quantitative detection of IgD according to claim 1, wherein qIgD has a detection sensitivity of 0.1mg/L.

3. The system for prognostic assessment of IgD-type multiple myeloma based on quantitative detection of IgD according to claim 2, wherein the qIgD is measured turbidimetrically using latex enhanced immunoassay with SPA PLUS professional protein analyzer.

4. The IgD type multiple myeloma prognosis evaluation system based on the quantitative IgD detection of any one of claims 1 to 3, wherein the data acquisition module is further used for acquiring rFLC of a sample and FLC level of serum; the judgment module judges and evaluates according to the following principle:

the rFLC is normal, and the ratio of the affected FLC to the unaffected FLC is in the range of 0.26-1.65; if the type is lambda, <0.26 is abnormal, and if the type is kappa, >1.65 is abnormal.

5. The IgD type multiple myeloma prognostic assessment system based on quantitative IgD detection according to claim 4, characterized in that if qIgD concentration > the upper limit of the preset range, the progression free survival of the subjects is assessed at [7, 12] month with a median PFS of 10 months.

6. The system for assessing the prognosis of IgD type multiple myeloma according to claim 4, wherein the data acquisition module is further used for acquiring a sample IMWG standard assessment index; the IMWG standard evaluation indexes comprise a serum and urine immune fixation electrophoresis result, a bone marrow plasma cell proportion and a 24-hour urine m protein content.

7. The IgD type multiple myeloma prognosis evaluation system based on the IgD quantitative detection, according to claim 6, characterized in that the judgment module judges the evaluation according to the following principles:

if the qIgD level is lower than the upper limit of the qIgD preset range, the immune fixation electrophoresis of serum and urine is negative, no soft tissue plasmacytoma exists, and the bone marrow plasmacytoma is less than or equal to 5 percent and is completely relieved;

if the qIgD level is lower than the upper limit of the qIgD preset range, the rFLC is normal and no clonal plasmacytoma exists in immune biopsy, the qIgD level is strictly and completely relieved; the non-cloning plasmacytoma refers to that the ratio of kappa/lambda of a kappa type patient is less than or equal to 4, or the ratio of kappa/lambda of a lambda type patient is more than or equal to 1;

subjects were evaluated for median PFS of strict complete remission > very good partial remission.

8. The system for the prognosis of IgD-type multiple myeloma based on the quantitative detection of IgD according to claim 7, wherein the progression-free survival of a subject is assessed at [27, 51] months with a median PFS of 39 months in a strictly complete remission subject.

9. The system for prognosis of IgD-type multiple myeloma according to claim 7, wherein the progression-free survival of a subject is assessed at [1, 58] months with a median PFS of 29 months in a completely remitting subject.

10. The system for prognosis evaluation of IgD-type multiple myeloma according to claim 9, wherein the progression-free survival of a subject is evaluated in [8, 18] months with a median PFS of 13 months in very good partial remission subjects.