Ultra-high-risk group of multiple myeloma : a real-world study based on two different prognostic evaluation systems


 Recently, two prognostic evaluation systems based on different angles, UK Myeloma Research Alliance proposed UK Myeloma Research Alliance Risk Profile(MRP) and chinese inflammatory prognostic scoring index(IPSI), have shown prognostic differences in newly diagnosed multiple myeloma(MM) patients without transplantation. However, there is no relevant research on whether there is a difference in the evaluation of the two systems. Here, we used these two systems to evaluate the prognosis of 160 patients with MM based on bortezomib without transplantation from January 2007 to June 2018. It was found that the evaluation of patients at medium and low risk was similar, but in the high-risk group of MRP, IPSI could be further stratified, and in the high-risk group of IPSI, MRP could also be further stratified. It is suggested that myeloma patients with high risk factors of MRP and IPSI are ultra high risk patients with poor prognosis.


Introduction
Multiple myeloma(MM) is a malignant plasma cell disease, in which the malignant proliferation of plasma cells in the bone marrow produces a large number of monoclonal immunoglobulins or their fragments, resulting in damage to related organs or tissues, accounting for about 10% of hematological tumors [1]. In recent years, based on the application of proteasome inhibitors and immunomodulatory inhibitors, the prognosis of patients with MM has been signi cantly improved. For different patients, screening patients with different risk strati cation through the corresponding prognosis evaluation system also provides guidance and help for clinical diagnosis and treatment. In 2019, UK Myeloma Research Alliance proposed UK Myeloma Research Alliance Risk Pro le(MRP) based on non-transplant patients [2], while in ammatory prognostic scoring index(IPSI) was proposed in China [3], both of which are based on blood and biochemical indicators that are easy to obtain clinically. Both of them can evaluate the prognosis of newly diagnosed non-transplant MM patients treated with proteasome inhibitors. However, at present, there is no related research on the comparison of the two prognostic scoring systems. Through the retrospective analysis of the same group of data, this study discusses the differences, advantages and disadvantages of the two prognostic scoring systems.

Materials And Methods
Patient Eligibility and Treatment 242 MM patients were collected from the Wuxi People's Hospital from January 2007 to June 2018 and the clinical and laboratory data (such as age, sex, β2 microglobulin, ISS stage, etc.) were analyzed.
Excluding those who did not use bortezomib, 160 patients were enrolled in the study. Diagnostic criteria for disease diagnosis and staging with reference to the International Myeloma Working Group (IMWG) and International Prognostic Stage System (ISS). [4] In IPSI, patients with high red cell distribution width(RDW) (RDW>14) were given a score of 1; patients with high neutrophil-to-lymphocyte ratio(NLR) (NLR>2) or low PLT (PLT≤150) were given a score of 2, thus patients were grouped into high-risk group (4-5 points), intermediate-risk group (3 points) and lowrisk group (0-2 points).
All patients were treated with bortezomib-containing therapy for induction and consolidation, including

Statistical Analysis
The differences in numerical variables between groups were tested using the Kruskal-Wallis and Mann-Whitney methods. The counting variables were assessed using the χ2 test, and corrected using Fisher's precision test, where correction was required. The Kaplan-Meier method was used in survival analysis and the log-rank test was used to test survival difference. p < 0.05 was considered to indicate statistical signi cance.

Result
The basic information of the patients in the study is as follows in Table 1.
The correlation analysis of MRP and IPSI showed that in MRP low-risk group 36.25% 58/160 , mediumrisk group 25% 40/160 , high-risk group 38.75% 62/160 , and in IPSI low-risk group 30% 48/160 , medium-risk group 37.5% 60/160 , high-risk group 32.5% 52/160 . The correlation analysis showed that there was no correlation between the two staging systems(r=-0.062 p=0.433). (Table 2) Through Kaplan-Meier survival analysis, all patients showed differences in prognosis on OS (p=0.019, 48 months vs 30 months vs 32 months) and PFS(p=0.013, 31 months vs 24 months vs 22 months) by MRP, similarly, in the IPSI group, it still shows such differences in OS(p=0.058, 38 months vs 23 months vs 22 months) and PFS(p=0.02, 54 months vs 40 months vs 29 months) seemingly. (Figure 1) It was found that the evaluation of patients at low and medium risk was similar( Figure 2)(p>0.05), but in the high-risk group of MRP, IPSI could be further strati ed in OS(p=0.027, 40 months vs 32 months vs 27 months) and PFS(p=0.055, 25 months vs 21 months vs 14months)( Figure 3A), and in the high-risk group of IPSI, MRP could also be further strati ed in OS(p=0.033, 35 months vs 24 months vs 27 months) and PFS(p=0.039, 25 months vs 15 months vs 14 months)( Figure 3B).Their respective baseline tables are as follows. (Table 3, Table 4).
Further including all patients in the study, our study can nd similar results in 242 patients (including those who were treated only with thalidomide). It was found that the ultra-high risk patients (de ned as patients with both MRP high-risk and IPSI high-risk patients) had signi cantly shorter OS(p 0.001, 18 months vs 39 months) and PFS(p 0.001, 12 months vs 26 months) compared to the other patients( Figure  4).

Discussion
At present, MM is still an incurable disease, but with the successive application of proteasome inhibitors, immunomodulators, monoclonal antibody drugs and autologous hematopoietic stem cell transplantation, the prognosis of MM patients has been signi cantly improved. In China, due to various reasons, few patients are willing to carry out autologous hematopoietic stem cell transplantation, and most patients only choose drug treatment. there is a need to choose an appropriate prognosis score to select appropriate induction, maintenance and consolidation programs. In recent years, with the continuous development of molecular detection technology, the corresponding second-generation sequencing and gene expression techniques have been gradually applied to predict the prognosis of MM. The MRP combines the four factors of WHO ECOG, age, ISS stage and CRP, including both tumor factors and host factors, while the IPSI creatively evaluates the prognosis of MM patients from the perspective of in ammation, combined with RDW, NLR and PLT, and selects patients with different prognostic grades. At present, there are few real-world studies related to MRP and IPSI. In addition to the data from the British Myeloma Research Alliance, Redder et al counted 1377 multiple myeloma patients over the age of 65 who were not eligible for transplantation in Denmark, and concluded that the MRP high-risk group had a higher early mortality rate than the low-risk group, and the MRP high-risk group had shorter duration of treatment and poorer treatment response [9]. Unfortunately, there is no other research data on IPSI at present. In this study, because the patients included in IPSI were patients based on bortezomib treatment, initially only patients who had been treated with bortezomib were studied, and both of them can show that there are statistical differences in OS and PFS strati cation of non-transplant patients based on bortezomib treatment.The sample was then further extended to all patients (including patients who were treated only with thalidomide at an early stage), and similar conclusions could be obtained.
In this study, through the MRP and IPSI analysis of the same group of data, both of them can show that there are statistical differences in OS and PFS strati cation of non-transplant patients based on bortezomib treatment, but by comparison, there are still some similarities and differences between them.
Among the subgroups of MRP, IPSI did not show prognostic signi cance in patients with low and moderate risk of MRP, but in the high-risk subgroup of MRP, the OS and PFS of patients with high-risk IPSI were shorter; Similarly, MRP in the high-risk subgroup of IPSI can further stratify the prognosis of patients. Considering that MRP and IPSI evaluate patients from different angles, it can be considered that patients with both MRP high-risk factors and IPSI high-risk factors have worse prognosis and shorter survival time than general high-risk patients, and belong to ultra-high-risk patients. For such ultra-high-risk patients, if autologous hematopoietic stem cell transplantation can be performed after evaluation, it is recommended that transplantation be carried out as soon as possible to improve the prognosis; if the patient is really unable to perform transplantation or has no intention to transplant, it may be necessary to add immunotargeted therapy with monoclonal antibodies such as daratumumab[10], and new immunomodulators may even enter clinical trials to further bene t. Of course, this needs to be assessed by further evidence-based research on this type of patients in the future.
In the actual process of clinical diagnosis and treatment, the factors affecting the prognosis of MM are complex. In recent years, a variety of new prognostic scoring systems about MM are constantly emerging, most of which require a variety of genetic testing. The MRP and IPSI scoring system avoids the relevant genetic indicators, and can also con rm its evaluation effect in the relevant clinical veri cation, indicating the value of application in the current medical conditions, especially through comparative analysis, it shows that the two systems have combined and complementary effects in some patients, which is helpful to further stratify the discrimination of this kind of patients and provide early warning for the next step of treatment. Of course, with the continuous development of scienti c and technological conditions, the corresponding molecular biotechnology can be widely carried out in clinical practice. It is believed that it can provide patients with more accurate and applicable prognosis and treatment strategies in the future.

Con ict of interest:
None.

Statement of Ethics
This work complies with the guidelines for human studies and was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Patients signed a written informed consent before receiving the treatments described here, but requirement of informed consent for this study was waived due to the retrospective chart review nature of this study This study was approved by the Institutional Review Board and received ethics committee clearance.

Funding Statement
This study was not supported by any funding.  Tables   Table 1 Clinical characteristics of all patients  Table 3 Clinical characteristics of patients in the high-risk group of MRP Proportion of Tumor Cells % 31 10-89 Table 4 Clinical characteristics of patients in the high-risk group of IPSI