VTE is a serious medical disorder and complication that can occur in individuals with MM who are undergoing IMiD treatment. Most of the guidelines [9, 15–17] that recommend primary thromboprophylaxis for MM patients receiving IMiDs were developed in Western countries. Notably, some Western experts have highlighted that these recommendations are not grounded on randomized controlled trials; additionally, several investigations had limited sample sizes and/or were not validated. Furthermore, the findings of these studies have been inconsistent and did not take ethnic differences into account [11]. In this study, we analysed a large multicentre dataset of MM patients who received IMiD treatment in China, and this study represents MM patients treated across the country. The findings of the present research revealed that the incidence of VTE in Chinese MM patients had at least three different characteristics.
One important finding of the present research was that there was a low VTE incidence (6.1%) in Chinese MM patients treated with IMiDs, despite the absence of thromboprophylaxis, which is consistent with previous reports within Asian populations [18, 19]. However, these results are lower than those of previous studies from Western countries [20], where the VTE incidences were highly variable among the different trials, and the incidence rate of VTE could be as high as 58% when IMiDs were given without thromboprophylaxis [21]. Although asymptomatic VTE might have been overlooked in these studies, most other investigations evaluated the incidence rate of symptomatic VTE [13, 22].
In addition, one of the most significant findings of the present research was that the well-known risk variables for the occurrence of VTE that have been previously reported in Western studies were different from the variables correlated with the incidence of VTE in Chinese subjects in the present research. Therefore, it is reasonable to hypothesize that the pathogenesis of VTE in Chinese patients differs from that in Western patients, which is in line with the lower frequencies and distinct patterns of VTE progression observed in our study compared to Western studies. It is possible that other factors, including nutrition and prothrombin mutations, lead to a lower incidence rate of VTE among the overall Asian population [23, 24].
The third finding of our study is that VTE prophylaxis (including antiplatelet and anticoagulant drugs) was provided to only 41.38% of the patients in the study cohort, which is lower in contrast with the percentages in Western nations. Most of the patients received antiplatelet drug prophylaxis (38.01%), and other prophylactic therapies, including low-molecular-weight warfarin or heparin, were utilized in a limited number of Chinese patients. According to the IMWG guidelines, 40.0% of the patients in our study were classified as having a high risk for VTE, whereas 60.0% were classified as having a low risk for VTE. Anticoagulant agents were given in only 26 (4.9%) of the high-risk patients, and antiplatelet drugs were given in only 297 (37.1%) of the low-risk patients. The strategies used to prevent VTE in Chinese patients are based on expert experiences and not official guidelines. However, the incidence of VTE was not reduced with thromboprophylaxis via antiplatelet drugs or anticoagulation therapies in the Chinese population based on expert experiences in this study, which is inconsistent with the results reported in Western myeloma patients treated with IMiDs [6, 25].
The above differences confirm that the current guidelines in Western countries are not suitable for Chinese MM patients; consequently, there is no proven clinical method that can be used to predict VTE in Chinese patients at present. To meet this particular clinical need, we analysed a large and nationally representative multicentre dataset that included MM patients in China who had IMiD treatment, and we used this new model to develop a new RAM that was capable of predicting the risk of IMiD-related VTE in MM patients. This model comprised the following five variables: diabetes; ECOG performance status; the use of an erythropoietin-stimulating agent; the use of dexamethasone; and a VTE history or a family history of thrombosis. Furthermore, we externally and independently validated the new RAM and confirmed its generalizability and robust predictive performance. This is the first clinical RAM that has been validated in China for patients with MM who are receiving IMiDs. It has been shown that the discriminative performance of this novel RAM model, which contains just five factors, is better than that of the more sophisticated consensus model proposed by the IMWG guidelines.
In this cohort, we found that diabetes, erythropoietin-stimulating agent use, dexamethasone use, and VTE history were independent predictors of IMiD-related VTE, which is in agreement with most previous studies, and our results are also in agreement with the IMWG guidelines for the risk variables correlated with IMiD-related VTE. In previous research, it was found that when thalidomide and dexamethasone or lenalidomide and dexamethasone were used in a combined manner, the incidence increased to 17% and that the incidence increased even more to 26–58% in patients who were also given further chemotherapy treatment [20, 26]. Furthermore, it has been observed that the administration of an erythropoiesis-stimulating drug in conjunction with lenalidomide and dexamethasone can elevate the risk of VTE from 5 to 23 percent in individuals receiving the combination therapy [27]. In addition, the ECOG performance status and family history of thrombosis, which were not included in the IMWG guidelines, were shown to be independent predictors in our study. Some previous studies have shown that a family history of thrombosis independently serves as a risk variable for VTE in 12 cancers, including MM [28]. Patients with decreased ECOG performance scores may represent a more chronically ill population, and a decreased ECOG performance status may be more prevalent in a population of MM patients where there is a high risk of VTE. This finding was similar to those of our previous MM studies [29, 30].
The present research found no significant predictors of VTE for a number of characteristics that had previously been correlated with an elevated risk of VTE in other groups. Patient-related risk and treatment-related factors, including age and male sex, concomitant infections, immobility, obesity, major illnesses (chronic renal disease, inflammatory bowel disease, autoimmune diseases, chronic obstructive pulmonary disease, cardiovascular disease, congestive cardiac failure), surgery, radiation, fractures, central venous catheters, and hormonal therapy, are critical cofactors in the pathophysiology of thromboses and were not correlated with the VTE risk in the sample of the present research, which is in contrast to prior studies [31–33].
Although approximately 39.7% of the 667 patients with MM in our derivation cohort could have been designated as “high thrombotic risk” based on the available IMWG consensus, the IMWG model failed to predict the initial VTE onset in a correct manner; with this model, the incidences of VTE at 6 and 12 months were 7.73% and 9.61%, respectively, in the high-risk group and 4.13% and 4.56%, respectively, in the low-risk group (HR, 1.77; P = 0.053; C index = 0.58) (Fig. 3 and Table 3). Based on the IMWG guidelines, 39.7% of the patients who had been classified as “high thrombotic risk” should be treated with anticoagulation therapy to prevent VTE, but these therapies may not effectively prevent thrombosis and may increase the financial burden and the risk of bleeding.
In our new RAM score, we used only five variables to differentiate between the high- and low-risk patients. A total of 62 patients (9.2 percent) with a score > 4 were defined as high-risk patients, and 605 patients (90.8 percent) with a score of ≤ 4 were categorized as low-risk patients. In the high-risk category, the incidence rates of VTE were 26.26% and 30.36% at 6 and 12 months, respectively, and in the low-risk category, the rates were 3.19% and 4.12% at 6 and 12 months, respectively (Fig. 2). The HR for VTE was 6.08 (P < 0.001), with a C index of 0.64 (0.60–0.69) (Table 2). In the present research, the superior clinical scores comprised C indices ranging from 0.58 to 0.64 within the validation cohort, and these parameters made the prediction model more accurate, sensitive, and effective. A sensitivity analysis, after excluding the patients who had anticoagulation therapy, of the derivation and validation cohorts showed that the model was still capable of discriminating the risk with C indices of 0.64 and 0.63.
Recently, several other risk models for MM patients with VTE have been constructed, including the IMPEDE VTE score and the SAVED score. However, these scores have certain shortcomings for evaluating Chinese MM patients who we assessed with the new RAM score in this study. A nationally representative sample population was used to construct the IMPEDE VTE and SAVED scores, which were then verified for their excellent performance. Nevertheless, both included a smaller Asian population within the total sample size (SAVED included 7% Asian participants, and IMPEDE VTE included 1.3% Asian/Pacific Islander participants). The SAVED score [11] utilized data from patients with a recent MM diagnosis who were receiving chemotherapy in conjunction with an immunomodulatory drug. The SAVED score included 5 variables; nevertheless, the patients used to develop the score had a median age of 74 years. At six months, patients having a high-risk score exhibited a 12 percent incidence of VTE, as opposed to a 7 percent incidence in the low-risk category. However, this score was not suitable for young patients, and the discrimination between the low- and high-risk groups was not clear. IMPEDE VTE [14] tested 4446 patients with a recent MM diagnosis. IMiD therapy was administered to only 57% of the patients in this study, and a total of 11 parameters were included in the obtained risk model. The risk-adjusted 6-month cumulative incidence rates of VTE in the high-risk cohort was 15.2%. This model is more complicated than our RAM, and the VTE incidence rate at 6 months obtained by using the IMPEDE model for high-risk subgroups was lower than that obtained by using our new RAM.
To the best of our knowledge, IMiD-related VTE in Chinese MM patients has never been predicted before, and the novel RAM score is the first such score to be discovered. Our new model has shown good performance. We successfully identified a "highest-risk" group of patients who ought to be treated with primary anticoagulant thromboprophylaxis that is more aggressive than aspirin therapy at the onset of IMiD treatment. This simplified set of clinical risk predictive variables could function as novel guidelines for assessing innovative prognostic biological indicators among this high-risk population of patients. Medical physicians can gain insight from our innovative RAM rating system to establish the most effective treatment plan for each individual patient and to enhance their patient counselling efficiency. Nevertheless, a number of limitations exist in the present research. The retrospective research methodology made it difficult for us to determine whether gene biological markers might enhance the discrimination of scores. Even though the present research included the largest dataset of MM patients undergoing IMiD therapy in China, our proposed model still needs additional exploration and validation. Second, after this study was concluded, the FDA approved additional chemotherapeutic agents for the treatment of MM (e.g., pomalidomide, carfilzomib, ixazomib, daratumumab); therefore, the association of these agents with VTE was not analysed in our study.