VTE is a serious medical disorder and complication that can occur in individuals with MM undergoing IMiD treatment. As IMiD treatment remains a cornerstone of MM therapy, precise risk stratification for VTE is paramount. The risk stratification of multiple myeloma (MM) patients treated with immunomodulatory drugs (IMiDs) is mainly determined by the IMWG guideline, SAVED score, or IMPEDE-VTE score. The SAVED model was specifically developed for MM patients receiving IMiD. Most of the guidelines were developed in Western countries. However, individuals of Asian race have been found to have a lower risk of VTE. Although ethnic factors were considered, the guidelines did not fully consider ethnic differences. The sample size of Asian participants in the sample (SAVED), which was merely 7%, was relatively small. Furthermore, no independent external validation of this risk model has been conducted in China [13, 14, 22, 23]. In this study, we analyzed a large multicentre dataset of MM patients who received IMiD treatment in China, and this study represents MM patients treated across the country. The present research findings revealed that the incidence of VTE in Chinese MM patients had at least three different characteristics. One important finding of the present research 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 [20, 24]. However, these results are lower than those of previous studies from Western countries [25], 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 [26, 27].

In addition, one of the most significant findings of this study was that the most of risk variables and factors associated with VTE incidence in Chinese subjects differed from those previously reported in Western studies and outlined in the IMWG guidelines and SAVED score. Therefore, it is reasonable to hypothesize that the pathogenesis of VTE in Chinese patients differs from that in Western patients, which aligns 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 [28, 29].

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%) high-risk patients, and antiplatelet drugs were given in 297 (37.1%) low-risk patients. According to the SAVED score, only 1.0% were classified as having a high risk for VTE, and none of these high-risk patients were administered anticoagulant agents. The above data indicate that prevention strategies for VTE in Chinese patients are based on Chinese expert experiences rather than IMWG guidelines or SAVED scores. However, the use of antiplatelet drugs or anticoagulation therapies may not reduce the risk of VTE in the Chinese population based on Chinese expert experiences in this study (as shown in supplementary Tables 2, VTE with or without antiplatelet drugs: 7.2% and 5.5% (p = 0.392), and anticoagulation therapies: 9.1% and 6.0% (p = 0.636), respectively), which is consistent with previous reports from Korea and Japan, but inconsistent with some results reported in Western myeloma patients treated with IMiDs [18, 20, 30]. The ineffectiveness of anticoagulant and antiplatelet therapy in preventing VTE may be due to the failure to use prophylactic drugs in patients with genuine high risk.

The above three differences showed that the rate of VTE is lower in Chinese myeloma patients compared with Western patients. The current guidelines, such as IMWG and SAVED, include several factors that are not relevant to the incidence of VTE among Chinese subjects in the present study. Moreover, VTE prevention based on the experience of Chinese experts rather than on precise risk stratification guidance may not effectively prevent VTE. Therefore, more precise risk stratification is required for VTE in China. To address this particular clinical need, we analyzed 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 validated in China for MM patients 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. Furthermore, dexamethasone use and a history of VTE as predictors are consistent with the SAVED scores. 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 [25, 31]. Furthermore, it has been observed that administering an erythropoiesis-stimulating drug in conjunction with lenalidomide and dexamethasone can elevate the risk of VTE from 5 to 23% in individuals receiving the combination therapy [32]. Furthermore, our study revealed that the ECOG performance status and family history of thrombosis, variables not incorporated into the IMWG guidelines and SAVED scores, had significant predictive value as independent factors. Some previous studies have shown that a family history of thrombosis independently serves as a risk variable for VTE in 12 cancers, including MM [33]. Patients with decreased ECOG performance scores may represent a more chronically ill population, and a decreased ECOG performance status may be more prevalent in MM patients with a high risk of VTE. This finding was similar to our previous MM studies [34, 35].

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 [36,37,38].

In our cohort of Chinese patients, we compared the performance of IMWG guidelines and SAVED score assessment models for VTE in MM patients treated with IMiDs. Our results revealed that IMWG guidelines and SAVED scores failed to predict patients at risk for VTE development among our Chinese sample. 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 accurately; with this model, the incidences of VTE at 6 and 12 months were 7.7% (4.1-11.2%) and 9.6% (5.2-13.9%), respectively, in the high-risk group and 4.1% (2.0-6.2%) and 4.6% (2.3-6.8%), respectively, in the low-risk group (HR, 1.77; P = 0.053; C index = 0.58) (Fig. 3; 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.

The SAVED score [15] has recently been incorporated into the NCCN guidelines. It was introduced as a simpler method for VTE prediction among MM patients and took into consideration only five variables. However, the SAVED score could not effectively classify patients in our cohort into high and low-risk categories. Out of all patients, 6.1% have VTE. However, according to the SAVED score, only 1% of patients are identified as high-risk, indicating an overall low discrimination performance with a Harrell’s c-statistic of 0.51, which is even inferior to the predictive power of IMWG guidelines. The number of patients classified as high-risk following the SAVED score was too small in our study. The reasons for this result include the following: All the patients in our cohort are of Asian ethnicity. The median age of patients in the SAVED score development study was 74 years, which was higher than that of our cohort. Although a high dose of dexamethasone is considered a predictor in the SAVED score, none of the patients in our Chinese cohort exhibited this characteristic. Therefore, using the SAVED score for VTE risk stratification may underestimate the risk of VTE in Chinese patients.

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%) with a score > 4 were defined as high-risk patients, and 605 patients (90.8%) with a score of ≤ 4 were categorized as low-risk patients. In the high-risk category, the incidence rates of VTE were 26.3% (12.7-37.7%) and 30.4% (14.7-43.1%) at 6 and 12 months, respectively, and in the low-risk category, the rates were 3.4% (1.9-5.0%) and 4.1% (2.3-5.9%) 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. After excluding the patients who had anticoagulation therapy, a sensitivity analysis 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.

To the best of our knowledge, prediction of IMiD-related VTE has never been reported in Chinese MM patients, and the recently developed RAM score is the first tool for this purpose. Our new model has demonstrated superior performance compared to the IMWG guidelines and SAVED score. We successfully identified a “highest-risk” group of patients who ought to be treated with primary anticoagulant thromboprophylaxis, which 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 patient and to enhance their patient counseling efficiency. Nevertheless, several limitations exist in the present research. The retrospective research methodology made it difficult to determine whether biological gene 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. Secondly, 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 analyzed in our study. Thirdly, as this is a retrospective cohort study, we do not routinely perform imaging tests or structured assessments to detect thrombosis in our centers for MM patients who have used IMiD treatment unless they exhibit thrombotic-related symptoms. Asymptomatic VTE may have been neglected, which increases the possibility of missing VTE episodes in our cohort.