Thrombosis and risk of death

Multiple myeloma patients with any thrombosis after diagnosis had higher mortality rates compared to those without, at 1-, 5-, and 10-year follow up, with HR of 3.4 (95% CI: 3.0-3.8), HR 2.1 (95% CI: 2.0-2.2), and HR 2.0 (95% CI: 1.9-2.2), respectively (Table 1). The risk of death during the 1-, 5-, and 10-year follow up was significantly higher with diagnosis of any VTE, HR 2.9 (95% CI: 2.4-3.5), 1.6 (95% CI: 1.5-1.8), and 1.6 (95% CI: 1.4-1.7), respectively, as well as with arterial thrombosis, HR 3.4 (95% CI: 3.0-3.8), 2.2 (95% CI: 2.0-2.3), and 2.1 (95% CI: 1.9-2.1), respectively. There were no significant differences in the effect of thrombosis on mortality for multiple myeloma patients diagnosed before 2000 compared to those diagnosed after this date (Table 1), according to sex or to age of diagnosis (above/below 70 years of age). These findings are important as they confirm that thrombosis in multiple myeloma is a serious complication, increasing morbidity and even mortality, also in the era of novel anti-tumor agents.

Given that a multiple myeloma patient survived the first six months following diagnosis (landmark analyses), early VTE (within six months) was not associated with a higher risk of death at one year (HR 1.4; 95% CI: 0.9-2.0), five years (HR 1.1; 95% CI: 0.9-1.3), or ten years (HR 1.0; 95% CI: 0.9-1.2) (Figure 1). In contrast, in a landmark analysis, early arterial thrombosis was associated with a significantly higher risk of death at one year (Hr 1.5; 95% CI: 1.1-2.0), five years (HR 1.4; 95% CI: 1.2-1.6), and ten years (HR 1.4; 95% CI: 1.2-1.6) (Figure 2).

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Figure 1.

Survival among multiple myeloma patients with and without early venous thrombembolism (landmark analysis).

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Figure 2.

Survival among multiple myeloma patients with and without early arterial thrombosis (landmark analysis).

Thrombosis is a frequent complication in patients with cancer and patients with various types of cancer have a two times higher mortality if diagnosed with VTE and three times higher during the first year.16 The occurrence of DVT or pulmonary embolism in the general population is associated with a decreased survival during the first six months, and in cases of unprovoked VTE, up to three years after diagnosis.11 Our study is the first to evaluate the impact of VTE on survival in a large population-based cohort of multiple myeloma patients. In accordance with the findings from studies on other cancers,16 we show that multiple myeloma patients with VTE have an almost 3- fold higher risk of dying within one year after diagnosis of thrombosis (compared to multiple myeloma patients without a thrombosis) and 1.6-fold higher risk within the first ten years. This is in contrast to the three previously published retrospective clinical studies based on 668, 535, and 353 patients, which reported that multiple myeloma patients with VTE have a similar survival to those without.12-14

There are some important differences between these studies and ours. Firstly, we included all patients diagnosed with multiple myeloma in a whole population and followed them for a long time period. Secondly, the other studies are based on data from clinical trials, with some patients excluded, for example, because of poor performance status and reduced cardiopulmonary function.12-13 Furthermore, two of the studies included relapsed/refractory patients and it is well known that these have a lower risk of thrombosis compared to newly diagnosed patients.17-20 Accordingly, we found the risk of death in multiple myeloma patients with VTE to be highest during the first year following diagnosis of the disease. Thirdly, the patients in two clinical trials were younger than the patients in our study (median age 57 and 63 years vs. 71 years, respectively).14,15 Age is a strong predictor for VTE and this can, therefore, influence the outcome.9,21 Finally, and perhaps most importantly, not all patients in our study were treated with thalidomide or lenalidomide as these agents were not available during the largest part of the study period. We conclude that VTE in multiple myeloma is a serious complication with a considerable impact on overall survival.

Interestingly, based on landmark analyses, survival rates for multiple myeloma patients with an early VTE who survived their first six months were similar to multiple myeloma patients without VTE during the first six months. Based on data from the Total Therapy 2 study, 95% of the VTEs were diagnosed within the first 12 months.12 In their study into the impact of VTE on survival, a 12-month landmark analysis was used and early mortality was, therefore, not evaluated. In the study based on data on relapsed/refractory multiple myeloma patients treated with lenalidomide, 96.7% of thrombotic events occurred in the first 12 months from start of treatment, and a 6-month landmark was used.15 Taken together, VTE is associated with higher mortality; however, the findings from our study, as well as those from the previously published studies, show that those patients who survive a VTE within the first 6-12 months do not seem to have a poorer survival. There are several potential mechanisms to explain these findings. Firstly, it has been suggested that the occurrence of thrombosis is partly related to the response to the treatment, and that patients who respond have an increased risk of VTE. Furthermore, the impact of low-molecular weight heparin (LMWH) on survival needs to be evaluated as this is usually used to treat VTE, and has been shown to have anti-tumoral activity.22 In addition, it is possible that multiple myeloma patients who survive their early thrombosis are in some way healthier than those who do not, introducing a bias contributing to an observed improvement in long-term survival.

This is the first study to our knowledge to evaluate the impact of arterial thrombosis on survival in multiple myeloma patients. Overall, diagnosis of arterial thrombosis was associated with a 3.4-fold higher risk of death within one year following multiple myeloma (compared to multiple myeloma patients without an arterial event) and a 2.1-fold risk within the first ten years. In contrast to VTE, we found early arterial thrombosis to be associated with a higher risk of death also in those surviving their first six months. This confirms that arterial thrombosis (myocardial infarction, angina, stroke, and TIA) is a very serious complication in multiple myeloma patients and is associated with immediate morbidity, and early and long-term mortality.23-24 One explanation might also be that patients with arterial thrombosis are treated as aggressively as other multiple myeloma patients.

Our study has several strengths, including its large size and the application of high-quality data from Sweden, a country with a stable population who had access to standardized medical care during the entire study period. In our study, we used a register-based cohort design that ensured a population-based setting and the generalizability of our findings. In a recent validation study, we reported that ascertainment and diagnostic accuracy for multiple myeloma is very high in Sweden (>90-95%).15 Study limitations are the lack of detailed clinical data, including information on anti-multiple myeloma therapy, subtype of multiple myeloma, underlying diseases and risk factors for thrombosis. Another limitation is the potential inaccuracy and lack of independent validation of thrombotic diagnosis obtained from the centralized Patient Registry.

In summary, in this large population-based study based on over 9,000 multiple myeloma patients, we found, in contrast to previously published studies, that the occurrence of any thrombosis was associated with a significantly poorer survival. Multiple myeloma patients with an early arterial or venous thrombosis had a higher risk of death than patients without. However, multiple myeloma patients with an early VTE who survived their first six months had similar survival rates to those without VTE. Therefore, our findings confirm that thrombosis in multiple myeloma patients is a serious complication, and that it increases mortality, also in the era of novel agents. It is important to investigate whether more effective prevention of thromboembolism can improve the survival of multiple myeloma patients.