MGUS and Myeloma May Predispose to Venous Thromboembolism

Abstract & Commentary

By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship relevant to this field of study.

Synopsis: Recent studies have suggested that multiple myeloma and monoclonal gammopathy of unknown significance (MGUS) may predispose to venous thromboembolism, even in untreated patients. The authors retrospectively reviewed Veteran Affairs hospital discharge records from 1980 to 1996 for the diagnosis of MGUS or MM, as well as the subsequent development of a deep venous thrombosis (DVT) in the era before the regular use of thalidomide or lenalidomide. There was an increased adjusted risk of developing a DVT after the diagnosis of MGUS or MM of 3.3 (95% CI 2.3 - 4.7) and 9.2 (95% CI 7.9 - 10.8), respectively. Much of the excess risk occurred during the first year after diagnosis.

Source: Kristinsson SY, et al. Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma. Blood. 2008;112:3582-3586.

The association of cancer venous thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism have been long appreciated.1 Multiple myeloma (MM) may also predispose to thrombosis, though the risk is greatly magnified by use of immunomodulatory drugs (IMiDs) such as thalidomide or lenalidomide.2 Monoclonal gammopathy of unknown significance (MGUS) is a much more common plasma cell dyscrasia occurring in 1% or more of all adults and may evolve into MM.3 MGUS can be distinguished from MM by the presence of a serum monoclonal protein concentration < 3 g/dL, fewer than 10% plasma cells in the bone marrow, and absence of lytic bone lesions, anemia, hypercalcemia, or renal insufficiency related to a plasma cell disorder. Most cases of MGUS follow a benign course and do not require intervention. Interestingly, two recent series suggested that MGUS may predispose to VTE.4,5

Kristinsson et al retrospectively reviewed discharge records of more than 4 million patients admitted into the United States Veterans Affairs hospitals between 1980 to 1996 (before widespread use of IMiDs). They ascertained cases of MM and MGUS from the ICD codes. They identified 2374 (0.06%) cases of MGUS and 6192 (0.15%) patients with MM. They focused on DVT rather than PE because a PE diagnosis was less specific, especially in the time prior to faster CT scans that can detect pulmonary emboli. The crude incidence of DVT was 0.9 per 1000 person years. The risk of DVT was increased 3.3 times (95% CI, 2.3-4.7) for MGUS and 9.2 times (95% CI, 7.9-10.8) for MM. The cumulative risk of developing a DVT within four years after the diagnosis for MGUS was 1.4% (95% CI, 0.8 to 2.0) and 4.2% (95% CI, 3.5 - 4.9) for MM. The adjusted relative risk for a DVT compared to the entire cohort one year after diagnosis for MGUS was 8.4 (95% CI, 5.7-12.2) and for MM was 11.6 (95% CI, 9.2-14.5), respectively. The elevated risk for DVT appeared limited to the first year after diagnosis for MM, as opposed to a more constant risk for MGUS. No difference was found between whites and blacks in the risks of DVT for MGUS or MM. MM developed in 9.5% of patients diagnosed earlier with MGUS, and only one of these had a DVT diagnosed before a diagnosis of MM occurred, indicating that evolution to MM did not appear to account for the DVT risk for MGUS.

Commentary

Venous thromboembolic disease commonly complicates the care of cancer patients. Although the increased risks of using immunomodulatory drugs such as thalidomide and lenalidomide in MM has become well appreciated, a risk of DVT may also be present at baseline prior to treatment. Several studies have recently suggested that even in monoclonal gammopathy of unknown significance (MGUS), the risk of DVT may be elevated, suggesting a similar pathogenic mechanism for these plasma cell dyscrasias, leading to prothrombotic tendency.

In this study, Kristinsson et al sought to confirm the prior findings. They found in a large retrospective review of more than 4 million patients admitted to the Veterans Affairs hospitals that the risk of DVT was increased by three or nine times for patients having a pre-existing diagnosis of MGUS or MM, respectively. In addition, for patients with MM, the risk was mostly isolated to the first year after diagnosis, whereas for MGUS, the elevated risk for DVT persisted over time. Kristinsson et al point out that the data were derived from a period between 1980-1996 before routine use of thalidomide and lenalidomide. Also in this era, before low molecular weight heparins allowed outpatient treatment of DVT, cases almost always required an inpatient admission and, thus, discharge summaries capture most symptomatic DVTs. The data are the strongest yet to support the emerging hypothesis that both MM and MGUS predispose to DVT, rather than treatment alone.

The demographic composition of patients admitted to the VA system is skewed toward men and African-Americans compared to the general population, which limits generalizability. More important limitations relate to possible ascertainment bias that may complicate a retrospective review of hospital discharges. One can expect cases of MM and symptomatic DVT to be accurately recorded. However, for MGUS, ascertainment is much less reliable, and many, if not most, cases were either unrecognized or undocumented on the discharge diagnosis. For example, only 0.15% of patients had MGUS diagnosed, whereas one can expect around 2%-3% or more in those 50 or over. It remains quite plausible that factors leading to a diagnosis of MGUS may also be linked to DVT, thus giving the false impression that MGUS predisposes to DVT. For example, some cases of MGUS may have received treatment either because they were evolving into myeloma or practice patterns differed twenty years ago. Clearly, treatment of MGUS would increase the chance of documenting MGUS. Since the addition of chemotherapy or steroids to IMiDs increases the risks of DVT compared to IMiDs alone,6 it seems reasonable to assume that other treatments, if used, such as steroid, might also increase the risk of DVT. Alternatively, a diagnosis of MGUS may have led to closer follow-up or evaluation by a hematologist, where a diagnosis of DVT could be more likely.

If validated, the findings could have enormous implications related to the population attributable risk of DVT considering the high prevalence of MGUS among older adults, a population already at increased risk of DVT.3

Many questions remain unanswered: What are the mechanisms whereby DVT risk is increased for plasma cell dyscrasias? Does an increased risk of DVT correlate to a higher chance of pulmonary embolus? Is the relationship between MGUS or MM and DVT affected by the immunoglobulin isotype? Is DVT prophylaxis warranted?

In conclusion, MGUS and MM may have an increased risk of DVT, independent of treatment with lenalidomide or thalidomide.

References

1. Sorensen HT, et al. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 1998;338:1169-1173.

2. Bennett CL, et al. Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer. JAMA. 2006;296:2558-2560.

3. Kyle RA, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006; 354:1362-1369.

4. Sallah S, et al. The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance. Ann Oncol. 2004;15: 1490-1494.

5. Srkalovic G, et al. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer. 2004;101:558-566.

6. Zangari M, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98: 1614-1615.