Abstract CN03-03: Therapeutic interventions to prevent progression of MGUS to multiple myeloma

CN03-03 Multiple myeloma is the second most common hematological malignancy, affecting nearly 20,000 individuals each year with nearly 12,000 deaths during the same period. While considerable progress has been made in the treatment of this disease and the survival has improved in the recent years, myeloma still remains incurable. Given the incurable nature of the disease there has been considerable interest in understanding the pathogenesis and evolution of monoclonal gammopathies, which can improve the prospects for effective prevention strategies. Monoclonal gammopathy of undetermined significance has been recognized as precursor state for development of multiple myeloma for years. The prevalence of MGUS increases with age and forms nearly two thirds of the patients with a diagnosis of monoclonal gammopathy. The risk of progression from MGUS to myeloma has studied in several large cohort studies and is estimated to be around 1% per year. This risk remains fairly constant over the lifetime, highlighting the possibility that a ‘second hit’ is required in an individual with MGUS for its evolution to myeloma. Several clinical features have been identified that increases the risk of progression in any given individual, including the immunoglobulin isotype, M protein concentration, circulating plasma cells, and suppression of uninvolved immunoglobulin. More recently, the introduction of assays that can detect free light chains unbound to the heavy chain has allowed better identification of patients at increased risk of progression to myeloma. In fact, a staging system that incorporates the type of immunoglobulin, its concentration and presence of abnormal light chain ration allows us to identify a proportion of patients that are at high risk of progression. However, more recent epidemiologic studies suggest that nearly all patients with myeloma have a MGUS phase prior to the development of myeloma. This finding reinforces the importance of evaluating strategies that prevent the progression from MGUS to symptomatic myeloma. In addition, many patients are diagnosed with smoldering myeloma, a condition that falls between MGUS and symptomatic myeloma, and one which is typically observed with out any proven effective interventions. As in MGUS, there are several features that have been identified that allow risk stratification these patients. While patients with smoldering myeloma have several fold risk of progression compared to MGUS, it provides another point in the disease spectrum where prevention strategies may be valuable. The biggest obstacle to pursuing prevention strategies in patients with MGUS has been the low overall risk of progression, thus compromising the risk benefit ratio for most available anti-myeloma strategies to be used in a preventive fashion. Ongoing studies, especially that are examining potential genetic markers of progression, may allow better determination of an individual’s risk allowing us to focus on the small proportion of individuals with the highest level of risk. Another option would be to examine interventions with none or minimal adverse effects, that would allow a more universal approach to prevention. These could include vaccination strategies to modulate the immune system, use of food supplements and other measures which are being currently being evaluated. Given the much higher risk of progression among patients with smoldering myeloma, there have been clinical trials evaluating the role of anti-myeloma drugs as a strategy for preventing progression to symptomatic myeloma. Thalidomide has been studied with variable success. Clinical trials are being planned to evaluate the role of lenalidomide, an immunomodulatory analogue of thalidomide. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN03-03.