details the risks and benefits of maintenance therapy for multiple myeloma patients. Maintenance Therapy for Multiple Myeloma: Risks And Benefits By Michael Broder, PhD Reviewed by Alan S. Weinstein, MD, FACP, Senior Physician Advisor, Virtua Fox Chase Cancer Program, Marlton, NJ Multiple myeloma (MM) is the second most common blood malignancy worldwide, accounting for 1% of all cancers and 13% of hematologic malignancies and causing 20% of hematologic malignancy-related deaths. Patients with asymptomatic disease may remain stable for a long time without treatment. Symptomatic patients may present with one or more characteristic conditions including calcium elevation, renal insufficiency, anemia, and bone disease (commonly called the CRAB criteria). Any of these conditions, as well as others such as hyperviscosity, recurrent bacterial infections, and amyloidosis with organ involvement, are indications for initial treatment. While MM remains largely incurable, treatment may control the disease and minimize its impact on end organs. The past two decades have seen major advances in treatment for MM patients, particularly those eligible for autologous stem cell transplantation (ASCT). Transplant-eligible patients are generally those under 65 years of age without severe comorbidities. With the widespread use of ASCT and the use of newer agents, median overall survival (OS) has increased from 2 to 3 years to more than 8 years. Nevertheless, because myeloma recurs in the vast majority of patients, posttransplantation maintenance therapy has become an important strategy for maintaining remission, preventing tumor progression, and prolonging survival. Traditional chemotherapy agents, interferon, and prednisone have been used for maintenance therapy, but they’re limited by toxicity and modest efficacy. While maintenance therapy with thalidomide has been effective at improving progression-free survival (PFS), long-term thalidomide use is limited by progressive severe neuropathy. Moreover, thalidomide doesn’t improve OS in patients who achieved a complete response or a very good partial response to induction therapy, or in patients with chromosome 13 deletion, a genetic marker found in 50% of MM patients. Data from at least one study suggest that maintenance therapy with thalidomide may even be detrimental in patients with high-risk cytogenetics. Lenalidomide and bortezomib may be better tolerated and more effective as maintenance therapy for a wider range of patient types, according to Philip L. McCarthy, MD, Professor of Oncology and Director of the Blood and Marrow Transplant Program at the Roswell Park Cancer Institute in Buffalo, New York. “Two studies, CALGB 100104 and the Italian MPR [melphalan/prednisone/lenalidomide chemotherapy] versus MEL200 [high-dose melphalan and autologous transplantation] study, have shown a PFS and OS benefit for lenalidomide maintenance until disease progression,” says Dr. McCarthy. “The IFM 0502 study stopped lenalidomide maintenance at a median of 2 years (range 1 to 3 years) due to a concern regarding second primary malignancies (SPMs). There was a PFS but not OS benefit.” In fact, according to Dr. McCarthy, all lenalidomide studies to date have found an increase in SPMs. “The CALGB 100104 study found that there was an increase in the cumulative incidence risk of SPMs for patients receiving lenalidomide compared to placebo and an increase in the cumulative incidence risk of progression and death for patients receiving placebo,” says Dr. McCarthy. Maintenance therapy with bortezomib has been evaluated in one phase III study to date, a collaboration between the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and the German Multicenter Myeloma Group (GMMG). “The HOVON-65/GMMG-HD4 study showed a PFS and OS benefit for 2 years of bortezomib maintenance when compared to thalidomide for patients in renal failure and those with a 17p deletion,” says Dr. McCarthy, referring to a chromosomal abnormality associated with poor outcomes in MM patients. Based on these findings, certain approaches have gained wider acceptance for use in specific patient populations. “I would consider lenalidomide maintenance until progression to be a standard, and bortezomib for 2 years for renal failure and patients with a 17p deletion,” says Dr. McCarthy. Options for maintenance therapy are likely to increase in the coming years, adds Dr. McCarthy, who expects analogues of thalidomide, proteasome inhibitors, and monoclonal antibodies to play possible roles. He says a combination of agents could lead to synergy in preventing MM recurrence. Even with the increasing options for maintenance therapy, with fewer side effects and greater efficacy, the disease itself continues to pose the greatest barrier to remission and survival. “The greatest clinical challenge remains relapse or progression of the underlying disease,” says Dr. McCarthy. “Even with the use of novel agents for extended maintenance therapy, many patients will have progression of disease requiring treatment.” Despite the challenges, Dr. McCarthy sees a brighter future for the treatment of MM. “I expect that we’ll have more agents to treat MM over the next several years, in particular targeting different intracellular pathways. This should lead to better control of MM, with the long-term goal being the development of curative approaches.” For the complete article and references, click here.