Date Published: October 14, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Donna Reece, C. Tom Kouroukis, Richard LeBlanc, Michael Sebag, Kevin Song, John Ashkenas.
In Canada, lenalidomide combined with dexamethasone (Len/Dex) is approved for use in relapsed or refractory multiple myeloma (RRMM). Our expert panel sought to provide an up-to-date practical guide on the use of lenalidomide in the managing RRMM within the Canadian clinical setting, including management of common adverse events (AEs). The panel concluded that safe, effective administration of Len/Dex treatment involves the following steps: (1) lenalidomide dose adjustment based on creatinine clearance and the extent of neutropenia or thrombocytopenia, (2) dexamethasone administered at 20–40 mg/week, and (3) continuation of treatment until disease progression or until toxicity persists despite dose reduction. Based on available evidence, the following precautions should reduce the risk of common Len/Dex AEs: (1) all patients treated with Len/Dex should receive thromboprophylaxis, (2) erythropoiesis-stimulating agents (ESAs) should be used cautiously, and (3) females of child-bearing potential and males in contact with such females must use multiple contraception methods. Finally, while Len/Dex can be administered irrespective of prior therapy and in all prognostic subsets, patients with chromosomal deletion 17(p13) have less favorable outcomes with all treatments, including Len/Dex. New directions for the use of lenalidomide in RRMM are also considered.
Multiple myeloma (MM), the second most common hematological malignancy in adults, is associated with various clinical manifestations including anemia, lytic bone lesions, and renal and immune impairments. According to Canadian Cancer statistics, an estimated 2300 Canadians will be diagnosed with MM and 1350 will die from this disease in 2011 . While no cure for MM is available, five-year survival rates have risen substantially in Canada and elsewhere over the last decade, partly due to novel therapies such as thalidomide, bortezomib, and lenalidomide [2, 3]. Nonetheless, regardless of initial treatment, most patients will eventually relapse and require salvage therapy, often consisting of novel agents, alone or in combination.
The expert panel convened in Paris, France, on May 2, 2011, in conjunction with the 13th International Myeloma Workshop. The group met to discuss the use of lenalidomide in the management of RRMM in the Canadian environment. The Chair (DR) invited panelists to research and write individual sections of the paper.
In October 2008, the combination of lenalidomide and dexamethasone (Len/Dex) was approved in Canada for the treatment of RRMM in patients who had received at least one prior therapy. This approval was based on evidence from two phase III trials, namely, MM009  and MM010 , which showed significant benefits in response rate (RR), time to progression (TTP), and overall survival (OS) following Len/Dex therapy, compared with dexamethasone monotherapy. The benefits of Len/Dex over dexamethasone alone were seen in all age groups and were independent of previous therapy type. Based on the currently approved indication for this agent in Canada and the results of available studies, the initiation of lenalidomide therapy is not limited by the number or type of previous lines of therapy, although OS and progression-free survival are greater among patients with only one prior therapy versus those with two or more prior therapies .
The safety and toxicity of lenalidomide have been evaluated in published clinical trials [12, 13], as well as in an expanded-access program for Canadian and international patients . Although lenalidomide is well tolerated by most patients, some adverse effects are common during treatment. However, some of the more significant side effects associated with thalidomide are not seen with lenalidomide. Indeed, in the MM-009 and MM-010 studies, the incidences of grade 3-4 constipation, somnolence, and peripheral neuropathies were similar for the Len/Dex-treated group compared to the dexamethasone monotherapy group [12, 13]. Importantly, side effects associated with Len/Dex are not affected by the number of prior therapies .
Based on available evidence, Len/Dex appears to be an effective and safe treatment strategy for RRMM patients, regardless of the type and number of prior therapies. In order to ensure optimal balance between efficacy and tolerability, lenalidomide dose and schedule should be adjusted based on creatinine clearance and presence of neutropenia and thrombocytopenia; dexamethasone should typically be administered at weekly doses of 20–40 mg, and treatment should be continued until disease progression or toxicity, even in patients requiring dose reduction.