Managed Care - July 2008 - (Page H11) The guidelines provide recommendations for all treatments and assign each to a category that indicates the level of agreement among committee members with regard to appropriate use. Category 1 is assigned to therapy that is backed with a high level of evidence from randomized trial data; category 2A is assigned to treatments backed by less stringent evidence but uniformly approved of by committee members; 2B is assigned to therapies with even less supporting evidence and/or a lack of uniform approval by committee members; and category 3 is assigned to therapies that are regarded with significant disagreement among committee members. It is important to keep in mind that NCCN believes that the best place for any patient is in a clinical trial. cluding many over the age of 65, should be considered possible candidates for ASCT. Other key issues surrounding transplantation include the timing of the procedure, as some patients benefit from early ASCT and others from delay of the procedure; single versus tandem ASCT, with some patients showing a significant benefit from a second transplant; and the role of allogeneic and mini allogeneic transplantation, both of which involve donor stem cells and have shown promising results (Lee 2003, Kroger 2002, Maloney 2003). Induction therapy, transplant candidates No consensus exists with regard to upfront treatment for transplant candidates, as long as the induction therapy does not inhibit subsequent collection of peripheral blood stem cells. Melphalan is no longer used for transplant candidates because it is known to inhibit stem cell collection. High-dose dexamethasone, a synthetic corticosteroid, has been used previously as standard therapy in this setting alone and in combination with other drugs; increasingly, however, there are reports of drawbacks to its use, including serious side effects when combined with modern agents like lenalidomide (Rajkumar 2006b). Thalidomide (Thalomid), first introduced as a sedative in 1952 and subsequently withdrawn because of highly publicized teratogenicity, has since been proven to have immunomodulatory activity that is useful for the treatment of a number of autoimmune diseases and cancers. In the beginning of this decade, thalidomide was shown to induce apoptosis in myeloma cells resistant to dexamethasone alone, and also was proven to interact synergistically with dexamethasone to potentiate thalidomide’s activity (Hideshima 2000, Mitsiades 2002). After success with thalidomide in the relapse setting, frontline testing began. A number of trials, including a recently published multicenter, randomized, doubleblind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone alone as initial therapy for newly diagnosed multiple myeloma, have shown that the combination results both in significantly higher response rates and prolonged time to progression (TTP) (Rajkumar 2008). The addition of thalidomide also does not prohibit stem cell collection. Thalidomide/dexamethasone is a standard treatment for many transplant candidates, and has been approved in the frontline setting for newly diagnosed patients. This combination is associated, however, with a number of adverse effects, including deep vein thrombosis (DVT) and peripheral neuropathy (Rajkumar 2008). Several trials are evaluating the use of lenalidomide (Revlimid) as a frontline treatment in patients with myeloma. Lenalidomide, an analogue of thalidomide, was developed with the goal of improving the clinical efficacy and safety profiles of its precursor. It is currently FDA approved for use only in patients who have received Transplantation Most clinicians agree that the initial approach to treatment begins with determining whether a patient is a transplant candidate. All treatment algorithms recommended by the NCCN also begin with this approach (NCCN 2008). This initial decision is important because patients who are transplantation candidates must be given an induction therapy that spares stem cells. Autologous stem cell transplantation (ASCT) following high-dose chemotherapy was introduced as a treatment regimen for myeloma more than 20 years ago. For decades prior to its introduction, patients with myeloma primarily were treated with lower doses of conventional chemotherapeutic agents, such as melphalan (Alkeran) and prednisolone; transplantation — often bone marrow cells rather than the peripheral blood stem cells used today — was generally reserved for salvage or rescue therapy. Standard doses of chemotherapeutic agents alone yielded moderate responses without real survival benefits. However, an intensification of chemotherapy by way of high-dose melphalan, followed by transplantation to restore blood cell production, produced both higher rates of response and the first meaningful survival benefits for patients with myeloma (Attal 1996, Child 2003). Subsequent randomized trials confirmed the superiority of ASCT in terms of response, despite conflicting results with regard to survival (Bladé 2005; Femand 1998). Until recently, ASCT has been considered a standard treatment for newly diagnosed patients younger than 65 in generally good health, with a transplantrelated mortality rate of 1 to 2 percent in this population (Attal 2007). However, ongoing debates exist over the procedure’s ability to prolong disease-free survival (DFS) and overall survival (OS) in all patients. Clinical trials that showed a survival benefit with transplantation largely were conducted before the introduction of modern agents, and recent success with novel agents in the frontline setting has led to the prediction that transplantation may eventually become an outmoded procedure. For now, however, all patients in good general health, in- SUPPLEMENT / HEMATOLOGIC CANCER 11
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