Search

The clinical outcomes of 169 patients enrolled in the first clinical trial of thalidomide for advanced or refractory myeloma are updated. Seventeen patients remain alive and 10 are event-free, with a median follow-up of 9.2 years. According to multivariate analysis of pretreatment variables, cytogenetic abnormalities, present in 47% of patients within 3 months of enrollment, and lambda light chain isotype both affected overall survival and event-free survival adversely. Forty percent of the 58 patients lacking these 2 unfavorable features, one-half of whom had no disease recurrence, survived at least 6 years, in contrast to fewer than 5% among those with 1 or 2 risk features (P < .001). Patients who had received cumulative thalidomide doses in excess of 42 g in the first 3 months enjoyed superior overall and event-free survival. The poor outcome associated with lambda-type myeloma may relate to its overrepresentation in molecularly defined high-risk disease gleaned from studies in newly diagnosed myeloma.

The standard treatment approach to symptomatic myeloma consists of induction therapy, consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation in appropriate patients, maintenance therapy, and salvage therapy. Salvage therapy is of particular importance because not all patients respond to primary therapy, and relapse is virtually universal in responding patients. Newer agents such as thalidomide, bortezomib, and lenalidomide are very active in patients with relapsed or refractory disease. Their use singly and in combination results in excellent cytoreduction including complete remissions in patients relapsing - even after extensive prior therapy. These novel agents have been usually used as salvage therapy in patients relapsing after standard treatment options including transplantation; a setting in which they are thought to improve survival. However, there is an increasing trend to start using them early in the course of the disease; for induction therapy. While early deployment of these agents is certainly associated with high-response rates, evidence that this improves long-term outcome (survival) in patients who subsequently undergo intensive therapy and transplantation is lacking. Toxicity, expense, and possible long-term consequences on the biology of the disease (for example, development of refractory relapse) remain a concern. The most appropriate use of newer agents such as lenalidomide is as salvage therapy of relapsed or refractory disease, and their use as part of induction therapy should be confined to clinical trials until additional data and long-term follow-up are available.

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed. The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease. A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.

Background: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. Methods: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. Results: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan–Meier estimates of the mean (±SE) rates of event-free survival and overall survival for all patients were 22±5 percent and 58±5 percent, respectively. Conclusions: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy. (N Engl J Med 1999;341:1565-71.) [ABSTRACT FROM AUTHOR]