Whither Interferon for Myeloma and Other Hematologic Malignancies?

Multiple myeloma is one of the common hematologic malignancies now affecting approximately 12 500 persons in the United States each year. The number of patients with this condition continues to increase as a result of more frequent screening with electrophoresis and more diagnoses among a progressively aging population. Despite intensive study of many treatments, including those supported by stem cell transplantation, overall survival has not improved, and the disease remains incurable [1]. Accordingly, the best available strategy has been to achieve a high frequency of remission that can be sustained for several years, and then to repeatedly control relapsing disease with a series of effective and well-tolerated treatments.

Since interferon-α became available 15 years ago, its role in the treatment of multiple myeloma has been controversial. Early studies [2, 3] showed that disease could be controlled in approximately 20% of newly diagnosed patients, but only rarely in patients with disease resistant to standard therapies. Neither of two studies [4, 5] that assessed a combination of interferon and standard alkylating agent-glucocorticoid therapy detected a consistent improvement in long-term outcome. The median remission time of responding patients was prolonged by 4 to 12 months with interferon compared with no treatment in four controlled studies [6-9], although no benefit was seen in two other studies [10, 11]. Most analyses failed to detect any improvement in survival, because disease in patients who had relapse after treatment with interferon or after no treatment was controlled frequently on resumption of chemotherapy.

In this issue, the Nordic Myeloma Study Group [12] clarifies several questions about the role of interferon for patients with myeloma. Among 583 patients from more than 100 hospitals in Scandinavia, no improvement was seen in frequency of response when interferon was added to melphalan-prednisone. These findings confirm the negative results of studies by Cooper and colleagues [4] and Osterborg and coworkers [5]. Consistent with the prevailing view, Hjorth and colleagues failed to discern any prolongation of survival with a sequence of initial and maintenance interferon therapy given with repeated courses of melphalan-prednisone therapy. Yet, the remission time of responding patients was significantly longer (by a median of 5 months) among patients who received maintenance therapy with melphalan-prednisone and interferon than among patients who continued to receive melphalan-prednisone treatment. Thus, the report in this issue supports the slight prolongation of remission observed in most controlled studies on this subject. Even the studies that showed no apparent improvement in remission time had CIs wide enough to allow differences of several months in favor of interferon to be missed. Yet, can one justify the cytostatic effect of interferon maintenance therapy for all responding patients by what appears to be a limited gain in remission time? Such therapy is costly and has side effects, such as fatigue, to which older patients are more susceptible. No group of patients has been identified consistently as more likely to benefit from interferon, and the Nordic Myeloma Study Group [12] describes a high frequency of intolerance even to low doses. Moreover, no controlled study has compared the outcomes of patients receiving maintenance therapy with interferon alone with the outcomes of patients receiving intermittent maintenance chemotherapy. Other potential maintenance programs, such as those using short-term steroid therapy or interleukin-2, also require study. Thus, the burden of proof remains with those who might claim an established role for interferon in maintenance of remission.

The modest gain in remission now shown with interferon, coupled with the prognostic factors that influence remission time, re-opens the question of the best maintenance therapy for individual patients. The remission time with repeated courses of maintenance chemotherapy has been shorter (median, 18 months), and serious disease morbidity on relapse has been more likely among patients who had hypercalcemia or severe anemia at diagnosis than among patients who did not have these features. Relapses are more often rapid and unexpected among patients with remission who receive no maintenance therapy or who receive maintenance therapy with interferon when features of advanced disease were present at diagnosis. Repeated courses of alkylating agent-glucocorticoid therapy have side effects, are not free of cost, contribute to immune depression, and cause secondary leukemia in approximately 2% of patients. Nevertheless, for patients in whom the risk for early relapse and morbidity is high, repeated maintenance chemotherapy at 1- to 2-month intervals is a rational alternative. Among other patients who have less advanced disease that has been reduced markedly by initial therapy, remission without maintenance therapy often exceeds 1 year, and further studies may identify some patients who benefit more durably from interferon, especially when the drug is given alone and only during the remission period. After intensive consolidation therapy supported by autologous stem cell transplantation, the remission and survival of patients in complete remission appeared longer with interferon maintenance therapy than with no treatment [13]. Until more data are available, interferon maintenance therapy seems reasonable for these patients. For other responding patients who cannot be included in controlled trials, the decision to choose no treatment, interferon therapy, or continued chemotherapy should be made after considering both the risk for early disease recurrence and the side effects of each option.

The role of interferon-α for other hematologic malignancies differs in varying degrees from that observed for multiple myeloma. Interferon-α is the most active single agent for chronic myelogenous leukemia, inducing partial or complete cytogenetic remissions in many patients who received continuous therapy with this agent [14]. Maintenance therapy appears to be justified primarily for those who have responded well and who are not candidates for potentially curative myeloablative therapy with allogeneic stem cell transplantation or for studies that include chemotherapy or autologous stem cell transplantation, or both. As in myeloma, several studies of interferon therapy for low-grade lymphoma have shown a prolonged remission but no survival benefit [15]. The limited activity of interferon against chronic lymphocytic leukemia accounts for the limited trials to date, but one recent study [16] failed to detect any prolongation of remission after successful treatment with fludarabine. Although interferon is active against hairy cell leukemia, primary treatment with 2-chlorodeoxyadenosine has induced long remissions without maintenance therapy and is now the treatment of choice; interferon could be studied for a possible role in maintaining later remissions that are likely to be of shorter duration. Thus, looking more broadly, interferon-α is an important and useful agent for several hematologic malignancies but will have a gradually changing role as definitive studies are completed.

• Copyright ©2004 by the American College of Physicians