Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine whether interferon maintenance therapy improves overall survival and response duration in patients with multiple myeloma who have responded to induction therapy with melphalan and prednisone. PATIENTS AND METHODS: In a multicenter trial, patients with symptomatic clinical stage I and stage II and III multiple myeloma were registered at diagnosis and those who responded to melphalan-prednisone (MP) were randomized either to receive interferon (2 mU/m2) subcutaneously three times per week or no maintenance. MP was discontinued in both groups once a stable response plateau of the monoclonal protein was reached. Interferon was continued until relapse, and then was restarted on subsequent response to MP. Interferon toxicity was recorded using a self-report diary. Survival and response duration were calculated using life-table methods, and were adjusted in the analysis for imbalances in baseline prognostic factors. RESULTS: Four hundred two patients were registered and 176 responders were randomized (85 to interferon and 91 to control). At a median follow-up time of 43 months, the median survival duration was 43 months for interferon and 35 months for control (P = .16), but when adjusted for chance imbalances in baseline prognostic factors (mainly performance status), the median survival duration was 44 months and 33 months for interferon and control, respectively (P = .049). Progression-free survival from randomization to first relapse also favored interferon (unadjusted P < .002; adjusted P < .003). Interferon toxicity caused 58% of patients to reduce their dose, of which 84% were able to return to the initial dose; 14% had to discontinue interferon treatment. CONCLUSION: Interferon maintenance therapy improves progression-free and overall survival of patients with multiple myeloma who respond to melphalan and prednisone. Toxicity is substantial and must be weighed by patients against the potential benefits in response duration and survival.

Isolation and characterization of adriamycin-resistant HL-60 cells which are not defective in the initial intracellular accumulation of drug.

Two human leukemia cell lines (Molt-4 and HL-60) have been used for establishing cells which exhibit a low level resistance to Adriamycin. Analysis of drug uptake patterns shows that the Molt-4 resistant cells are defective in the initial intracellular accumulation of drug. In contrast to Molt-4 the levels of drug which accumulate in the sensitive and resistant HL-60 cells during a 60-min incubation period are essentially the same. However, when incubations are continued there is a major reduction in intracellular drug levels in the resistant cell. Further studies show that resistant cells incubated in the presence of drug for extended time periods efflux drug at a rate considerably greater than that exhibited by the sensitive parent line. Similar efflux patterns are obtained with nuclei isolated from drug-sensitive and -resistant cells. Additional studies using an in vitro phosphorylation system demonstrate distinct protein changes in membranes of Molt-4 and HL-60 resistant cells. Thus, we have found that a membrane fraction from the Molt-4 resistant line contains a Mr 170,000 protein which is not detected in a similar fraction from cells sensitive to drug. HL-60 resistant membranes contain two proteins with molecular weights of 150,000 and 120,000 which are also not found in membranes from drug-sensitive cells. The results of this study suggest that drug resistance in HL-60 cells is related to an efflux mechanism which is triggered only after cells are exposed to drug for prolonged periods.