Original Article
Maintenance Treatment with Recombinant Interferon Alfa-2b in Patients with Multiple Myeloma Responding to Conventional Induction Chemotherapy
N Engl J Med 1990; 322:1430-1434May 17, 1990
- Abstract
- Abstract
The use of interferon for the induction treatment of multiple myeloma has been shown to be effective in about 20 percent of patients. We studied its effects on long-term survival when it was used for maintenance treatment. Between April 1985 and May 1988, 101 patients with symptomatic multiple myeloma who had had a substantial objective response or a lesser objective response with disappearance of symptoms ("disease stabilization") after 12 courses of induction chemotherapy were randomly assigned to receive recombinant interferon alfa-2b as maintenance therapy (n = 50) or to receive no treatment (n = 51).
As of December 1989, 66 of the 101 patients have relapsed (25 given interferon and 41 not treated). The median duration of response (from the time of randomization) was 26 months in the patients given interferon and 14 months in the untreated patients (P = 0.0002). A total of 37 patients have died (14 given interferon and 23 not treated). The median duration of survival (from randomization) was 52 months in the interferon group and 39 months in the control group (P = 0.0526). Among the patients who had had a substantial objective response to induction chemotherapy, the difference in survival time was statistically significant (P = 0.0352). Interferon had to be stopped because of toxic effects in 3 of 12 patients initially treated with 10 MU (megaunits) per square meter of body-surface area. After the dose was reduced to 3 MU per square meter, the only toxic effect was a mild influenza-like syndrome lasting two to three weeks.
We conclude that maintenance treatment with interferon prolongs response and survival in patients with multiple myeloma who have responded to conventional induction chemotherapy. (N Engl J Med 1990; 322:1430–4.)
Media in This Article
Figure 1
Kaplan–Meier Curves for Response and Survival after Randomization of Patients to the Interferon Group or Control Group.Table 1
Clinical and Laboratory Characteristics of the Study Groups.Article Activity
- Article
CLINICAL trials conducted in large series of patients with different hematologic neoplasms have confirmed the antitumor activity of interferon.1 , 2 So far, the most impressive responses have occurred in patients with hairy-cell or chronic myelogenous leukemia.3 4 5 6
When interferon has been used as a single induction agent in previously treated or untreated patients with multiple myeloma, the overall response rate has been 20 percent.7 8 9 10 11 12 13 14 However, experimental studies of myeloma cells have shown that interferon decreases both in vitro colony formation and the labeling index of myeloma cells (i.e., the percentage of plasma cells labeled after incubation with [3H]thymidine)15 16 17 and can reduce the capacity for self-renewal in myeloma-forming cells.18
These observations and the lack of another treatment capable of prolonging survival19 20 21 led us to evaluate the role of recombinant interferon alfa-2b as maintenance therapy for prolonging response and survival in patients with multiple myeloma who had responded to induction treatment. Patients who responded to conventional induction chemotherapy given in 12 monthly courses were randomly assigned either to receive no treatment or to receive interferon until relapse. Our preliminary results, from the first 60 patients who entered this study, indicated that response was prolonged in the patients treated with interferon.22 We now present data on the survival and response among all 101 patients who underwent randomization.
Methods
Enrollment of Patients
Between April 1, 1985, and May 31, 1988, 101 patients who had multiple myeloma that had responded to treatment with first-line induction chemotherapy were enrolled in the study. These patients were recruited from a group of 202 symptomatic patients with multiple myeloma evaluated at three participating institutions (in Rome, Bari, and Turin) from February 1984 to April 1987, who had been treated with the induction chemotherapeutic regimens described below. Patients were eligible for our study if they had multiple myeloma that had responded to induction chemotherapy, had normal renal and hepatic function, did not have cardiac failure, and gave informed consent before randomization (see below).
Induction therapy consisted of 12 monthly courses of orally administered melphalan plus prednisone for seven days or, after randomization, a combination regimen (VMCP) of vincristine, melphalan, cyclophosphamide, and prednisone, alternating with a regimen (VBAP) of vincristine, carmustine (BCNU), doxorubicin (Adriamycin), and prednisone (VMCP/VBAP). A response to induction chemotherapy was defined as an "objective response" (≥50 percent decrease in the base-line serum concentration of M component, a monoclonal immunoglobulin, and a >90 percent decrease in the base-line value for 24-hour urinary excretion of light-chain proteins) or as "disease stabilization" (a decrease of <50 percent but ≥25 percent in the base-line serum M component level, regardless of the extent of the decrease in the base-line value for the excretion of light-chain proteins, with disappearance of all symptoms present at diagnosis). Of the 202 patients, 79 had refractory disease, as indicated by a lack of response (<25 percent reduction in the M component level) at the end of induction treatment, a relapse, or disease progression during induction therapy; 18 patients were lost to follow-up.
Of the 105 remaining patients, 80 had an objective response and 25 had disease stabilization. Four of these 105 patients chose not to participate in the study. Therefore, a total of 101 patients underwent randomization, which was carried out by a central trial secretariat using coded envelopes.
Study Design
The patients were stratified on the basis of their induction treatment and then randomly assigned to receive interferon as maintenance treatment or to receive no treatment. This was done to minimize any effect of the induction therapy on outcome. The study was not double-blinded, and the patients assigned to the untreated (control) group did not receive placebo.
Interferon alfa-2b (Intron-A, kindly provided by the Essex Italia–Schering Corp.) was administered subcutaneously three times a week in a dose of 10 MU (megaunits) per square meter of body-surface area to the first 12 patients. Because of drug intolerance, the dose was reduced to 3 MU per square meter in all patients. The patients were treated on an outpatient basis until their tolerance of interferon was established; thereafter, they administered the drug themselves.
Concomitant Medication
During the entire period of the study, the use of acetaminophen (paracetamol) to reduce influenza-like symptoms was left to the discretion of the patients. However, the use of steroids was prohibited.
Follow-up
Clinical and routine laboratory evaluations were performed in all patients before randomization and thereafter at regular intervals of 30 to 40 days. Renal and hepatic function was evaluated at the same intervals by measuring the serum concentrations of urea nitrogen, creatinine, bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and amylase. Moreover, at each examination, electrophoresis of serum and 24-hour urine samples was performed to monitor the duration of response. Developments looked for in particular were myelotoxicity, systemic influenza-like symptoms, and organ dysfunction (grade 3 or 4 according to the criteria of the World Health Organization [WHO]).
Cytologic examination of the bone marrow and measurement of the labeling index were performed every six months. A complete radiographic skeletal survey was done every 12 months, or more often if clinically indicated. Every 30 to 40 days, serum samples were obtained from the 50 patients treated with interferon and were assayed for the presence of antibodies to interferon, according to a method previously described.23
Relapse and Retreatment
Relapse was indicated by the presence of one or more of the following findings, which were confirmed at two successive evaluations: an increase of 25 percent in the serum M component level above the nadir, an increase in the urinary M protein level to more than 2.0 g per day, and reappearance of the M component in serum or urine. Relapse was also indicated by an increase in the size or number of lytic bone lesions, without any evidence of an increase in the serum or urinary M component level. All patients were retreated on relapse; 70 percent were treated with conventional induction chemotherapy (melphalan with prednisone or VMCP/VBAP), 18 percent with high doses of cyclophosphamide (1.2 g per square meter on days 1 and 3) and prednisone (80 mg per square meter from day 1 to day 4), 12 percent with intravenous melphalan (25 mg per square meter on day 1) and prednisone (40 mg per square meter from day 1 to day 7). The frequency of the use of these treatments among patients with relapses was similar in the two study groups.
Statistical Analysis
Analysis was based on the patients' status as of December 31, 1989. The durations of actuarial response and survival were plotted as Kaplan–Meier curves.24 Differences between the curves were analyzed with the log-rank test.25 All directional P values were two-tailed. The durations of response and survival were measured from the date of randomization (after the completion of induction chemotherapy). Patients who discontinued the maintenance treatment because of toxicity or incomplete compliance remained in the same group to which they had been assigned. Patients who died without evidence of disease progression were included in the analysis of response, on an intention-to-treat basis.
Results
Characteristics of the Patients
The distributions of clinical and laboratory characteristics in the two study groups were comparable and not significantly different (Table 1Table 1
Clinical and Laboratory Characteristics of the Study Groups.). In particular, no differences were observed in the disease stage, type of paraprotein, labeling index, or beta2-microglobulin level. Among the 45 patients who received melphalan with prednisone, 23 were assigned to the interferon group and 22 to the control group. Of the 56 patients treated with VMCP/VBAP, 27 were assigned to the interferon group and 29 to the control group. The distributions of the type of response to induction treatment were also similar.Follow-up
As of December 31, 1989, the median follow-up period was 46 months (range, 32 to 70) from the beginning of the induction treatment and 33 months (range, 19 to 57) after the completion of the induction treatment. Two patients were lost to follow-up 13 and 28 months after they entered the study; however, their survival status was known at the time of this report. Thirty-seven patients died — 14 (28 percent) of the 50 in the interferon group, and 23 (45 percent) of the 51 in the control group. The patients in the interferon group died of the following causes: 10 died of disease progression, 1 of lung cancer, 1 of cerebral hemorrhage after a hypertensive crisis, 1 of acute myeloid leukemia (after 10 months of interferon treatment), and 1 of myocardial infarction (25 months after entering the study). The causes of death in the control group were disease progression in 21 patients, liver cancer in 1 patient, and colon cancer in 1 patient. Relapse occurred in 66 patients — 25 (50 percent) in the interferon group and 41 (80 percent) in the control group. All patients with relapses were retreated; 48 percent had no sign of progression of disease during or after the second induction (salvage) treatment; however, 47 percent died of progressive disease. The remaining 5 percent of patients survived with progressive disease at the time of this report. Thirteen of the 25 interferon-treated patients (52 percent) and 19 of 41 untreated patients (46 percent) who had relapses did not have disease progression during or after the second induction treatment. Moreover, 21 (42 percent) of the 50 patients in the interferon group and 8 (16 percent) of the 51 in the control group are still alive and responding to the first induction treatment. The outcome in the first 12 patients treated with a higher dose of interferon for a short period did not differ from the outcome in the other patients.
Compliance
Assessment of compliance with treatment was based on interviews with the patients and their relatives. Because of their low degree of compliance, two patients discontinued interferon treatment (one after receiving treatment for 12 months and the other after receiving three doses). Both patients are still alive at the time of this report but had relapses 10 and 21 months, respectively, after discontinuing treatment.
Toxicity
Because of severe toxic reactions, interferon was discontinued in 3 of the 12 patients initially treated with 10 MU of interferon per square meter. These three patients had a severe influenza-like syndrome and hematologic toxic reactions (WHO grade 3 or 4); one also had a high creatinine concentration (554 μmol per liter), and another had high levels of alanine and aspartate aminotransferase. These reactions, with the exception of the influenza-like syndrome, persisted after the dosage of interferon was reduced to 3 MU per square meter. All symptoms completely resolved when therapy with interferon was stopped. After treatment was discontinued, two patients relapsed at 20 and 24 months, respectively. One of these two patients is still alive; the second died of progressive disease eight months after relapse. The third patient who discontinued treatment is still in remission 53 months after entering the study.
The remaining nine patients treated with 10 MU of interferon per square meter had severe constitutional symptoms, which were associated with mild hematologic toxicity in five patients and with hepatic toxicity in two patients.
Because of these toxic effects, the usual dose of interferon was reduced to 3 MU per square meter, given subcutaneously three times a week. After dose reduction, the toxic effects were limited to a mild influenza-like syndrome during the first two or three weeks of treatment; this reaction was controlled with acetaminophen.
Effect of Interferon on Antibody Formation, Tumor Mass, and Relapse
All serum samples were negative for the presence of antibodies to interferon. The level of residual myeloma protein did not decrease in the group of patients given interferon as maintenance therapy. The tumor doubling time in the 25 patients given interferon who relapsed was longer than in the 41 untreated patients who relapsed. As a consequence, the median duration of survival as measured from the time of relapse was 35 months in the interferon group and 16 months in the control group.
Analysis of Response
The overall duration of response in the interferon and control groups is shown in Figure 1Figure 1
Kaplan–Meier Curves for Response and Survival after Randomization of Patients to the Interferon Group or Control Group.. The median duration of response as measured from the time of the completion of induction therapy was 26 months in the interferon group and 14 months in the control group (P = 0.0002; Fig. 1A). The analysis of the duration of response in patients who had an objective response to induction chemotherapy (38 in the interferon group and 39 in the control group) revealed a statistically significant difference in favor of the interferon group (P = 0.0008; Fig. 1C). No difference in response duration was observed between the control group and the interferon group in the number of patients with disease stabilization at the end of induction treatment (P = 0.1130; Fig. 1E).Analysis of Survival
As of December 31, 1989, the overall median duration of survival was 39 months in the control group and 52 months in the interferon group (P = 0.0526; Fig. 1B). Analysis revealed that among the patients who had had an objective response to induction chemotherapy, those in the interferon group had a significantly longer duration of survival (P = 0.0352; Fig. 1D). No significant difference in survival was observed among the patients who had disease stabilization at the end of induction chemotherapy (P = 0.6036; Fig. 1F).
Discussion
To date, maintenance therapy has not been shown to be beneficial in prolonging survival in patients with multiple myeloma.19 20 21 Moreover, the continuation of chemotherapy may lead to refractory anemia or acute leukemia.26 Interferon, in addition to having antiviral activity, has potent immunomodulatory effects, direct antiproliferative action, and the capacity to modulate oncogene expression.27 28 29 Each of these biologic properties has been postulated as a source of the antitumor activity of interferon. However, the extent to which each property contributes to the antitumor activity of the drug is unclear.30
In evaluating interferon as maintenance therapy for multiple myeloma, the present study has clearly demonstrated that among patients who had had an objective response to induction therapy, those treated with interferon had a significantly longer overall response (P = 0.0008) and survived longer (P = 0.0352) than did those who were not treated. The increase in the duration of response and survival observed in the interferon group is evidence that maintenance treatment with interferon is effective in controlling the reappearance of malignant plasma cells.
At the end of induction chemotherapy for multiple myeloma, the plasma cells of patients with a response are in a state ("plateau phase") similar to the G0 (quiescent) phase of the cell cycle.31 Interferon is capable of prolonging all phases of the cell cycle and the overall cell-generation time. Moreover, in some cases, interferon causes an accumulation of cells in the G0 phase, which is accompanied by a decrease in the number of cells making the transition to the G1 phase (the gap before cell synthesis). This decrease in the cell-growth rate with interferon may explain the effectiveness of the drug in controlling the plateau phase in patients with a response, in whom the tumor mass is relatively small.
This hypothesis is supported by the observation that in our study, patients with an objective response to induction chemotherapy had a significantly better response and survived significantly longer if they received maintenance therapy with interferon than if they received no treatment. In contrast, no difference in the duration of response or survival was observed among patients in whom disease stabilization occurred before they received maintenance treatment with interferon or did not receive treatment.
Another possible explanation for the efficacy of interferon is the observation made by Bergsagel et al. that interferons inhibit the capacity of myeloma cells for self-renewal,18 thus prolonging the plateau phase. In our study, the absence of a further reduction in the tumor load and the longer duration of survival in patients given maintenance interferon in whom relapse occurred suggest that interferon had both immunomodulating effects and inhibitory effects on the proliferation of myeloma cells.
Among the risk factors that we investigated in order to find an explanation for the observed results, we found that more patients with Stage I disease and fewer with Stage II disease were assigned to the interferon group. However, this difference was not statistically significant. The two groups were also comparable with respect to immunologic variables. In the evaluation of the possible effect of induction chemotherapy on the study outcome, patients were stratified according to the induction regimen with which they had been treated, before randomization. Corresponding differences in outcome were not observed, and the groups were comparable with respect to the therapeutic response to the induction chemotherapy.
The bone marrow plasma-cell labeling index and the beta2-microglobulin concentration are considered to be powerful prognostic factors: patients with a labeling index of ≥2 percent or a beta2-microglobulin level of ≥509 nmol per liter (or both) have very short survival.32 33 34 We did not prospectively stratify our patients according to these factors. However, the differences in the distribution of patients with a labeling index of ≥2 percent between the two study groups did not appear to influence the results. Patients with beta2-microglobulin levels of ≥509 nmol per liter were equally distributed between the groups.
The first 12 patients assigned to the interferon group received 10 MU of interferon per square meter; 3 of them had a severe influenza-like syndrome and toxic hematologic reactions necessitating the discontinuation of interferon. When the dose was reduced to 3 MU per square meter, tolerance of the drug improved considerably and the treatment continued to have clinical efficacy.
In conclusion, we find that maintenance treatment with interferon significantly prolonged response and survival with an acceptable level of toxicity in patients with multiple myeloma who had responded to standard induction chemotherapy.
Supported by grants from the Italian National Research Council under Special Project Oncology contracts (87.001192.44 and 87.02801.44).
Presented in part in Cancer Treatment Reviews (1988; 15:Suppl A:43–8).
Source Information
From the Section of Hematology, Department of Human Biopathology, University "La Sapienza," Rome (F.M., G.A., S.A., M.T.P., M.L.V.); the Section of Hematology, Department of Experimental Hematology and Oncology, University of Turin (M.B., A.P.); the Institute of Medical Pathology, University of Bari (A.G., V.M.L., F.D.); the Hematology Service, Division of Medicine, S. Giovanni Hospital, Turin (F.M.); and the Division of Hematology, S. Eugenio Hospital, University "Tor Vergata," Rome (M.T.); all in Italy. Address reprint requests to Dr. Avvisati at Hematology, Department of Human Biopathology, University "La Sapienza," Via Benevento 6, 00161 Rome, Italy.
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