Göran Zador

Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study

This clinical trial was designed to investigate if maintenance therapy with alfa‐interferon could prolong the plateau phase in patients with multiple myeloma. In addition, the tolerability of interferon treatment and its effect on survival were evaluated.

Interferon-α 2b Added to Melphalan-Prednisone for Initial and Maintenance Therapy in Multiple Myeloma: A Randomized, Controlled Trial

Since alkylating agent therapy was introduced in the 1960s, only minor advances have been made in the management of multiple myeloma. Intermittent melphalan-prednisone therapy is still recommended at many centers for the initial treatment of most patients with newly diagnosed myeloma [1-4]. In 1979, interferon- was introduced as an agent with antitumor activity in patients with myeloma [5]. When used as a single agent for initial therapy, interferon has shown efficacy [6, 7], but this efficacy is inferior to that of alkylating agents [8, 9]. Nonetheless, when used in combination with chemotherapy, interferon may have a presumably synergistic anti-tumor effect [10, 11]. This possibility has provided the incentive for several trials, some of which are still in progress. Different doses of interferon and different dosing schedules have been tried: Low doses of interferon have been given continuously or intermittently in some trials, and high doses have been given intermittently in others. The trials reported on to date, however, show divergent results [12-14]. When given as maintenance therapy in patients responding to standard initial therapy, interferon has been found to prolong response or plateau phase duration but not survival [15, 16]. However, two recently published trials [17, 18] were unable to confirm these results. Thus, the role of interferon, both for initial treatment and in combination with chemotherapy, is still controversial [19]. Our purpose was to evaluate low-dose interferon, for initial and maintenance therapy, given in addition to standard melphalan-prednisone therapy in patients with multiple myeloma. Our primary aim was to study the effects of this combined therapy on survival. Secondary objectives were to compare patients receiving melphalan-prednisone alone with patients receiving melphalan-prednisone and interferon in terms of response rate, time to response, response duration, time to definitive failure of initial therapy, and side effects. A study of quality of life and health economics was done in conjunction with the main trial, and the results of that study will be reported separately. Methods Participating Centers One hundred seven hospitals in Sweden, Norway, Denmark, Finland, and Iceland, representing a combined population of 12 million persons, cooperated in this study. Fifteen were university hospitals, and 92 were county hospitals. The participating centers were asked to report all newly diagnosed cases of myeloma. Our study was approved by the ethics committees and health authorities of the Nordic countries. Diagnostic Criteria The following criteria were established: A) serum monoclonal immunoglobulin [M protein] concentration of IgG greater than 30 g/L, M protein concentration of IgA greater than 20 g/L, the presence of M protein of IgD or IgE regardless of concentration, or Bence Jones proteinuria greater than 1 g/24 h; B) M protein in serum or urine at a lower concentration than that described in criterion A; C) at least 10% plasma cells in a bone marrow aspirate or biopsy-verified plasmacytoma of bone or in soft tissue; and D) osteolytic bone lesions. A diagnosis of multiple myeloma was accepted if criteria A + C, A + D, or B + C + D were fulfilled. Eligibility Criteria Only patients with symptomatic disease were accepted for randomization. Patients were considered ineligible if they were elderly (usually more than 80 years of age), if they were young (usually less than 55 years of age) and were being considered for intensive chemotherapy protocols, if they had psychiatric disease, if they had other active malignant disease, if they had severe heart disease or other severe coincident illness, or if they were terminally ill. Statistical Considerations Assuming a median survival in the control arm of 30 months, a prolongation of median survival by 12 months in the experimental arm, a follow-up period of 2 years after the last included patient, and a survival analysis with a statistical power of 80% and a significance level of 5%, we estimated that 580 patients would be needed for the trial. Given an expected accrual rate of 50% of all patients with newly diagnosed myeloma in a population of 10 million persons in which the crude incidence of myeloma is 6.3 per 100 000 inhabitants per year [20], we anticipated entering the 580 patients within 24 months. This goal was nearly reached, but the inclusion period had to be prolonged by 5 months before the accrual was completed. Patients From 1 June 1990 to 3 November 1992, a total of 1083 patients with myeloma were reported. This corresponds to 67% of the estimated total number of patients with newly diagnosed myeloma [20] during the inclusion period. The reasons for non-entry into the trial are shown in Table 1. Of 1083 reported patients, 592 (55%) were randomly assigned to receive melphalan-prednisone or melphalan-prednisone and interferon. All patients were given both verbal and written information and were asked to give verbal consent before being entered into the study. All patients were followed until death or until November 1994. Table 1. Patient Characteristics Study Design Randomization The study was stratified according to coordinating center. Patients were randomly assigned to treatment in blocks of four. This was done at the coordinating center by means of sealed envelopes at a telephone call from the responsible clinician. Treatment Protocol Patients randomly assigned to receive melphalan-prednisone were given oral melphalan, 0.25 mg/kg of body weight, and prednisone, 100 mg/d, on days 1 to 4. This course was repeated every 6 weeks. If tolerated, the three initial courses could be given at 4-week intervals; this was optional. We checked the degree of myelosuppression by measuring neutrophil and platelet counts 2 to 3 weeks after the first courses were given and before each additional course; standard guidelines were provided for escalation and reduction of melphalan dose to guarantee that all patients received adequate doses without undue hematologic toxicity. Patients randomly assigned to receive melphalan-prednisone and interferon were given the same doses of melphalan and prednisone that were given to those patients receiving melphalan-prednisone alone. In addition, they were given interferon- 2b (Introna, Schering-Plough, Stockholm, Sweden) from the start of therapy at a dose of 5 MU, subcutaneously, three times weekly. Melphalan doses were adjusted according to the same rules in both treatment groups. To avoid undue reductions of melphalan dose caused by combined melphalan-interferon bone marrow suppression, interferon therapy was temporarily suspended if the interval between two courses of melphalan-prednisone had to be prolonged by more than 2 weeks or if the melphalan dose had to be reduced to less than 50% of the initial dose. For patients with other symptoms that suggested substantial interferon toxicity, interferon therapy was reduced or interrupted and later, if feasible, reinstituted at a dose of 3 or 1 MU, three times weekly. Duration of Initial Therapy In both treatment groups, at least eight courses of melphalan-prednisone were given if progression was not seen. In patients who achieved at least a minor response and a plateau phase, melphalan-prednisone therapy was discontinued and was reinstituted after relapse. Interferon therapy was continued throughout the plateau phase and relapse, until definitive failure of melphalan-prednisone therapy occurred. For patients who did not respond to melphalan-prednisone therapy, the responsible physician was free to choose any therapy, but combination chemotherapy, including that with doxorubicin or mitoxantrone, was generally recommended as second-line therapy. All patients, including those who stopped receiving interferon therapy because of toxicity, were considered to be on study until the time of definitive melphalan-prednisone failure. Follow-up Evaluation All patients were seen at intervals of no more than 6 weeks for clinical and laboratory evaluation. Partial response was considered to have occurred if the initial serum M protein concentration was reduced by at least 50%, if the Bence Jones protein level was reduced to less than 0.2 g/24 h, and if the patients clinical status was improved without persistent anemia (hemoglobin concentration more than equals to 90 g/L without transfusions), hypercalcemia, or signs of progressive renal or skeletal disease. Complete response was considered to have occurred in patients who fulfilled the criteria for partial response if the M protein in serum and urine was no longer detectable with agarose gel electrophoresis and if the proportion of plasma cells in a bone marrow aspirate was less than 5%. Minor response was considered to have occurred if the initial serum M protein concentration was reduced by 25% to 50% and the Bence Jones protein level was reduced by at least 50% but to no less than 0.2 g/24 h in patients fulfilling the criteria for partial response. Failure was defined as a confirmed increase of the M protein concentration in serum or urine of more than 25%, persistent hypercalcemia or progression of renal failure, skeletal lesions, or soft-tissue plasmacytomas. The term definitive failure on melphalan-prednisone therapy (or melphalan-prednisone and interferon therapy) included patients with primary failure and patients with secondary failure after reinstitution of melphalan-prednisone therapy. Time to response was calculated from the start of treatment until the first time the patient fulfilled the criteria for response. A plateau phase was considered to be present in responding patients if three consecutive measurements of the M protein concentration, 6 weeks apart, varied by less than 20%. Time to plateau phase was calculated from the start of therapy until the time of the first of the three M protein concentration measurements done to identify plateau phase. Relapse was defined as a confirmed increase

Recombinant interferon-alpha-2b treatment of hairy-cell leukaemia: experience with a low-dose schedule.

50 patients with hairy cell leukaemia (HCL) were treated with recombinant interferon (IFN) alpha‐2b 2.0 × 106 IU/m2 subcutaneously three times weekly to evaluate the efficacy of low‐dose IFN therapy in inducing and maintaining remission of the disease. At the time of this report 48 patients, of whom 22 were splenectomized, had been treated for at least 3 months and were considered evaluable for response. The median observation time on IFN‐alpha‐2b was 11 months (range 3 to 20). 4 cases with atypical disease (spongy lymphoid myelofibrosis) were also included. All patients responded to IFN. After 3 months 11/48 patients (23%) had achieved a partial remission (PR) with normalization of peripheral blood values. After 6 months 27/43 patients (63%) had achieved a favourable response; complete remission (CR) was recorded in 4 and PR in 23 patients. The proportion of patients with favourable responses (CR + PR) increased with the duration of therapy and after 12 months of therapy 23/28 (82 %) patients showed CR or PR, 9 patients (32 %) being in CR. Splenectomized patients disclosed a trend towards a more rapid response. It is concluded that IFN‐alpha‐2b is a highly effective first‐line therapy for HCL

Interferon therapy during the plateau phase of multiple myeloma: An update of the Swedish study

A multicentre clinical trial was carried out in order to evaluate the effect of interferon (IFN) in patients with multiple myeloma. Patients (n = 120) who had shown response to conventional intermittent melphalan-prednisone induction therapy, and achieved a plateau phase, were randomized at that point to receive either interferon alfa-2b in a dose of 5 million units (MU) three times per week or no therapy. This report presents the results of an interim analysis, performed when the patients had been followed for a median of 20 months. The duration of the plateau phase was significantly longer in the IFN arm (59 weeks), compared to the no therapy arm (26 weeks). A total of 34 deaths have occurred, 13 in the IFN arm and 21 in the no therapy arm. In spite of the high median age of the patients studied (70 years), most patients were able to tolerate a full or only slightly reduced IFN dose.

Serum Levels of FSH, LH, Estradiol-17β and Progesterone following the Administration of a Combined Oral Contraceptive Containing 20 μg Ethinylestradiol

An oral contraceptive containing 20 µg of ethinylestradiol and 250 µg of levonorgestrel was given to 5 normally menstruating women for two consecutive cycles. Peripheral serum levels of FSH,

Demonstrated Benefit of Continuous Interferon-Alpha-2b Therapy in Hairy Cell Leukemia. A Two-Year Follow-Up

Interferon-alpha-2b (IFN) was given to a series of 50 patients with hairy cell leukemia (HCL). The IFN dose for both induction and maintenance was 2.0 × 10(6) IU/m(2) s.c. three times weekly. At 24 months 38 patients remained in the study. The proportion of complete responders (CR) increased during the follow-up, and had at 24 months reached 58%, while 28% at the same time had a partial (PR) and 14% a minor response (MR). During the two years of continuous IFN treatment none of the 38 patients showed any signs of relapse. The response rate was similar between splenectomized (n = 15) and non-splenectomized (n = 23) patients, but the rise in platelets was much steeper and reached a significantly higher plateau in patients, who previously had undergone splenectomy. The IFN therapy was generally well tolerated, but when evaluated at 24 months at least some (mostly mild) toxicity was noted in 76% of the patients. None of the patients developed neutralizing antibodies to IFN.

Evaluation of the Possible Interaction of the Antifungal Triazole SCH 39304 with Oral Contraceptives in Normal Healthy Women

The possible interaction of the newly developed triazole antifungal SCH 39304 with low-dose combined oral contraceptives (OCs) was studied in 15 healthy women. Serum levels of ovarian and adrenocortical steroids and sex hormone-binding globulin (SHBG) were analyzed in samples collected during the OC cycles immediately before, during and after the administration of SCH 39304. The drug was given as a single 400-mg oral dose on day 7 in the second cycle. SCH 39304 did not interfere with the ovulatory inhibitory action of low-dose combined OCs as judged from serum progesterone values. Administration of SCH 39304 caused minor decreases in serum SHBG, cortisol and dehydroepiandrosterone sulfate. The mechanism(s) behind these minor changes is not known.

HCG, Progesterone and 17-Beta-Estradiol Levels during Extra-Amniotically Induced Early Abortion by a New Prostaglandin Derivative (Sulprostone)

A new prostaglandin E2 derivative (Sulprostone) was given extra-amniotically to 17 healthy women, who were 7-8 weeks pregnant, in order to assess the plasma profile of HCG, 17 beta-estradiol (E2), and progesterone and to evaluate the effectiveness and overall acceptability of the method in relation to different dose levels. On the lowest dose level (5 micrograms) only 3 of 7 patients aborted within a 3-to 6-day period. At higher dose levels (10 and 15 micrograms, respectively) 9 out of 10 women exhibited clinical evidence of an abortion. In the group who aborted, E2, progesterone, and HCG decreased continuously, whereas in the nonabortion group decreased levels were found 3 and 6 h after administration of the drug, but already after 24 h the values had again increased. Practically all treated women experienced lower abdominal discomfort, 7 (41%) reported the pains being severe. Vomiting and/or diarrhea occurred in 4 patients (24%). Similarly to other hitherto tested prostaglandins in humans, this new analogue exhibits its effect primarily through direct stimulatory effect on the uterine smooth muscle, resulting in subsequent decline in the concentrations of HCG, E2, and progesterone. In the group of successful inductions the decrease of the HCG concentration was close the half-time of HCG, indicating a permanent damage to the placenta. Despite the high success rate at a dose of 10 micrograms or more, the side effects, mainly abdominal cramps. were too severe to make this method feasible for the induction of early abortion when comparing to the available routine procedure of rapid vacuum curettage used on an outpatients basis.