Stig Rödjer

Initial versus deferred melphalan‐prednisone therapy for asymptomatic multiple myeloma stage I — A randomized study

Abstract:  From October 1983 until December 1988, 50 patients with asymptomatic multiple myeloma stage I were included in a prospective randomized multi‐centre study comparing melphalan‐prednisone (MP) therapy started at the time of diagnosis with deferred therapy where MP was started at the time of disease progression. Twenty‐five patients were randomized to each group. The median time from diagnosis to start of therapy in the group with deferred therapy was 12 months. The reasons for starting therapy were increasing M‐protein in 8 cases, symptomatic bone disease in 9 and anaemia in 5. In 2 cases, disease progression was complicated by vertebral fractures necessitating radiotherapy. Two patients in the group in which MP was started at the time of diagnosis developed acute leukaemia. No differences in response rate, response duration or survival were observed between the treatment groups. We conclude that in asymptomatic myeloma deferral of chemotherapy is feasible in well‐informed and well‐controlled patients but conveys no advantage in survival. In clinical practice the benefits of treatment deferral are to some extent outweighed by disease progression before start of treatment.

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.

Impact of active and passive exclusions on the results of a clinical trial in multiple myeloma

Summary. During the 3 years 1984–86, 314 cases of multiple myeloma were diagnosed in the Health Care Region of Western Sweden. 180 of these cases were included in a clinical trial; 71 were notified to the trial but excluded; 49 cases were not reported to the trial; 14 were diagnosed post mortem.

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

Initial treatment in multiple myeloma: no advantage of multidrug chemotherapy over melphalan‐prednisone

From October 1983 until December 1986, 164 patients with multiple myeloma stage II–III were included in a prospective randomized multi‐centre study comparing melphalan‐prednisone (MP) with multidrug chemotherapy (MDC). The patients comprised 77% of all newly diagnosed myeloma stage II–III cases reported from 18 hospitals covering the entire Health Care Region of Western Sweden (1.5 million inhabitants). Patients randomized to MP (29 stage II and 55 stage III patients) were given oral melphalan and prednisone every 6 weeks. For patients randomized to MDC, stage II patients (n= 25) were given VMCP every 4 weeks and stage III patients (n= 53) VBAP and VMCP alternately every 4 weeks.

Survival in conventionally treated younger (<60 years) multiple myeloma patients: no improvement during two decades

Abstract:  The patient registers of five prospective population based Nordic studies were reviewed for patients <60 yr. A total of 313 patients with symptomatic multiple myeloma were identified. Thirty‐nine of them were judged retrospectively to have been ineligible for intensive chemotherapy regimens. The remaining 274 patients were considered appropriate as a historical control group for comparison with patients treated with high‐dose chemotherapy and autologous stem cell support. Of these, 32 had been diagnosed during the period 1970–83, 101 during the period 1984–89 and 141 during the period 1990–92. The median age was 54 yr. Six percent were Durie/Salmon stage I, 38% stage II and 56% stage III. Melphalan‐prednisone was used for initial therapy in 87%. Median survival for all patients with symptomatic myeloma was found to be 41 months, and for those selected for the control group 44 months, with no noted differences between the aforementioned diagnostic periods. We conclude that the expected median survival is 44 months for myeloma patients <60 yr who may be considered for high‐dose therapy protocols. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high‐dose chemotherapy with stem cell rescue, have not changed the overall prognosis in multiple myeloma.

Empiric Monotherapy for Febrile Neutropenia - a Randomized Study Comparing Meropenem with Ceftazidime

In this Swedish multicentre study we compared the efficacy of meropenem with ceftazidime for treatment of febrile neutropenia. 192 patients were randomized and the number of evaluable patients was 92 in the meropenem group and 95 in the ceftazidime group. 40 (43%) patients in the meropenem arm and 49 (52%) in the ceftazidime arm had acute leukaemia. 56 (61%) and 52 (55%) patients respectively had a neutrophil count of < 0.1 x 10(9)/l at randomization and the median duration of neutropenia was 6.5 and 8 d, respectively. Thirty-one (34%) and 28 (29%) patients had a microbiologically defined infection, 14 (15%) and 17 (18%) a clinically defined infection and the remaining 47 (51%) and 50 (53%) had unexplained fever. After 72 h of treatment, 46 (50%) patients in the meropenem arm and 53 (56%) patients in the ceftazidime arm were alive on unmodified monotherapy. 42 (46%) and 47 (49%) of these completed the study on monotherapy alone. Only 2 patients (2%) in each arm had to stop treatment owing to allergic reactions. None of the observed differences were statistically significant and we therefore conclude that meropenem was an effective and safe alternative to ceftazidime for empiric treatment of fever during neutropenia.

Granulocyte‐macrophage colony‐stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial

A total of 110 patients, aged 64 years or over, with de novo acute myeloid leukaemia (AML) and white blood cell counts <50 × 109/l were treated with 3 d of cytarabine 1 g/m2 twice daily, mitoxantrone 12 mg/m2 and etoposide 200 mg/m2, randomized with or without the addition of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) 200 μg/m2. The primary aim was to evaluate the effect of GM‐CSF on the remission rate. Secondary aims included comparison of duration of remission, survival and infectious complications and the impact of maintenance therapy with thioguanine. Complete remission (CR) was achieved by 64% of patients without GM‐CSF, and by 65% of patients who received GM‐CSF, the median remission duration was 13 vs. 6 months, the median overall survival (OS) was 14 vs. 9 months, the mean time to neutrophil recovery was 25 vs. 17 d (P = 0·03) and the number of positive blood cultures was 46 vs. 39 (P = 0·05) respectively. The impact of thioguanine remains unanswered since only 30 patients remained in CR after consolidation therapy. We conclude that induction therapy is feasible with acceptable toxicity in elderly patients with AML, albeit with a high relapse rate and short OS. GM‐CSF prior to, and in combination with, induction treatment reduced the time to neutrophil recovery and the number of neutropenic septicaemia cases but did not improve the OS of AML in the elderly.

Hepcidin, interleukin-6 and hematological iron markers in males before and after heart surgery.

Anemia of inflammation in patients with acute or chronic acute-phase activation is a common clinical problem. Hepcidin is a peptide shown to be the principal regulator of the absorption and systemic distribution of iron. Main inducers of hepcidin are iron overload, hypoxia and inflammation, where the latter has been linked to hepcidin via increased interleukin-6 (IL-6). This article addresses the impact and time course of postoperative acute-phase reaction in humans following heart surgery on prohepcidin, hepcidin, hematological markers and IL-6 concentrations. Serum concentrations of prohepcidin, hepcidin, IL-6 and hematological iron parameters were studied in five male patients without infection before and after heart surgery. This study, which is the first to report the impact on serum hepcidin and serum prohepcidin concentrations in patients following surgery, clearly demonstrates the induction of hypoferremia due to the postoperative acute-phase reaction. Significant changes were seen for serum iron concentration, transferrin saturation, total iron binding capacity and hemoglobin concentration. A significant increase in ferritin concentration was seen 96-144 h postoperatively. Additionally, there were significant alterations in both serum hepcidin after 96-144 h and serum prohepcidin after 48 h compared with preoperative values. Serum prohepcidin decreased, whereas serum hepcidin increased. In conclusion, changes in serum prohepcidin were followed by an increase in serum hepcidin. This speaks in favor of a chain of action where proteolytic trimming of serum prohepcidin results in increased serum hepcidin. However, hypoferremia appeared prior to the changes in serum prohepcidin and serum hepcidin.

Cytogenetic Studies in Patients with Mastocytosis

Chromosomal aberrations in hematopoietic cells are common in malignant hematological disorders and have also been reported in some patients with mastocytosis. In this study, 34 patients with either urticaria pigmentosa or systemic mastocytosis were investigated by cytogenetic analysis of bone marrow cells. A follow-up investigation was performed in 22 patients. Clones with chromosome abnormalities were found in 32% of the patients at the first examination and in 27% at the second examination; in total, 41% of the patients had an abnormal clone in at least one examination. No clinical correlation was found with regard to cytogenetic results, with the exception of four patients who had an associated hematological disease and poor prognosis. In the second examination, only 6 patients had an unchanged chromosome pattern, and 4 of the patients with an initial normal pattern had appearance of abnormal clones; however, in 7 patients, the initial abnormal cells disappeared. The abnormalities were, among others, deletions of chromosomes 5, 7, 11, and 20. The proportion of cells with structural or numerical chromosome changes was higher in comparison with reported control groups. The frequency and type of chromosome abnormalities in bone marrow cells from patients with mastocytosis was about the same as observed in other chronic myeloproliferative disorders and myelodysplastic syndromes, diseases which also developed in 4 of our patients. An association between malignant hematological disorders and mastocytosis have been suggested by us and others. The chromosome abnormalities maybe reflect a genetic instability of the hematopoietic cells in mastocytosis.