Erik Hippe

Renal failure in multiple myeloma : reversibility and impact on the prognosis

Abstract: The purpose of the present study was to analyse the importance and prognostic value of renal failure in multiple myeloma patients. The frequency and reversibility of renal failure in 775 multiple myeloma patients diagnosed between 1984–86 and 1990–92 in the Nordic countries were studied. Renal failure, defined as plasma creatinine >130μmol/l, was observed in 29% of the cases at the time of diagnosis. During the first year after diagnosis 58% achieved normalisation of p‐creatinine, and this was achieved mainly during the first 3 months. Reversibility of renal failure was more frequently observed in patients with moderate renal failure, hypercalcaemia and low Bence‐Jones protein excretion. In a multivariate analysis renal failure, high age, stage III disease and hypercalcaemia were independent prognostic factors for survival. Patients who needed dialysis had a poor prognosis, with a median survival of 3.5 months. A 12‐months landmark analysis showed that reversibility of renal failure was a more important prognostic factor than response to chemotherapy. It is concluded that renal failure in multiple myeloma is reversible in about half the cases, and reversibility of renal failure improves long‐term survival.

Autoantibodies to cytokines--friends or foes?

Cytokines form a network of communication signals between cells of the immune system, and between the immune system and other organs. They interact with structurally complex and often dynamically expressed target cell receptors. The recent demonstration of autoantibodies to cytokines, even in sera of normal individuals, suggests further complexities in the way that nature regulates cytokine functions. Based mainly on evidence obtained by investigating autoantibodies to interleukin 1 alpha (IL-1 alpha), Klaus Bendtzen and colleagues discuss the possibility that naturally occurring antibodies may function as specific physiological carriers and regulators of cytokines.

Renal function in newly diagnosed multiple myeloma — A demographic study of 1353 patients

This study describes the occurrence of renal failure among 1353 newly diagnosed cases of multiple myeloma. Renal function was evaluated by serum creatinine concentration in 1353 cases, 31% of whom had renal failure at the time of diagnosis. In 1206 cases an estimation of creatinine clearance was made. When renal failure was defined by using creatinine clearance estimation, 49% had renal failure at the time of diagnosis. Renal failure was present in 24% of patients with an M component of IgG‐, 31% of IgA‐ and 100% of IgD‐type. 52% of patients with light chain disease had renal failure. The frequency of renal failure was similar in lambda‐and kappa‐light chain disease. Patients with a high excretion of Bence Jones protein in the urine (> 10 g/24 h) had renal failure significantly more often than patients with lower excretion. Renal failure was related to advanced disease; 41% of patients with stage III (Durie‐Salmon) disease had renal failure. Renal failure was found in 45% of patients with hypercalcaemia. When estimated creatinine clearance was used as a predictor of renal function, the same trends were found as mentioned above. In addition, the proportion of patients with renal failure was found to increase with advancing age.

Measurement of health-related quality of life in multiple myeloma

When a randomized trial (NMSG 4/90) comparing treatment with melphalan/prednisone to melphalan/prednisone + interferon α‐2b in newly diagnosed multiple myeloma was inititated in 1990, a quality‐of‐life assessment was integrated into the study. We used the questionnaire (QLQ‐C30) developed by the European Organization of Research and Treatment of Cancer (EORTC) Study Group on Quality of Life. The QLQ‐C30 incorporates five functional scales, three symptom scales, a global health and quality‐of‐life scale and some single symptom measures. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 524 (90.2%) of 581 patients enrolled in the NMSG 4/90 completed the first questionnaire, and 484 (83.3%) completed all questionnaires given to them. All but one of the scales met the minimum criteria of reliability (Cronbach’s alpha ≥0.70). Validity was shown by (1) the ability of the scales to discriminate clearly between patients differing in clinical status as defined by pre‐treatment W.H.O. performance index and Durie & Salmon stage, and (2) the sensitivity to changes in objective disease status (response and relapse). This is the first report of the measurement of health‐related quality of life in a prospective clinical trial in multiple myeloma. The results demonstrate that the QLQ‐C30 is a reliable and valid instrument for the measurement of quality of life in these patients. The data will be used for a cost–utility analysis of the results of the NMSG 4/90 trial.

Health-related quality of life in multiple myeloma patients receiving high-dose chemotherapy with autologous blood stem-cell support

In a population-based study, the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age (risk ratio: 1.62; confidence interval [CI] 1.22–2.15; p=0.001). A study of health-related quality of life (HRQoL) was integrated in the trial, using the EORTC QLQ-C30 questionnaire. Of the 274 patients receiving intensive therapy 221 (81%) were compared to 113 (94%) of 120 patients receiving conventional melphalan-prednisone treatment.Prior to treatment, there were no statistically significant differences in any HRQoL score between the two groups. One month after the start of induction chemotherapy, the patients on intensive treatment had more sleep disturbance than the control patients. At 6 mo, corresponding to a mean of 52 d after high-dose melphalan, the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss. At 12 and 24 mo, the HRQoL was similar to that of the control patients. At 36 mo, there was a trend toward less fatigue, pain, nausea, and appetite loss in the intensive-treatment group. Thus, the 18 mo of prolonged survival seem to be associated with a good health-related quality of life. Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase, this treatment modality must be regarded as an important step forward in the care of multiple myeloma.

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

Development of an EORTC questionnaire module to be used in health‐related quality‐of‐life assessment for patients with multiple myeloma

A multiple myeloma‐specific quality‐of‐life questionnaire module has been designed in collaboration with the EORTC Quality‐of‐Life Study Group to be used in clinical trials with the EORTC QLQ‐C30, a general cancer questionnaire. Strict methodology was employed to ensure thorough and appropriate development of the module. An extensive literature review was performed to identify health‐related quality‐of‐life issues relevant to patients with multiple myeloma. Semi‐structured interviews were then carried out in several European countries with health‐care providers experienced in the treatment of patients with multiple myeloma, and with a group of patients with multiple myeloma, to identify the issues which were most important to patients. A questionnaire was devised from the list of issues, using a 1‐week time‐frame and response categories consistent with the EORTC QLQ‐C30. The provisional questionnaire and the EORTC QLQ‐C30 were administered to patients with multiple myeloma in each participating country with further semi‐structured interviews to refine the content and design of the questionnaire. A review of the results obtained in each stage of development resulted in a 24‐item myeloma‐specific module, the EORTC QLQ‐MY24, which assesses disease‐specific symptoms and their impact on everyday life, treatment side‐effects, social support, and future perspective. The module is currently undergoing further international field‐testing to assess its psychometric properties.

Serum erythropoietin (EPO) levels correlate with survival and independently predict response to EPO treatment in patients with myelodysplastic syndromes

Abstract: Treatment with recombinant erythropoietin (EPO) can alleviate anaemia in patients with myelodysplastic syndromes (MDS). The present study, based on a long‐term follow‐up of 68 MDS patients (26RA, 16 RAS, 26 RAEB) treated with EPO alone, pinpoints pre‐treatment variables associated with response induction, response duration and overall survival. Response, defined as an increase in haemoglobin >15 g L−1 or eliminated erythrocyte transfusion requirements, was observed in 22 of 66 (33%) evaluable patients. The median response duration was 15 (range 3–64 +) months. Using univariate logistic regression models, responders displayed significantly lower baseline serum EPO levels (S‐EPO), more often normal bone marrow blast cell content (RA/RAS vs. RAEB), normal cytogenetics and no need for erythrocyte transfusion. In a multiple logistic regression model, S‐EPO (P = 0.009), marrow blast content (P = 0.031) and erythrocyte transfusion need (P = 0.024) remained associated with response induction. The probability of response for a patient with S‐EPO >50 U L−1, RA/RAS and no transfusion need was 0.79 (0.53–0.93, 95% CI). The median overall survival time from start of EPO treatment was 26 months, significantly longer for responders than for non‐responders (49 vs. 18 months, P = 0.018). Survival was also predicted by baseline S‐EPO; patients with S‐EPO > 50 U L−1 (n = 50) had a median survival of 17 months, as compared to 65 months for those with S‐EPO >50 U L−1 (n = 14, P = 0.024). The international prognostic scoring system (IPSS) for MDS predicted survival (P = 0.003) and progression to acute leukemia (P < 0.001) but not response to EPO treatment. Furthermore, in a logistic regression model with S‐EPO and IPSS, S‐EPO (but not IPSS) was again a significant predictor for response (P = 0.007). Our data facilitate the optimal selection of MDS patients suitable for EPO treatment and pinpoint S‐EPO as a powerful predictor of response and overall survival in MDS.

Diurnal variations of serum erythropoietin in trained and untrained subjects

The diurnal variations of serum-erythropoietin concentration ([s-EPO]) were investigated in six physically trained (T) and eight untrained (UT) men. The T subjects had a higher mean maximal oxygen uptake than UT subjects [75.7 (SEM 1.6) ml · min−1 · kg−1 versus 48.3 (SEM 1.4) ml · min−1 · kg−1, P < 0.0001] and a lower mean body mass index [BMI, 21.7 (SEM 0.7) kg · m−2 versus 24.4 (SEM 0.6) kg · m−2, P=0.02]. Each subject was followed individually for 24 h as they performed their normal daily activities. Venous blood samples were collected from awakening (0 min) until the end of the 24-h period (1440 min). Both T and UT had a nadir of [s-EPO] 120 min after awakening [10.0 (SEM 0.3) U · 1−1 versus 11.5 (SEM 2.1) U · 1−1, P > 0.05]. The UT and T increased their [s-EPO] to peak values at 960 min and 960–1200 min, respectively (ANOVA P=0.03) after awakening [UT: 18.4 (SEM 2.8) U · l−1; T: 16.2 (SEM 2.5) U · l−1, P > 0.05]. The mean 24-h [s-EPO] were 14.5 (SEM 1.0) U · l−1 and 14.9 (SEM 0.9) U · l−1 in T and UT, respectively (P > 0.05). The individual mean 24-h [s-EPO] were not correlated to body mass, BMI or maximal oxygen uptaken. Significant diurnal variations in [s-EPO] occurred in these healthy subjects irrespective of their levels of physical activity.

A sequential erythropoietin and GM-CSF schedule offers clinical benefits in the treatment of anaemia in myelodysplastic syndromes

In order to reduce anaemia in patients with myelodysplastic syndromes (MDS) a stepwise treatment protocol including erythropoietin (EP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was designed. Thirty-seven MDS patients (stages I-III) with symptomatic anaemia were first given EPO 10,000 U s.c. 3 times weekly for 6 weeks. Those not responding, i.e. increased their haemoglobin levels > 15 g/l, proceeded into the second phase of the study where GM-CSF (200 micrograms/d. s.c. on weeks 1-6) was combined with EPO (10,000 U s.c. 3 times weekly on weeks 5-14). Following the initial EPO treatment phase, 14 of the 37 patients (38%) responded with increased haemoglobin levels. Responders were significantly different from non-responders in that their pre-treatment values of s-EPO, s-LDH and bone marrow blast cell counts were lower, their baseline haemoglobin levels higher and their transfusion dependency less pronounced. Eighteen of the 23 non-responders proceeded into the second phase, 13 of those were evaluable having completed the entire schedule. Three of the 13 initially EPO resistant patients (23%) responded to the GM-CSF/EPO combination with increased haemoglobin levels, suggesting a positive synergy between the two cytokines. Thus, the overall response rate to the present protocol was 46% (17 of 37 cases), but only a limited subset of the patients did clearly benefit from the combined GM-CSF/EPO administration. Therefore, we believe this step-wise approach to multiple growth factor treatment in MDS, starting with EPO alone and reserving the combination for refractory cases, has considerable advantages, taking into account both medical and socio-economical aspects.