Martin Hjorth

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life

Summary. We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S‐Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony‐stimulating factor (G‐CSF) + Epo. S‐Epo ≤ 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S‐Epo > 500 U/l and ≥ 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G‐CSF + Epo. The overall response rate was 42% with 28·3% achieving a complete and 13·2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0·001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0·01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48–74%) to treatment with G‐CSF + Epo. The majority of these patients have shown complete and durable responses.

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.

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

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.

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.

Health‐related quality of life assessed before and during chemotherapy predicts for survival in multiple myeloma

Measurement of health‐related quality of life was integrated into a randomized trial (NMSG 4/90) comparing melphalan/prednisone to melphalan/prednisone + interferon α‐2b in newly diagnosed multiple myeloma. One of the aims of the study was to assess the prognostic significance of quality‐of‐life scores, using the EORTC QLQ‐C30 questionnaire. Univariate analysis showed a highly significant association with survival from the start of therapy for physical functioning as well as role and cognitive functioning, global quality of life, fatigue and pain. In multivariate analysis, physical functioning and W.H.O. performance status were independent prognostic factors (P values=0.001 for both) when analysed in a Cox regression model with the somatic variables β‐2 microglobulin, skeletal disease and age. The best prediction for survival from the start of therapy was obtained by combining the β‐2 microglobulin and physical functioning scores in a variable consisting of three risk factor levels with an estimated median survival of 17, 29 and 49 months, respectively. At a 12 months landmark analysis, the relative risk for patients with physical functioning score 0–20 v 80–100 was 5.63 (99% CI 2.76–11.49), whereas the relative risk for patients without an objective response to chemotherapy compared to those with at least a minor response was 2.32 (99% CI 1.44–3.74). Quality‐of‐life assessment may be an independent and valuable addition to the known prognostic factors in multiple myeloma.

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.

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.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

BACKGROUND Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. METHODS This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883. FINDINGS From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. INTERPRETATION Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma. FUNDING Nordic Cancer Union and Novartis Healthcare.

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.