Henrik Gregersen

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the ≥ VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M‐proteins and the management of monoclonal gammopathy of undetermined significance (MGUS)

Avon Haematology Unit, Bristol Haematology and Oncology Centre, Bristol, Department of Haematology, St Helier Hospital, Carshalton, Surrey, UK, Department of Haematology, Sahlgrenska University Hospital, Gothenburg, Sweden, Department of Medicine, Malmo University Hospital, Malmo, Sweden, Division of Immunity and Infection, University of Birmingham, Birmingham, Department of Clinical Biochemistry, Frenchay Hospital, Bristol, Department Haematology, University College, London, Glasgow Western Infirmary, Glasgow, UK, Department of Haematology, NTNU/St Olavs Hospital, Trondheim, Department of Haematology, Ulleval University Hospital, Oslo, Norway, Department of Haematology Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark, and Myeloma UK.

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.

Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance

To evaluate the mortality and causes of death in monoclonal gammopathy of undetermined significance (MGUS), we identified 1324 cases of MGUS in the period 1978–93 in North Jutland County, Denmark. Data on mortality were obtained by record linkage to the Danish Death Registry. There were 868 deaths in the MGUS cohort during 7785 years of follow‐up vs. 409·6 expected, giving a standardized mortality ratio (SMR) of 2·1 (95% confidence interval 2·0–2·3). Malignant transformation was the cause of death in 97 patients vs. 4·9 expected, yielding a SMR of 20·0 (16·2–24·4), which explained about 20% of the excess mortality in the cohort. The mortality was increased for several other malignant and non‐malignant causes of death during the first 4 years of follow‐up. For late follow‐up, 5–18 years after detection of the M‐component, the overall SMR was 1·7 (1·5–1·9), and malignant transformation was the only cause of death with a substantial increase of SMR. Although malignant transformation is an important cause of death in MGUS patients, it did not entirely explain the increased mortality. MGUS patients often suffer from coexisting clinical conditions that increase the mortality, especially during the first years after detection of the M‐component.

Multimodal sensory testing of the rectum and rectosigmoid: development and reproducibility of a new method

Abstract  Evaluation of rectal and rectosigmoid sensation is important in basic, clinical and pharmacological studies. New methods to evoke and assess multimodal (electrical, thermal and mechanical) experimental pain of the upper gut activate distinct pathways and mimics clinical pain. The aims of the current study were to characterize the sensory response and reproducibility to multimodal stimulation of rectum and the rectosigmoid. A multimodal rectal probe was developed. Mucosal electrostimulation was delivered at the recto‐sigmoid junction. In Rectum, impedance planimetry was used for measurement of cross‐sectional area (CSA) during distension. Circulation of water within the bag at either 4 or 60 °C was applied for thermal stimulation. The method was tested in 12 healthy volunteers (six men mean age 32 years) on two subsequent days. Mechanical and sensory responses and referred pain areas were assessed. Stimulation with electrical, thermal and mechanical modalities resulted in different sensory perceptions. The relationship between stimulus intensity and sensory response was linear for all modalities. Sensory response to different modalities did not differ between investigation days (all P‐values > 0.1). Approximately 75% of subjects felt referred pain in distinct skin locations. Between‐days reproducibility was good for all modalities [intra‐class correlation (ICC) ≥0.6]. At sensory threshold, CSA showed best reproducibility (ICC ≥ 0.9). At pain detection threshold stretch ratio, CSA and electrostimulation showed best reproducibility (ICC = 1.0; 0.9; 0.9). The present model was easily implemented, robust and showed good reproducibility. It can be used to study pathophysiology or pharmacological interventions in healthy controls and in patients with diseases involving the distal hindgut.

The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network

Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenström’s macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance.

The data quality of haematological malignancy ICD-10 diagnoses in a population-based Hospital Discharge Registry

The objectives of this study were to estimate the data quality of haematological malignancy diagnoses in a hospital discharge registry, and to quantify the impact of any misclassification of diagnoses on survival estimates. We included all patients ≥15 years living in North Jutland County, Denmark with a first-time discharge diagnosis of a haematological malignancy registered in the Hospital Discharge Registry and the Danish Cancer Registry, the reference standard, from 1994 to 1999. We estimated completeness and positive predictive value (PPV) of haematological malignancies and specific subcategories, as a measure of data quality, and compared mortality rates based on data from the two registries by Cox regression analysis. Completeness in the Hospital Discharge Registry for all haematological malignancies was 91.5% (95% confidence interval (CI) 89.6–93.1) and PPV was 84.5% (95% CI 82.2–86.5). Reviews of the pathological files showed misclassified cases in both registries and thus indicated that both completeness and PPV of the Hospital Discharge Registry were underestimates. Mortality rate ratio for all haematological malignancies when registered in the Hospital Discharge Registry compared with being registered in the Danish Cancer Registry was 0.98 (95% CI 0.88–1.09). Discharge data had some misclassifications but these had no major impact on survival estimates.

Fracture risk in patients with monoclonal gammopathy of undetermined significance

Little information is available on the risk of fractures in patients with monoclonal gammopathy of undetermined significance (MGUS). We identified 1535 patients with MGUS between 1978 and 2003 in North Jutland County, Denmark. The population control group consisted of 15 350 persons selected from the Danish Central Population Registry, matched by age and sex. Data on fractures in the two groups were obtained from the regional Hospital Discharge Registry. In the MGUS cohort, 187 first‐time fractures were identified during 9754 person‐years of follow‐up, corresponding to an incidence rate of 19/1000 person‐years. The adjusted relative risk for fractures among MGUS patients compared with population controls was 1·4 [95% confidence interval (CI), 1·2–1·6]. After 5 years of follow‐up, the risk difference was 1·8% (95% CI, 0·5–3·0). Six of the 187 MGUS patients with fractures were later diagnosed with malignant transformation. Relative risks for fractures were increased in IgG‐type MGUS [1·3 (95% CI,1·1–1·6)], IgM‐type MGUS [1·6 (95% CI, 1·1–2·2)] and MGUS with kappa light chain [1·4 (95% CI, 1·1–1·7)]. MGUS patients had an increased risk of fractures, which could not be explained by comorbidity, advanced age, gender or malignant transformation.

Oesophageal pressure–cross-sectional area distributions and secondary peristalsis in relation to subclassification of systemic sclerosis

The aim of the present study was to correlate the severity of oesophageal motor dysfunction with the severity of cutaneous disease in systemic sclerosis (SS). Patients were divided into three groups based on the degree of skin involvement: type I, acrosclerosis distal to the wrist; type II, scleroderma extending above the wrist in proximal direction; type III, diffuse cutaneous systemic sclerosis. Impedance planimetry employing distensions with pressures up to 5 kPa with the concomitant measurement of oesophageal cross‐sectional area (CSA) was used in combination with standard oesophageal manometry. Measurements were made at 7 and 15 cm above the lower oesophageal sphincter (LOS). Thirty patients (16 type I, six type II and eight type III patients) and 23 normal controls were included. LOS pressure was lower in SS patients than in normal patients, with the lowest values in type III. The CSAs were higher in SS patients than in controls at both sites (P < 0.001). The CSAs at the distal site were highest in type III, as compared to type I and II (P < 0.03). The CSA at the highest induced pressure (5.0 kPa) was 613 ± 45, 719 ± 79, and 808 ± 115 mm2 in types I, II and III, respectively. No differences in CSA were found at the proximal site between the three types of SS. The distensibility did not differ between SS and normal patients at the distal site. The distensibility was lowest in SS patients (P < 0.001) at the proximal distension site. The distensibility did not vary with the type of SS at either site. Significant differences in contraction frequency of the secondary peristalsis as function of wall tension were demonstrated between the SS patients and controls at the distal site (P < 0.05). No differences were found at the proximal site. The contraction frequency and amplitude at the distal and proximal sites did not differ among the three types. In conclusion for most parameters studied, SS patients differed from normal patients. Among SS types, the most pronounced changes were found in type III.

Biomechanical wall properties in the isolated perfused porcine duodenum: an experimental study using impedance planimetry

The aims were to investigate duodenal biomechanical wall properties and properties of the ascending peristaltic reflex using impedance planimetry in the isolated perfused porcine duodenum. Stepwise inflation from 0.5 to 3.0 kPa of an intraluminal duodenal balloon, in which the pressure and balloon cross‐sectional area (Bcsa) were measured simultaneously, provided the distension stimulus. The biomechanical wall parameters were calculated from these measurements.