Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial.

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741).

Long-term efficacy of pulmonary rehabilitation in patients with occupational respiratory diseases.

BACKGROUND: Pulmonary rehabilitation is a well-recognized treatment option in chronic obstructive lung disease improving exercise performance, respiratory symptoms and quality of life. In occupational respiratory diseases, which can be rather cost-intensive due to the compensation needs, very little information is available. OBJECTIVES: This study aims at the evaluation of the usefulness of pulmonary rehabilitation in patients with occupational respiratory diseases, partly involving complex alterations of lung function and of the sustainability of effects. METHODS: We studied 263 patients with occupational respiratory diseases (asthma, silicosis, asbestosis, chronic obstructive pulmonary disease) using a 4-week inpatient rehabilitation program and follow-up examinations 3 and 12 months later. The outcomes evaluated were lung function, 6-min walking distance (6MWD), maximum exercise capacity (Wmax), skeletal muscle strength, respiratory symptoms, exacerbations and associated medical consultations, quality of life (SF-36, SGRQ), anxiety/depression (HADS) and Medical Research Council and Baseline and Transition Dyspnea Index scores. RESULTS: Compared to baseline, there were significant (p < 0.05) improvements in 6MWD, Wmax and muscle strength immediately after rehabilitation, and these were maintained over 12 months (p < 0.05). Effects were less pronounced in asbestosis. Overall, a significant reduction in the rate of exacerbations by 35%, antibiotic therapy by 27% and use of health care services by 17% occurred within 12 months after rehabilitation. No changes were seen in the questionnaire outcomes. CONCLUSIONS: Pulmonary rehabilitation is effective even in the complex settings of occupational respiratory diseases, providing sustained improvement of functional capacity and reducing health care utilization.

Whole-body MRI versus whole-body MDCT for staging of multiple myeloma.

OBJECTIVE: The purpose of our study was to compare the detection rate of bone manifestations of multiple myeloma in whole-body MRI compared with MDCT and to assess accuracy in staging. SUBJECTS AND METHODS: Forty-one patients with histologically confirmed myeloma were prospectively examined with a whole-body MDCT protocol and whole-body MRI on a 1.5-T system. The MRI protocol consisted of T1-weighted spin-echo and STIR sequences. For data analysis, the entire skeleton was divided into 61 regions per patient. Image evaluation was performed in a consensus reading by two radiologists blinded to the patients' history, with separate evaluation of each technique. The patients were staged by MRI and MDCT data separately according to the Durie and Salmon PLUS staging system. RESULTS: On MRI, 15 patients showed no involvement. In 26 patients, 975 regions were affected: 21 patients were stage I, two were stage II, and 18 were stage III. On MDCT, 19 patients showed no involvement. In 22 patients, 462 regions were affected. For the detection rate, MRI was statistically superior to MDCT (p < 0.001, Wilcoxon's signed rank test). According to MDCT, 25 patients were stage I, seven were stage II, and nine were stage III. In 21 patients with involvement detected on both methods, MRI showed more extensive disease than MDCT. Eleven patients were understaged with MDCT compared with MRI, which was statistically significant (p < 0.001, chi-square test). CONCLUSION: Whole-body MDCT leads to a significantly lower detection rate and staging in patients with multiple myeloma.

A fuzzy-classifier using a marker panel for the detection of lung cancers in asbestosis patients.

BACKGROUND: The aim of this study was to evaluate the diagnostic power of a fuzzy classifier and a marker panel (CYFRA 21-1, NSE, CRP) for the detection of lung cancers in comparison to asbestosis patients at high-risk of developing lung cancer. PATIENTS AND METHODS: A panel of four tumour markers, i.e. CEA, CYFRA 21-1, NSE, SCC and CRP, was measured in newly diagnosed lung cancer patients of different histological types and stages in comparison to asbestosis patients. In this prospective study, a fuzzy classifier was generated with the data of 216 primary lung cancer patients and 76 patients suffering from asbestosis. The patients and controls were recruited in the clinics of the University in Giessen. RESULTS: At 95%-specificity, it was possible with this tool to detect non-small cell lung cancers in 70% at stage I (n = 30), in 95% at stage II (n = 22), in 98% at stage III (n = 56), in 92% at stage IV (n = 50) and small cell lung cancers with limited disease status (n = 21) in 90.7% and with extensive disease status (n = 37) in 97.3%. In contrast, single markers had a detection rate significantly far below these. The application of the classifier was examined on an independent collective of 38 non-small cell lung cancers and 76 asbestosis patients. The latter underwent stationary rehabilitation in the clinics for occupational diseases in Bad Reichenhall or Falkenstein. The fuzzy classifier showed correct negative classification in 75 out of the 76 cancer-free asbestosis patients, which confirmed a specificity of 97.4%. The overall sensitivity for lung cancer detection in high risk populations was 73.6%. All large cell carcinomas were detected. The positive predictive value was 77.7%. The negative predictive value reached 94.8%. CONCLUSION: With the fuzzy classifier and a marker panel, a reliable diagnostic tool for the detection of lung cancers in a high risk population is available.

Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma.

A phase 2 trial was performed to study the combination of bortezomib (VELCADE) with intermediate-dose dexamethasone (DEX), and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM were enroled to receive eight 3-week treatment cycles with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, followed by three 5-week cycles with bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.

Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups.

In multiple myeloma (MM), both vascular endothelial (VEGF) and basic fibroblast growth factor (bFGF) promote tumor growth and survival. We have used the novel indolinone BIBF 1000 to study effects of simultaneous inhibition of VEGF, FGF and transforming growth factor-beta on MM cells and their interactions with bone marrow stroma cells (BMSCs). Both, in the absence and presence of myeloma-stroma cell contacts, BIBF 1000 abrogated BMSC-derived secretion of interleukin-6 (IL-6). In addition, BIBF 1000 directly induced apoptosis in t(4;14)-positive cell lines as well as in CD138+ marrow cells from patients with t(4;14) myeloma. To a similar extent, BIBF 1000 induced apoptosis in MM.1S and MM.1R cells carrying the translocation t(14;16). In case of MM.1S and other dexamethasone-sensitive t(14;16) cell lines, BIBF 1000 and dexamethasone had additive proapoptotic effects. Induction of apoptosis by BIBF 1000 was associated with inhibition of the mitogen-activated protein kinases (MAPK) pathway in t(4;14) and inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway in t(14;16) cells. Apoptotic effects did not occur in t(4;14)-or t(14;16)-positive MM cells carrying n- or k-Ras mutations. The data provide the rationale for clinical evaluation of this class of targeted kinase inhibitors in MM with focus on defined cytogenetic subgroups.

Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma.

Sixty patients with advanced multiple myeloma received 2-6 monthly treatment courses combining hyperfractionated cyclophosphamide (300 mg/m2 i.v. over 3 h q 12 h x 6, d 1-3) with pulsed dexamethasone (20 mg/m2/d p.o., d 1-4, 9-12, 17-20) and once daily thalidomide at individually escalating doses (100-400 mg/d) depending on tolerability (HyperCDT). Responding patients were maintained on daily thalidomide and monthly dexamethasone pulses. Complete, partial and minor response rates were 4%, 68% and 12% respectively; overall response rate was 84% (efficacy analysis). Median event-free and overall survival was 11 and 19 months respectively. During at least one treatment cycle, 67% of patients experienced grade 4 neutropenia resulting in 17% grade 3 and 9% grade 4 infections. Side-effects, presumably related to thalidomide, included neuropathy (40% grade 2, 16% grade 3), constipation (17%), oedema (5%), bradycardia (5%), skin reactions (3%), cerebrovascular events (5%) and deep vein thromboses (8%). Thromboses were not related to known thrombophilic risk factors. Four patients with prior myeloma therapy > 50 months developed myelodysplastic syndrome or secondary acute myeloid leukaemia 2-4 months after study entry. HyperCDT is a highly active and reasonably well-tolerated salvage regimen in advanced or refractory multiple myeloma.