A phase 2 clinical trial of combined BRAF/MEK inhibition for BRAFV600E-mutated multiple myeloma.

Activating BRAF mutations are found in a small subset of patients with newly diagnosed multiple myeloma, but prevalence increases in late-stage, refractory disease, and the mutations are associated with adverse outcome. This prospective single-arm, open-label, multicenter phase 2 trial assessed the efficacy and safety of combined BRAF/MEK inhibition, using encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying a BRAFV600E mutation. Patients received 450 mg encorafenib once daily and binimetinib 45 mg twice daily. The primary end point was the overall response rate achieved within the first year after start of treatment according to International Myeloma Working Group criteria. Twelve RRMM patients with a median of 5 prior lines of therapy were enrolled. The overall response rate was 83.3%, with 10 patients achieving at least a partial response. The median progression-free survival was 5.6 months, and overall survival was 55% at 24 months. Emerging resistance to therapy was driven by RAS mutations and structural variants involving the BRAF locus. This is the first prospective clinical trial to demonstrate that combined BRAF/MEK inhibition is highly effective in patients with BRAFV600E-mutated RRMM, and it represents a successful targeted precision medicine approach in this disease. This trial was registered at www.clinicaltrials.gov as #NCT02834364.

Uptake of novel therapies into first-line treatment for acute myeloid leukemia patients: EU4 + UK perspective.

Aim: To explore the incorporation of novel agents in the first-line setting for acute myeloid leukemia patients. Materials & methods: Observational study based on data from a multi-country cross-sectional retrospective web-based survey sent to 518 physicians in Europe between 2020 and 2021. Information from 2040 patients was analyzed. Results: 604 patients (29.6%) received novel agents in both intensive and non-intensive setting. Comorbidities were not a barrier for the use of novel agents. The presence of tumor mutations was observed to be an important element for treatment decision. Conclusion: There is a progressive incorporation of novel agents for newly diagnosed acute myeloid leukemia patients.

What is this article about? We now have new treatments for patients suffering from a type of blood cancer called acute myeloid leukemia (acronym AML). They are available as the first choice of therapy. In this study we explored how these new treatments are included in daily patient care. What were the results? We reviewed the data of 2040 patients in Europe, obtained from an online survey sent to physicians in two waves (between 2020 and 2021). The use of these new AML treatments was more frequent in patients who presented some specific gene alterations (changes in their DNA sequence) and were in worse health due to other diseases and old age. Most of the new treatments were administered together with other milder chemotherapies. What do the results of the study mean? The results of this study help us understand how new AML treatments are being used.

First-line therapy with bendamustine/prednisone/bortezomib-A GMMG trial for non-transplant eligible symptomatic multiple myeloma patients.

OBJECTIVES: The German-speaking Myeloma Multicenter Group (GMMG) conducted this trial to investigate efficacy and safety of the three-drug combination bendamustine/prednisone/bortezomib (BPV) as first-line therapy for elderly patients with multiple myeloma (MM). METHODS: Elderly MM patients requiring first-line therapy and not eligible for intensive treatment were enrolled in this phase IIb multicenter study. Patients were treated with BPV regimen for a maximum of nine cycles. RESULTS: Forty-six patients were included in the trial with a median age of 76 years. Nineteen patients had renal impairment at baseline. The ORR was 78.8% for patients treated with 3 and more BPV cycles and 71.1% for all evaluable patients. The median progression-free survival was 25 months, and overall survival at 24 months was 83.3%. The clinical benefit rate including MR was 91.2%. In patients with renal impairment at baseline, a renal response was observed in 11 pts. with complete recovery of the renal function in six patients. The most frequent CTC grade 3/4 AEs experienced by patients were hematological (17.5%) and infectious (9.8%) complications. No new safety signals were observed for the study drugs under investigation. CONCLUSIONS: Bendamustine/prednisone/bortezomib may serve as a first-line regimen for transplant-ineligible elderly MM patients in particular for patients with renal impairment requiring a fast and durable renal response.

Increased microcirculation detected by dynamic contrast-enhanced magnetic resonance imaging is of prognostic significance in asymptomatic myeloma.

This prospective study aimed to investigate the prognostic significance of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) as a non-invasive imaging technique delivering the quantitative parameters amplitude A (reflecting blood volume) and exchange rate constant kep (reflecting vascular permeability) in patients with asymptomatic monoclonal plasma cell diseases. We analysed DCE-MRI parameters in 33 healthy controls and 148 patients with monoclonal gammopathy of undetermined significance (MGUS) or smouldering multiple myeloma (SMM) according to the 2003 IMWG guidelines. All individuals underwent standardized DCE-MRI of the lumbar spine. Regions of interest were drawn manually on T1-weighted images encompassing the bone marrow of each of the 5 lumbar vertebrae sparing the vertebral vessel. Prognostic significance for median of amplitude A (univariate: P < 0·001, hazard ratio (HR) 2·42, multivariate P = 0·02, HR 2·7) and exchange rate constant kep (univariate P = 0·03, HR 1·92, multivariate P = 0·46, HR 1·5) for time to progression of 79 patients with SMM was found. Patients with amplitude A above the optimal cut-off point of 0·89 arbitrary units had a 2-year progression rate into symptomatic disease of 80%. In conclusion, DCE-MRI parameters are of prognostic significance for time to progression in patients with SMM but not in individuals with MGUS.

Prognostic significance of increased bone marrow microcirculation in newly diagnosed multiple myeloma: results of a prospective DCE-MRI study.

OBJECTIVES: Aim of this prospective study was to investigate prognostic significance of increased bone marrow microcirculation as detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for survival and local complications in patients with multiple myeloma (MM). METHODS: We performed DCE-MRI of the lumbar spine in 131 patients with newly diagnosed MM and analysed data according to the Brix model to acquire amplitude A and exchange rate constant kep. In 61 patients a second MRI performed after therapy was evaluated to assess changes in vertebral height and identify vertebral fractures. RESULTS: Correlation analysis revealed significant positive association between beta2-microglobulin as well as immunoparesis with DCE-MRI parameters A and kep. Additionally, A was negatively correlated with haemoglobin levels and kep was positively correlated with LDH levels. Higher baseline kep values were associated with decreased vertebral height in a second MRI (P = 0.007) and A values were associated with new vertebral fractures in the lower lumbar spine (P = 0.03 for L4). Pre-existing lytic bone lesions or remission after therapy had no impact on the occurrence of vertebral fractures. Multivariate analysis revealed that amplitude A is an independent adverse risk factor for overall survival. CONCLUSION: DCE-MRI is a non-invasive tool with significance for systemic prognosis and vertebral complications. KEY POINTS: • Qualitative parameters from DCE-MRI are correlated with established factors of disease activity • Increased marrow microcirculation might be a risk factor for loss of vertebral height and fractures • Amplitude A is an independent predictor for shortened overall survival.

Sorafenib in patients with refractory or recurrent multiple myeloma.

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and rapidly accelerated fibrosarcoma kinases, targeting signal transduction and angiogenic pathways. It is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. The objectives of this prospective phase II trial were to assess the activity and tolerability of sorafenib in patients with recurrent or refractory myeloma. In total, 11 patients were enrolled. Patients received 2 × 200 mg of sorafenib orally twice daily until completing 13 full cycles or disease progression. Of the side effects, 8.8% grade 3 and 1.1% grade 4 occurred. Sorafenib treatment was effective in two patients who achieved a partial response and a continuous stable disease with duration of 24.4 months and 6.9 month, respectively. Further clinical investigations are recommended to investigate sorafenib single agent activity in myeloma subgroups with ras-/BRAF-/vascular endothelial growth factor receptor pathway activation and combination therapy approaches.

Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial.

BACKGROUND: Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma. DESIGN AND METHODS: We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression. RESULTS: In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide. CONCLUSIONS: Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00452569).

Therapy of relapsed and refractory multiple myeloma.

Despite considerable improvements in first line treatment still the majority of patients experience relapse of multiple myeloma. Treatment decisions for relapse or refractory multiple myeloma should be based on a clinical decision path taking response and adverse events to previous therapy, myeloma specific complications and organ dysfunctions, overall clinical condition, age, cytogenetic information and prognostic factors into account. Bortezomib, thalidomide and lenalidomide have improved the therapeutic armentarium for patients with refractory or relapsed disease and are often used in combination with dexamethasone or chemotherapeutic agents. Combination therapies of novel agents in drug combination regimen are currently under investigation as well. For patients with a disease free survival of 12 month or longer after initial single or tandem high dose therapy and autologous stem cell transplantation (ASCT) repeat of high dose therapy with melphalan and ASCT should be considered in case of relapse. Radiotherapy and osteoplastic procedures can be used as adjunct to systemic therapy to treat local complications in particular vertebral pain caused by osteolytic bone disease. Cytogenetic tests, molecular techniques as gene expression profiling and other diagnostic will lead to a more individualized therapy. The integration of novel compounds into established regimen will be a major challenge for future clinical studies.

Molecular pathogenesis of multiple myeloma: chromosomal aberrations, changes in gene expression, cytokine networks, and the bone marrow microenvironment.

This chapter focuses on two aspects of myeloma pathogenesis: (1) chromosomal aberrations and resulting changes in gene and protein expression with a special focus on growth and survival factors of malignant (and normal) plasma cells and (2) the remodeling of the bone marrow microenvironment induced by accumulating myeloma cells. We begin this chapter with a discussion of normal plasma cell generation, their survival, and a novel class of inhibitory factors. This is crucial for the understanding of multiple myeloma, as several abilities attributed to malignant plasma cells are already present in their normal counterpart, especially the production of survival factors and interaction with the bone marrow microenvironment (niche). The chapter closes with a new model of pathogenesis of myeloma.

Monoclonal gammopathy and smoldering multiple myeloma: diagnosis, staging, prognosis, management.

Monoclonal gammopathy of unknown significance (MGUS) as one of the most common premalignant disorders and smoldering multiple myeloma (sMM) are both caused by a proliferation of monoclonal plasma cells leading to a detectable serum monoclonal protein and/or excess of plasma cells in the bone marrow. Prerequisite for the diagnosis is that plasma cell disease does not cause clinical symptoms. Cytogenetic aberrations are detectable in the majority of patient in the clonally expanded plasma cells. MGUS consistently proceeds symptomatic MM. The lifetime risk of progression into symptomatic multiple myeloma lies between 15% and 59% for patients with MGUS or sMM. Prognostic parameters for development of symptomatic multiple myeloma from MGUS or sMM are concentration of monoclonal protein, bone marrow plasmocytosis, a non- IgG subtype and an abnormal free-light chain ratio. Detection of more than 1 focal lesion in whole body MRI, 95% or more of bone marrow plasma cells displaying an aberrant phenotype in flow cytometry and an evolving clinical course in two consecutive follow-up visits are additional prognostic parameters for sMM. Currently there is no accepted secondary prevention strategy available for sMM and MGUS progression. Future studies are required to combine increasing knowledge on risk factors and molecular pathogenesis with targeted agents to prevent progression.

Transcriptional regulation of the vascular endothelial glycome by angiogenic and inflammatory signalling.

Vascular endothelial cells undergo many molecular changes during pathological processes such as inflammation and tumour development. Tumours such as malignant lymphomas affecting bone marrow are dependent on interactions with endothelial cells for (1) site-specific homing and (2) tumour-induced angiogenesis. Modifications in glycosylation are responsible for fine-tuning of distinct endothelial surface receptors. In order to gain a comprehensive insight into the regulation of the endothelial glycome, comprising genes encoding for sugar transporters (sugar s/t), glycosyltransferases (GT), glycan-degrading enzymes (GD) and lectins (GBP), we performed gene profiling analysis of the human bone marrow-derived microvascular endothelial cell line HBMEC-60 that resembles closely in its biological behaviour primary bone marrow endothelial cells. HBMEC were activated by either angiogenic VEGF or the inflammatory cytokine TNF. Approximately 48% (207 genes) of the 432 glycome genes tested were found to be expressed in HBMEC-60 cells. Inflammatory and angiogenic signals produce different profiles of up- or down-regulated glycome genes, most prominent changes were seen under TNF stimulation in terms of signal intensity and number of alterations. Stimulation by VEGF and TNF affected primarily genes encoding for glycosyltransferases and in particular those important for terminal modulation. For instance, an enhanced alpha2,6 sialylation was observed after TNF stimulation at the transcriptional and glycan expression level whereas transcription of ST3Gal1 sialylating in alpha2,3 position was enhanced after VEGF stimulation. Transcriptional analysis of the glycome gives insights into the differential regulation of glycosylation pathways and may help to understand the functional impact of endothelial glycosylation.

Combined phase I/II study of imexon (AOP99.0001) for treatment of relapsed or refractory multiple myeloma.

Imexon [AOP99.0001 (4-imino-1,3-diazobicyclo[3. 1. 0]-hexan-2-one)] belongs to a novel class of promising anticancer agents that induce tumor apoptosis through oxidative stress. Clinical experience since the late 1960s has provided initial evidence for a clinical antitumor activity. Our open-label, multicenter phase I clinical trial was designed to further investigate the adverse event (AEs) profile and pharmacokinetics of AOP99.0001 in pretreated myeloma patients and collect initial data on the potential clinical efficacy in this indication. Thirty-six patients with relapsed or refractory myeloma, who had been pretreated with at least two lines of therapy earlier, were included. Imexon was applied intravenously on 5 consecutive days for 2 weeks (d1-5 and d8-12) for a 3-week cycle. The plasma half-life of AOP99.0001 and its active metabolite AOP99.0002 was found to be approximately 1.2 and 2.6 h, respectively. The mean duration of treatment with Imexon was 6.8 weeks in a dose range between 50 and 1000 mg/m without reaching dose-limiting toxicity. Drug-related AEs occurring with a frequency of greater than 10% were fatigue, nausea, constipation, headache, asthenia, anemia, thrombocytopenia, leukopenia and creatinine increase. A total of nine severe adverse events occurred in three patients. No mortality was encountered when patients were on treatment with Imexon. Preliminary antimyeloma efficacy of AOP99.0001 was observed with 1 minimal response, 12 (36%) stable disease responses, and all other evaluable patients had progressive disease. Remarkably, the patient with minimal response also experienced a complete clinical resolution of myeloma-associated polyneuropathy. Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon showed minor clinical activity as a single agent in heavily pretreated myeloma patients. On account of its unique mechanism of action, favorable toxicity profile, initial clinical evidence for antimyeloma activity, and its known synergistic activity in combination with approved agents for myeloma treatment, AOP99.0001 is recommended for future clinical studies in combination regimens in multiple myeloma.

Dynamic contrast-enhanced magnetic resonance imaging identifies a subgroup of patients with asymptomatic monoclonal plasma cell disease and pathologic microcirculation.

PURPOSE: The aim of our study was to investigate whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows visualization of changes in microcirculation between healthy controls on the one side and early/advanced stages of plasma cell disease on the other. EXPERIMENTAL DESIGN: We examined a group of 222 individuals consisting of 60 patients with monoclonal gammopathy of undetermined significance (MGUS), 65 patients with asymptomatic multiple myeloma (aMM), 75 patients with newly diagnosed symptomatic MM (sMM), and 22 healthy controls with DCE-MRI of the lumbar spine. RESULTS: A continuous increase in microcirculation parameters amplitude A and exchange rate constant kep reflecting vascular volume and permeability, respectively, was detected from normal controls over MGUS and aMM to sMM. For A and kep, significant differences were found between controls and aMM (P = 0.03 and P = 0.004, respectively) as well as controls and sMM (P = 0.001 and P < 0.001, respectively). Although diffuse microcirculation patterns were found in healthy controls as well as MGUS and MM, a pattern with focal hotspots was exclusively detected in 42.6% of sMM and in 3 MGUS and 3 aMM patients. MGUS and aMM patients with increased microcirculation patterns showed significantly higher bone marrow plasmocytosis compared with patients with a low microcirculation pattern. CONCLUSIONS: Our investigations substantiate the concept of an angiogenic switch from early plasma cell disorders to sMM. Pathologic DCE-MRI findings correlate with adverse prognostic factors and DCE-MRI identifies a distinct group of patients with increased microcirculation parameters in aMM and MGUS patients.

Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of whole-body versus spinal MR imaging.

PURPOSE: To examine if standard magnetic resonance (MR) imaging of the axial skeleton is sufficient for evaluation of patients with multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS) or if whole-body MR is necessary. MATERIALS AND METHODS: A total of 100 untreated patients with MGUS (n = 27) or any stages of MM (n = 73) were examined with whole-body MR imaging and MR imaging of the axial skeleton. The study was approved by the institutional ethics committee, and written informed consent was given. Spinal pattern ("no diffuse involvement" or "diffuse involvement" as assessed from the signal intensity of the spinal bone marrow), serum parameters, and stage of disease were correlated with the probability of detecting extra-axial lesions with and without destruction of cortical bone by using a multiple logistic regression model. RESULTS: Of 100 patients, 39 had lesions in the axial skeleton and 37 had lesions in the extra-axial skeleton. Of the latter group, nine patients had no axial lesions and 13 patients had lesions that violated cortical bone, which implied an increased fracture risk. Because of the extraaxial location, lesions in these patients could be diagnosed with whole-body MR only. In addition, no single or combination of clinical factors observed (stage of disease, serum parameters, and spinal pattern) allowed investigators to identify patients with a significantly increased probability of having extra-axial lesions or lesions violating cortical bone. CONCLUSION: Whole-body MR imaging has potential for use in the initial work-up of patients with MGUS or MM, since almost one-half of all observed lesions would have been missed by using spinal MR imaging only and clinical parameters could not exclude the presence of extra-axial lesions.

Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone.

The immunomodulatory drugs thalidomide and lenalidomide have enhanced activity in patients with multiple myeloma (MM). Their efficacy is increased with the addition of dexamethasone, but significant rates of venous thromboembolism (VTE) are a severe side effect. Based on this evidence, it is recommended that VTE prophylaxis be prescribed in these patients. However, the optimal prophylaxis remains controversial. We analyzed 45 patients with relapsed MM who were treated with lenalidomide and dexamethasone at our center. The 45 patients received a total number of 192 cycles, respectively a median of three cycles; the median dosage of dexamethasone was 240 mg per cycle. All patients received prophylactic anticoagulation with low molecular weight heparin (LMWH). Moreover, 86.6% of patients had at least one additional VTE risk factor beside the myeloma-related risk. One out of 45 patients developed a deep vein thrombosis and pulmonary embolism. None of the other 44 patients had clinical signs of thrombosis or embolism and none of all patients experienced complications or side effects due to anticoagulation. Our results indicate that prophylactic anticoagulation with LMWH is safe and effective. Therefore, we propose LMWH should be used in patients being treated with lenalidomide and dexamethasone at least for the first 3 months of treatment until randomized trials have proven the equality of other pharmacological prophylaxis.

Involvement of alpha 1-2-fucosyltransferase I (FUT1) and surface-expressed Lewis(y) (CD174) in first endothelial cell-cell contacts during angiogenesis.

During the initiation of tumor associated angiogenesis endothelial cells migrate, adhere to extracellular matrix and form cell-cell contacts. Humoral factors of malignant cells conduct this process. We investigated whether cell surface expression of the carbohydrate blood group determinant Lewis(y) (CD174) and its precursor structure H2 (CD173) on endothelial cells is influenced by soluble factors of tumor cells. Using a bone marrow derived endothelial cell line we observed an enhanced expression of CD173/CD174 and transcription of FUT1, the key enzyme for their synthesis, after treatment with tumor necrosis factor-alpha (TNF-alpha) or conditioned supernatants of the leukemia cell line KG1a. CD173/CD174 are concentrated on pseudopodial extensions responsible for initial contacts between endothelial cells. Endothelial migration induced by TNF-alpha could be diminished by antibodies to CD174 as well as by siRNA induced downmodulation of FUT1 transcription. Endothelial FUT1-siRNA-transfectants displayed impaired in vitro angiogenesis when cultivated on extracellular matrix and in spheroid assays. In vivo upregulation of CD174 expression was observed immunocytologically in capillaries of tumor-infiltrated tissue. Together, our observations point to a tumor induced transcription of endothelial FUT1 and consequently an enhanced expression of CD174 which is involved in migration and early cell-cell contacts during tumor associated angiogenesis.

Gain of 1q21 and distinct adverse cytogenetic abnormalities correlate with increased microcirculation in multiple myeloma.

To identify genetic mechanisms controlling bone marrow microcirculation and angiogenesis in patients with plasma cell disease we simultaneously performed bone marrow dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and cytogenetics (iFISH) on CD138 purified plasma cells of MGUS (n=31) and untreated multiple myeloma (MM) (n = 87) patients. The adverse cytogenetic abnormalities gain of 1q21, deletion 17p13 and deletion 13q14 significantly correlated with at least one DCE-MRI finding (aberrant "focal" microcirculation pattern, increase in median microcirculation parameter Amplitude A or exchange rate constant kep). We conclude that gain of 1q21, deletion 13q14 and deletion 17p13 trigger the angiogenic cascade in MM. Our findings will have important implications for the design, analysis and stratification for clinical studies of patients with MM in particular if compounds with antiangiogenic activity are used.

Lumbar bone marrow microcirculation measurements from dynamic contrast-enhanced magnetic resonance imaging is a predictor of event-free survival in progressive multiple myeloma.

PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with high temporal resolution enables the detection of microcirculation variables amplitude A and exchange rate constant k(ep). In this study, the prognostic value of the DCE-MRI variables for overall survival and event-free survival in patients with progressive multiple myeloma was investigated. EXPERIMENTAL DESIGN: Between 1999 and 2001, 65 patients with progressive or relapse of multiple myeloma requiring therapy were investigated with DCE-MRI of the lumbar spine before start of therapy. The contrast uptake was quantified using a two-compartment model with the output variables amplitude A and exchange rate constant k(ep) reflecting bone marrow microcirculation. The estimated median follow-up was 56 months. Event-free survival and overall survival were investigated for DCE-MRI variables and for established prognosis variables (beta(2)-microglobulin, lactate dehydrogenase, albumin, and age). RESULTS: Using a multivariate Cox regression model, beta(2)-microglobulin and amplitude A of DCE-MRI were identified as statistically significant prognostic variable of event-free survival with Ps of 0.01 and 0.02, respectively. A statistical correlation of DCE-MRI variables with overall survival could not be found. The multivariate analysis of beta(2)-microglobulin, age, lactate dehydrogenase, and albumin revealed beta(2)-microglobulin as statistically significant prognostic factor for overall survival in this group of patients (P < 0.001). CONCLUSIONS: This analysis identifies contrast-enhanced DCE-MRI variable amplitude A reflecting increased bone marrow microcirculation and angiogenesis as a novel and possibly useful prognostic factor in patients with multiple myeloma. Prospective studies are currently done to further investigate this functional variable for prognosis and stratification of myeloma patients.

The outcome of autologous stem cell transplantation in patients with plasma cell disorders and dialysis-dependent renal failure.

Patients with multiple myeloma and end-stage renal failure on dialysis are frequently not considered eligible for high-dose therapy (HDT) due to higher transplant-related mortality (TRM). Our aim was to evaluate the toxicity and survival of dialysis-dependent patients after HDT with melphalan (100 mg/m(2)) compared to those of patients without renal insufficiency (melphalan 200 mg/m(2)) in a matched pairs analysis of 34 patients. No significant differences were observed between hematologic toxicity, TRM or disease response. Dialysis patients showed comparable event-free and overall survival. They required significantly extended intravenous antibiotic treatment and longer hospitalization. Thus, melphalan 100 mg/m2 is less toxic, yet equally efficient and improves the prognosis of this group of patients.

Diagnostic and therapeutic approaches to multiple myeloma patients: 'Real-world' data from representative multicentre treatment surveys in Germany between 2008 and 2011.

A survey was conducted to investigate the standard of care for multiple myeloma in Germany, in order to clarify the status of implementation of international and national treatment guidelines. In addition, the changes in disease management over time were investigated by comparison with surveys conducted in 2008 and 2009. The survey captured a representative sample of 478 myeloma patients with a mean age of 67.9 years across various stages of the disease. Diagnostic approaches, prognostic aspects and treatment decisions were evaluated based on a survey conducted in 2011 in 58 representative centres in Germany, including university and non-university hospitals and office-based haematologists. Data were collected from chart reviews and were analysed retrospectively. Over time, an increasing number of patients were investigated for cytogenetic abnormalities (53%). Age <69 years and lack of comorbid conditions were major determinants for cytogenetic testing. Bortezomib/chemotherapy-based regimens have become the preferred first-line treatments independent of planning autologous blood stem cell transplantation (ASCT) in first-line therapy. Thalidomide- and lenalidomide-based combination therapies are typically used as second-line treatments in 31% of patients. Compared with previous reviews, the frequency of ASCT was stable, at ~30% of patients. Younger age and indicators of more severe disease, such as the presence of CRAB criteria, influenced the decision in favour of performing ASCT. Compared to previous surveys, the requirement for erythropoietin and granulocyte colony-stimulating factor, as well as transfusions of red blood cells and platelets, respectively, have decreased considerably. In summary, novel agents have led to a substantial change in the first-line and relapsed treatment approaches. Age and comorbidities remain major factors influencing treatment decisions, but cytogenetic testing to investigate myeloma-related risk profiles is increasingly integrated. The use of novel agents has affected supportive care, with reduced necessity for substitute blood products and reduced administration of bone marrow-stimulating factors.