Wilhelminen Cancer Research Institute

Vienna, Austria

Wilhelminen Cancer Research Institute

Vienna, Austria
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Stewart A.K.,Mayo Medical School | Rajkumar S.V.,Mayo Medical School | Dimopoulos M.A.,Alexandra Hospital | Masszi T.,Semmelweis University | And 26 more authors.
New England Journal of Medicine | Year: 2015

Background Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. Methods We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. Results Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P = 0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = 0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. Conclusions In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.) Copyright © 2015 Massachusetts Medical Society. All rights reserved.


Dimopoulos M.A.,National and Kapodistrian University of Athens | Moreau P.,University of Nantes | Palumbo A.,University of Turin | Joshua D.,Royal Prince Alfred Hospital | And 27 more authors.
The Lancet Oncology | Year: 2016

Background: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding: Onyx Pharmaceuticals, Inc., an Amgen subsidiary. © 2016 Elsevier Ltd.


PubMed | Southampton General Hospital, National and Kapodistrian University of Athens, Palacky University, University of Turin and 26 more.
Type: | Journal: Leukemia | Year: 2016

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20mg/m


PubMed | University Hospital of Tuebingen, Wilhelminen Cancer Research Institute, University of Ostrava, University of Piemonte Orientale and 15 more.
Type: Journal Article | Journal: Leukemia | Year: 2016

The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with 2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide.


PubMed | University Hospital of Tuebingen, Hospital Clinic Of Barcelona, Wilhelminen Cancer Research Institute, University of Ostrava and 15 more.
Type: | Journal: Leukemia | Year: 2016

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 [25%]; Vd, n=113 [28%]) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 [75%]; Vd, n=291 [72%]). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.Leukemia accepted article preview online, 27 December 2016. doi:10.1038/leu.2016.390.


PubMed | University of Turin, Royal Infirmary, Wilhelminen Cancer Research Institute and Medical University of Vienna
Type: | Journal: American journal of hematology | Year: 2017

Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide-dexamethasone. Expression of CRBN (R=0.30, P=0.05), IKZF1 (R=0.31, P=0.04), IRF4 (R=0.38, P=0.01), MCT-1 (R=0.30, P=0.05) and CD147 (R=0.38, P=0.01), but not IKZF3 (R=-0.15, P=0.34), was significantly associated with response. Interestingly, IKZF1 expression was elevated in BM environmental cells and thus selected for further investigation by multicolour flow cytometry. High IKAROS protein levels in total BM mononuclear cells (median OS 83.4 vs 32.2 months, P=0.02), CD19


PubMed | Institute Multidisciplinaire dOncologie, Wilhelminen Cancer Research Institute, Matrix45, University of Basel and 4 more.
Type: | Journal: Journal of geriatric oncology | Year: 2016

Myelotoxic chemotherapy is associated with chemotherapy-induced (febrile) neutropenia (CIN/FN). The MONITOR-GCSF study evaluated biosimilar filgrastim (Zarzio) prophylaxis patterns, associated outcomes, and determinants. We performed stratified analyses comparing elderly and non-elderly patients.Comparative (elderly/non-elderly) analysis of demographics and clinical status, prophylaxis, associated CIN/FN outcomes (CIN grade 4 [CIN4], FN, CIN/FN-related hospitalizations and chemodisturbances, composite), and, per hierarchical modeling, determinants thereof evaluated at the patient- and cycle-level.There were no significant differences between both cohorts in prophylaxis initiation/duration and associated outcomes, but proportionately more elderly patients were correctly-prophylacted and fewer over-prophylacted. Common determinants of poor CIN/FN outcomes included concomitant antibiotic prophylaxis, impaired performance status, and any grade CIN in a previous cycle, whereas common determinants of good outcomes included over-prophylaxis and prophylaxis initiation within 24-72h. In the elderly, female gender, liver/renal/cardiovascular disease, secondary prophylaxis, and under-prophylaxis were associated with poorer outcomes. In the non-elderly, CIN4 at baseline or in a prior cycle was associated with poorer CIN/FN outcomes, and higher biosimilar filgrastim dose and, perhaps counter-intuitively, under-prophylaxis with better outcomes.Adequate GCSF support is essential for all patients, but especially for elderly patients with serious chronic disease, certainly, if concomitant antibiotic prophylaxis is indicated and if a CIN4 episode occurred in a prior cycle. The potential impact of impaired performance status, especially ECOG2 at chemotherapy start or a worsening to such during chemotherapy; under-prophylaxis, including inadequate secondary prophylaxis, should be considered in elderly patients. Timely GCSF initiation and over-prophylaxis is associated with lower rates of adverse CIN/FN events in elderly and non-elderly patients, and should be further evaluated in prospective randomized trials.


PubMed | University of Houston, Dalhousie University, New York University, University of Nantes and 30 more.
Type: Journal Article | Journal: Leukemia | Year: 2016

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.


Ludwig H.,Wilhelminen Cancer Research Institute | Aapro M.,IMO Clinique de Genolier | Bokemeyer C.,University of Hamburg | Glaspy J.,University of California at Los Angeles | And 6 more authors.
Supportive Care in Cancer | Year: 2014

Purpose: Patients with cancer frequently experience chemotherapy-induced anaemia (CIA) and iron deficiency. Erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions are available therapies. This study evaluated routine practice in CIA management. Methods: Medical oncologists and/or haematologists from nine European countries (n=375) were surveyed on their last five cancer patients treated for CIA (n=1,730). Information was collected on tests performed at diagnosis of anaemia, levels of haemoglobin (Hb), serum ferritin and transferrin saturation (TSAT), as well as applied anaemia therapies. Results: Diagnostic tests and therapies for CIA varied across Europe. Anaemia and iron status were mainly assessed by Hb (94 %) and ferritin (48 %) measurements. TSAT was only tested in 14 %. At anaemia diagnosis, 74 % of patients had Hb ≤10 g/dL, including 15 % with severe anaemia (Hb <8 g/dL). Low-iron levels (ferritin ≤100 ng/mL) were detected in 42 % of evaluated patients. ESA was used in 63 % of patients, blood transfusions in 52 % and iron supplementation in 31 % (74 % oral, 26 % intravenous iron). Only 30 % of ESA-treated patients received a combination of ESA and iron supplementation. Blood transfusions formed part of a regular anaemia treatment regimen in 76 % of transfused patients. Management practices were similar in 2009 and 2011. Conclusion: Management of anaemia and iron status in patients treated for CIA varies substantially across Europe. Iron status is only assessed in half of the patients. In contrast to clinical evidence, iron treatment is underutilised and mainly based on oral iron supplementation. Implementation of guidelines needs to be increased to minimize the use of blood transfusions. © 2014 The Author(s).

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