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1.  Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma 
American Journal of Hematology  2016;91(3):295-301.
Heavy light chain (HLC) assays allow precise measurement of the monoclonal and of the noninvolved polyclonal immunoglobulins of the same isotype as the M‐protein (e.g., monoclonal IgAκ and polyclonal IgAλ in case of an IgAκ myeloma), which was not possible before. The noninvolved polyclonal immunoglobulin is termed ‘HLC‐matched pair’. We investigated the impact of the suppression of the HLC‐matched pair on outcome in 203 patients with multiple myeloma, a phenomenon that likely reflects the host's attempt to control the myeloma clone. Severe (>50%) HLC‐matched pair suppression was identified in 54.5% of the 156 newly diagnosed patients and was associated with significantly shorter survival (45.4 vs. 71.9 months, P = 0.019). This correlation was statistically significant in IgG patients (46.4 vs. 105.1 months, P = 0.017), but not in patients with IgA myelomas (32.9 vs. 54.1 months, P = 0.498). At best response, HLC‐matched pair suppression improved only in patients with ≥VGPR, indicating partial or complete humoral immune reconstitution during remission in those with excellent response. Severe HLC‐matched pair suppression retained its prognostic impact also during follow‐up after first response. In the 47 pretreated patients with relapsed/refractory disease, a similar correlation between severe HLC suppression and survival was noted (22.8 vs. not reached, P = 0.028). Suppression of the polyclonal immunoglobulins of the other isotypes than the myeloma protein correlated neither with HLC‐matched pair suppression, nor with outcome. Multivariate analysis identified severe HLC‐matched pair suppression as independent risk factor for shorter survival, highlighting the impact of isotype specific immune dysregulation on outcome in multiple myeloma. Am. J. Hematol. 91:295–301, 2016. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
doi:10.1002/ajh.24268
PMCID: PMC4832268  PMID: 26662888
2.  Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment 
Background
The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM.
Methods
BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed.
Results
We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone.
Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA (up to 3.6 ± 1.2-fold induction, P = 0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1) protein levels, which likely mediates the apoptotic effects of PTC-209. Importantly, the anti-MM activity was upheld in the presence of stromal support or myeloma growth factors insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6).
In the MM microenvironment, PTC-209 impaired tube formation, impaired osteoclast development and decreased osteoblast formation in a dose-dependent manner (P < 0.01 at 1 μM, respectively). The latter might be attributed to an induction of DKK1 and was reversed by concurrent anti-DKK1 antibody treatment.
Conclusions
We confirmed overexpression of BMI-1 in MM highlighting its role as an attractive drug target and reveal therapeutic targeting of BMI-1 by PTC-209 as a promising novel therapeutic intervention for MM.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-016-0247-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13045-016-0247-4
PMCID: PMC4776359  PMID: 26935956
Multiple myeloma; BMI-1; PTC-209; Microenvironment
3.  Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5‐year follow‐up 
British Journal of Haematology  2015;171(3):344-354.
Summary
This follow‐up extension of a randomised phase II study assessed differences in long‐term outcomes between bortezomib‐thalidomide‐dexamethasone (VTD) and VTD‐cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m2; days 1, 4, 8, 11), thalidomide (100 mg; days 1–21), and dexamethasone (40 mg; days 1–4, 9–12), with/without cyclophosphamide (400 mg/m2; days 1, 8), for four 21‐day cycles before stem‐cell mobilisation/transplantation. After a median follow‐up of 64·8 months, median time‐to‐next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76–2·09; P = 0·370]. Five‐year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD‐negative versus MRD‐positive patients with bone marrow‐confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long‐term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).
doi:10.1111/bjh.13582
PMCID: PMC4758383  PMID: 26153365
multiple myeloma; minimal residual disease; transplantation
4.  American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma 
In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to “best non-HCT” therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.
doi:10.1016/j.bbmt.2015.09.016
PMCID: PMC4757494  PMID: 26428082
Myeloma; Stem cell transplantation; Salvage therapy
6.  Iron metabolism and iron supplementation in cancer patients 
Wiener Klinische Wochenschrift  2015;127:907-919.
Summary
Iron deficiency and iron deficiency-associated anemia are common complications in cancer patients. Most iron deficient cancer patients present with functional iron deficiency (FID), a status with adequate storage iron, but insufficient iron supply for erythroblasts and other iron dependent tissues. FID is the consequence of the cancer-associated cytokine release, while in absolute iron deficiency iron stores are depleted resulting in similar but often more severe symptoms of insufficient iron supply. Here we present a short review on the epidemiology, pathophysiology, diagnosis, clinical symptoms, and treatment of iron deficiency in cancer patients. Special emphasis is given to intravenous iron supplementation and on the benefits and limitations of different formulations. Based on these considerations and recommendations from current international guidelines we developed recommendations for clinical practice and classified the level of evidence and grade of recommendation according to the principles of evidence-based medicine.
doi:10.1007/s00508-015-0842-3
PMCID: PMC4679104  PMID: 26373748
Iron deficiency; Functional and absolute iron deficiency; Tumor anemia; Iron supplementation; Recommendations for clinical practice
7.  European Perspective on Multiple Myeloma Treatment Strategies in 2014 
The Oncologist  2014;19(8):829-844.
This manuscript presents the summary of the discussions and recommendations of an Advisory Board of European experts, which was convened to discuss current European treatment practices and the impact of new data, with the aim of providing recommendations for routine clinical practice that can be broadly applied.
The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on “fitness,” with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results.
doi:10.1634/theoncologist.2014-0042
PMCID: PMC4122482  PMID: 25063227
Multiple myeloma; Risk stratification; Consolidation; Maintenance; Autologous stem cell transplantation; Nontransplant setting; Elderly patients
8.  Insulin like growth factor binding protein 7 (IGFBP7) expression is linked to poor prognosis but may protect from bone disease in multiple myeloma 
Background
Insulin like growth factor binding protein 7 (IGFBP7) is a secreted protein binding insulin like growth factor 1 (IGF-1), insulin, vascular endothelial growth factor A (VEGFA), and activin A. It antagonizes bone morphogenetic proteins and is involved in the tumour propagation of solid as well as haematological malignancies. Its role in multiple myeloma (MM) is not defined so far. We therefore aim here to investigate its prognostic and pathophysiological role in MM.
Methods
The clinical significance of IGFBP7 gene expression was investigated by gene expression profiling in two independent cohorts (n = 948) of newly-diagnosed MM patients. Methylation of the IGFBP7 promoter was analysed by pyrosequencing and treatment of MM cell lines with 5-aza-2-deoxycytidine. The impact of IGFBP7 on MM cells was studied by CCK-8 assay, BrdU assay and flow cytometry, respectively. IGFBP7 expression in bone marrow stromal cells (BMSCs) was studied by quantitative RT-PCR. For osteoblast development, immortalized and primary human BMSCs were cultured in osteogenic differentiation medium for 7–14 days in the presence of recombinant human IGFBP7 and/or activin A.
Results
Median IGFBP7 expression is significantly lower in CD138-purified plasma cells from individuals with MGUS and MM, compared to normal bone marrow plasma cells. IGFBP7 gene expression in MM cells is regulated by methylation, shown by pyrosequencing and exposure to demethylating agents (5-aza-2-deoxycytidine). High expression of IGFBP7 in MM cells is associated with adverse survival in two independent cohorts of 247 and 701 newly-diagnosed MM patients treated with high-dose therapy and autologous stem cell transplantation. IGFBP7 is associated with prognostically adverse chromosomal aberrations (t(4;14) and gain of 1q21), MMSET expression, and higher myeloma cell proliferation. In vitro, IGFBP7 overcomes activin A induced osteoblast suppression and promotes osteogenesis. MM cells downregulate IGFBP7 in stromal cells, possibly contributing to the osteoblast suppression found in MM. Conversely, higher IGFBP7 expression is associated with a lower probability of myeloma bone disease.
Conclusions
Our data indicate that IGFBP7 expression is a marker for a specific methylation pattern in myeloma, linked to translocation t(4;14) associated MMSET expression, showing clinical features of adverse prognosis with absence of myeloma bone disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-014-0105-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13045-014-0105-1
PMCID: PMC4333268  PMID: 25887188
Multiple myeloma; IGFBP7; Microenvironment; Myeloma bone disease; Survival
9.  Intravenous iron alone resolves anemia in patients with functional iron deficiency and lymphoid malignancies undergoing chemotherapy 
This randomized trial evaluated ferric carboxymaltose without erythropoiesis-stimulating agents (ESA) for correction of anemia in cancer patients with functional iron deficiency. Patients on treatment for indolent lymphoid malignancies, who had anemia [hemoglobin (Hb) 8.5–10.5 g/dL] and functional iron deficiency [transferrin saturation (TSAT) ≤20 %, ferritin >30 ng/mL (women) or >40 ng/mL (men)], were randomized to ferric carboxymaltose (1,000 mg iron) or control. Primary end point was the mean change in Hb from baseline to weeks 4, 6 and 8 without transfusions or ESA. Difficulties with patient recruitment led to premature termination of the study. Seventeen patients (8 ferric carboxymaltose and 9 control) were included in the analysis. In the ferric carboxymaltose arm, mean Hb increase was significantly higher versus control at week 8 (p = 0.021). All ferric carboxymaltose-treated patients achieved an Hb increase >1 g/dL (control 6/9; p = 0.087), and mean TSAT was >20 % from week 2 onwards. No treatment-related adverse events were reported. In conclusion, ferric carboxymaltose without ESA effectively increased Hb and iron status in this small patient population.
Electronic supplementary material
The online version of this article (doi:10.1007/s12032-014-0302-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s12032-014-0302-3
PMCID: PMC4221625  PMID: 25373320
Ferric carboxymaltose; Intravenous iron; Anemia; Lymphoid malignancies; Functional iron deficiency
10.  Pharmacovigilance in practice: erythropoiesis-stimulating agents 
Cancer Medicine  2014;3(5):1416-1429.
Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.
doi:10.1002/cam4.275
PMCID: PMC4302692  PMID: 24890561
Adverse event; chemotherapy induced anemia; erythropoiesis-stimulating agent; pharmacovigilance; safety signal
11.  PLASMA CELL LEUKEMIA 
Leukemia  2012;27(4):780-791.
Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathologic entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10 9/L) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be reexamined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.
doi:10.1038/leu.2012.336
PMCID: PMC4112539  PMID: 23288300
plasma cell leukemia; cytogenetics; bortezomib; transplantation; myeloma; prognosis
12.  A European patient record study on diagnosis and treatment of chemotherapy-induced anaemia 
Supportive Care in Cancer  2014;22(8):2197-2206.
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.
doi:10.1007/s00520-014-2189-0
PMCID: PMC4082648  PMID: 24659244
Anaemia; Chemotherapy-induced anaemia; Intravenous iron; Iron deficiency; Diagnosis; Erythropoiesis-stimulating agents
14.  European Perspective on Multiple Myeloma Treatment Strategies: Update Following Recent Congresses 
The Oncologist  2012;17(5):592-606.
An update to a previous review of European treatment practices is presented based on discussions during an expert meeting that was convened to review novel agent data published or presented at medical meetings until the end of 2011 and to assess their impact on treatment strategies.
The management of multiple myeloma has undergone profound changes over the recent past as a result of advances in our understanding of the disease biology as well as improvements in treatment and supportive care strategies. Notably, recent years have seen a surge in studies incorporating the novel agents thalidomide, bortezomib, and lenalidomide into treatment for different disease stages and across different patient groups. This article presents an update to a previous review of European treatment practices and is based on discussions during an expert meeting that was convened to review novel agent data published or presented at medical meetings until the end of 2011 and to assess their impact on treatment strategies.
doi:10.1634/theoncologist.2011-0391
PMCID: PMC3360899  PMID: 22573721
Multiple myeloma; Novel agents; Thalidomide; Bortezomib; Lenalidomide
15.  Design and rationale of FOCUS (PX-171-011): A randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM) 
BMC Cancer  2012;12:415.
Background
Carfilzomib is a next-generation proteasome inhibitor with single-agent activity in patients with relapsed and refractory multiple myeloma (R/R MM). In PX-171-003-A1, a single-arm phase 2 study of carfilzomib monotherapy in heavily pretreated patients, the overall response rate was 23.7%, 37% of patients achieved ≥ minimal response and median overall survival (OS) was 15.6 months. Based on this study, carfilzomib was recently approved by the US Food and Drug Administration for the treatment of R/R MM. Herein we describe the trial design and rationale for a phase 3 randomized study, FOCUS (CarFilzOmib for AdvanCed Refractory MUltiple Myeloma European Study), being conducted to compare OS after treatment with single-agent carfilzomib to best supportive care (BSC) regimen in R/R MM.
Methods
Patients must have received ≥3 prior regimens, must be responsive to at least 1 line of therapy, and be refractory to their most recent therapy. Eligible patients are randomized 1:1 to receive either carfilzomib (28-day cycles at 20 mg/m2 IV on Days 1–2 of Cycle 1, escalating to 27 mg/m2 IV on Days 8, 9, 15, and 16 and continuing at 27 mg/m2 through Cycle 9 and Days 1, 2, 15, and 16 ≥ Cycle 10) or an active BSC regimen (corticosteroid treatment of prednisolone 30 mg, dexamethasone 6 mg, or equivalent every other day with optional cyclophosphamide 50 mg PO once daily). Patients will continue treatment until disease progression, unacceptable toxicity, or treatment discontinuation and will then enter long-term follow-up for survival. The primary endpoint is OS and secondary endpoints include progression-free survival, overall response rate, and safety. Disease assessments will be determined according to the International Myeloma Working Group Uniform Response Criteria with minimal response per European Blood and Marrow Transplantation Group criteria.
Conclusions
This phase 3 trial will provide more rigorous data for carfilzomib, as this is the first carfilzomib study with OS as the primary endpoint and will not be confounded by crossover and will provide more robust secondary response and safety results that will add to the data set from prior phase 2 studies. FOCUS will facilitate regulatory approvals around the world and expand treatment options for patients with R/R MM.
Trial registration
EudraCT No. 2009-016840-38; NCT01302392.
doi:10.1186/1471-2407-12-415
PMCID: PMC3489882  PMID: 22992303
Multiple myeloma; Proteasome inhibitor; Phase 3 trial; Relapsed; Refractory; Overall survival
16.  Multiple Myeloma Treatment Strategies with Novel Agents in 2011: A European Perspective 
The Oncologist  2011;16(4):388-403.
This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.
The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.
doi:10.1634/theoncologist.2010-0386
PMCID: PMC3228121  PMID: 21441574
17.  Current Multiple Myeloma Treatment Strategies with Novel Agents: A European Perspective 
The Oncologist  2010;15(1):6-25.
This review presents an overview of the most recent data using the novel agents thalidomide, bortezomib, and lenalidomide in the treatment of multiple myeloma and summarizes European treatment practices incorporating these novel agents.
The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.
doi:10.1634/theoncologist.2009-0203
PMCID: PMC3227886  PMID: 20086168
Multiple myeloma; Thalidomide; Bortezomib; Lenalidomide
18.  Darbepoetin alfa for treating chemotherapy-induced anemia in patients with a baseline hemoglobin level < 10 g/dL versus ≥10 g/dL: an exploratory analysis from a randomized, double-blind, active-controlled trial 
BMC Cancer  2009;9:311.
Background
Several studies have shown that darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), can reduce transfusions and increase hemoglobin (Hb) levels in patients with chemotherapy-induced anemia (CIA). Recent safety concerns, however, have prompted changes to ESA product information. In the European Union and United States, ESA therapy initiation for CIA is now recommended at a Hb level ≤10 g/dL. The present exploratory analysis examined how ESA initiation at this Hb level may impact patient care.
Methods
Data from a phase 3 randomized trial were retrospectively reanalyzed. CIA patients with nonmyeloid malignancies were randomized 1:1 to 500 mcg darbepoetin alfa every three weeks (Q3W) or 2.25 mcg/kg darbepoetin alfa weekly (QW) for 15 weeks. A previously published report from this trial showed Q3W dosing was non-inferior to QW dosing for reducing transfusions from week 5 to end-of-the-treatment period (EOTP). In the present analysis, outcomes were reanalyzed by baseline Hb <10 g/dL and ≥10 g/dL. Endpoints included transfusion rates, Hb outcomes, and safety profiles.
Results
This study reanalyzed 351 and 354 patients who initiated ESA therapy at a baseline Hb of <10 g/dL or ≥10 g/dL, respectively. From week 5 to EOTP, the estimated Kaplan-Meier transfusion incidence (Q3W vs QW) was lower in the ≥10 g/dL baseline-Hb group (14% vs 21%) compared with the <10 g/dL baseline-Hb group (36% vs 41%). By week 5, the ≥10 g/dL baseline-Hb group, but not the <10 g/dL baseline-Hb group, achieved a mean Hb ≥11 g/dL. The Kaplan-Meier estimate of percentage of patients (Q3W vs QW) who achieved Hb ≥11 g/dL from week 1 to EOTP was 90% vs 85% in the ≥10 g/dL baseline-Hb group and 54% vs 57% in the <10 g/dL baseline-Hb group. Both baseline-Hb groups maintained mean Hb levels <12 g/dL and had similar safety profiles, though more patients in the ≥10 g/dL baseline-Hb group reached the threshold Hb of ≥13 g/dL.
Conclusion
In this exploratory analysis, darbepoetin alfa Q3W and QW raised Hb levels and maintained mean Hb at <12 g/dL in both baseline-Hb groups. The ≥10 g/dL baseline-Hb group had fewer transfusions and faster anemia correction. Additional studies should prospectively evaluate the relationship between Hb levels at ESA initiation and outcomes.
Trial Registration
ClinicalTrials.gov Identifier NCT00118638.
doi:10.1186/1471-2407-9-311
PMCID: PMC2744706  PMID: 19728887
19.  Update on the rational use of 90Y-ibritumomab tiuxetan in the treatment of follicular lymphoma 
OncoTargets and therapy  2009;2:199-208.
The development of radiolabeled antibodies against CD20 has facilitated targeted treatment of follicular lymphoma (FL). By using 90Y-ibritumomab tiuxetan (Zevalin®), a radionuclide (yttrium-90, linked by the chelator tiuxetan to the antibody ibritumomab) is brought into the vicinity of lymphoma cells. By the so-called cross-fire effect, this beta emitter has the capacity to destroy not only the lymphoma cells having bound the antibody, but also neighboring lymphoma cells. Currently this antibody is licensed in the European Union for use in relapsed or refractory FL. It is anticipated that this drug will also be approved for use as consolidation therapy after successful first-line treatment. Here we first will review the published literature supporting the use of 90Y-ibritumomab tiuxetan in the aforementioned indications and emerging data showing applicability of ibritumomab tiuxetan as sole first-line therapy for FL, as well as in the transplant setting. Possible strategies of incorporating ibritumomab tiuxetan into the treatment algorithm of FL are discussed.
PMCID: PMC2886339  PMID: 20616907
follicular lymphoma; 90Y-ibritumomab tiuxetan
20.  Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European CANCER ANAEMIA SURVEY 
European Journal of Haematology  2006;77(5):378-386.
Birgegård G, Gascón P, Ludwig H. Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European CANCER ANAEMIA SURVEY.
Objectives: Until recently, no prospective epidemiologic survey of lymphoma and multiple myeloma (L/MM) in European cancer patients had been conducted; furthermore, data on prevalence, incidence, and treatment patterns of L/MM were limited or unavailable. Here we define anemia prevalence, incidence, and treatment patterns, and identify anemia risk factors in European L/MM patients. Methods: Data for a subgroup of 2360 L/MM patients in the European Cancer Anaemia Survey (ECAS) were analyzed; variables included age, gender, tumor type/stage, cancer and anemia treatment, WHO performance status, and hemoglobin (Hb) levels. Results: 2316 patients were evaluable (1612 L and 704 MM). Anemia rate at enrollment was 52.5%. At enrollment, Hb levels correlated significantly with WHO scores (r = −0.306, P < 0.001). Anemia prevalence during ECAS was 72.9% (MM, 85.3%; non-Hodgkin's lymphoma, 77.9%; Hodgkin's disease, 57.4%); incidence in chemotherapy patients was 55.4%. Only 47.3% of patients anemic any time during ECAS received anemia treatment; overall Hb nadir for initiating treatment was 8.9 g/dL (epoetin, 9.5 g/dL; transfusion, 8.2 g/dL). Factors found to significantly (P < 0.03) increase anemia risk were low initial Hb, female gender, persistent/resistant disease, and platinum chemotherapy. Conclusions:L/MM patients have a high prevalence and incidence of anemia; however, anemia is not optimally treated. Anemia is common in L/MM patients and, given its known adverse impact on physical functioning and quality-of-life variables including fatigue and cognitive function, anemia management should be an integral part of their care. Predictive factors identified by ECAS may help clinicians develop optimal anemia treatment strategies for L/MM patients.
doi:10.1111/j.1600-0609.2006.00739.x
PMCID: PMC1618958  PMID: 17044835
European cancer anaemia survey; anaemia; epoetin alpha; lymphoma; multiple myeloma
21.  Comparison of Technetium-99m-MIBI imaging with MRI for detection of spine involvement in patients with multiple myeloma 
Background
Recently, radiopharmaceutical scanning with Tc-99m-MIBI was reported to depict areas with active bone disease in multiple myeloma (MM) with both high sensitivity and specificity. This observation was explained by the uptake of Tc-99m-MIBI by neoplastic cells. The present investigation evaluates whether Tc-99m-MIBI imaging and magnetic resonance imaging (MRI) perform equally well in detecting myelomatous bone marrow lesions.
Methods
In 21 patients with MM, MRIs of the vertebral region TH12 to S1 and whole body scans with Tc-99m-MIBI were done.
Results
Tc-99m-MIBI scanning missed bone marrow infiltration in 43 of 87 vertebrae (50.5%) in which MRI showed neoplastic bone marrow involvement. In patients with disease stage I+II, Tc-99m-MIBI scanning was negative in all of 24 vertebrae infiltrated according to MRI. In patients with disease stage III, Tc-99m-MIBI scanning detected 44 of 63 (70%) vertebrae involved by neoplastic disease.
Conclusion
Tc-99m-MIBI scanning underestimated the extent of myelomatous bone marrow infiltration in the spine, especially in patients with low disease stage.
doi:10.1186/1471-2385-3-2
PMCID: PMC317308  PMID: 14670090

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