Publications by authors named "Annamaria Brioli"

45 Publications

Kinetics of Renal Function during Induction in Newly Diagnosed Multiple Myeloma: Results of Two Prospective Studies by the German Myeloma Study Group DSMM.

Cancers (Basel) 2021 Mar 16;13(6). Epub 2021 Mar 16.

Division of Hematology and Oncology, Würzburg University Hospital Medical Center, 97080 Würzburg, Germany.

Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories.

Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd ( < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR ( = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd ( = 0.4747).

Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.
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http://dx.doi.org/10.3390/cancers13061322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999479PMC
March 2021

Melphalan 200 mg/m does not increase toxicity and improves survival in comparison to reduced doses of melphalan in multiple myeloma patients.

Bone Marrow Transplant 2020 Dec 9. Epub 2020 Dec 9.

Universitätsklinikum Jena, Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie, Jena, Germany.

Autologous stem cell transplantation (ASCT) conditioned with melphalan 200 mg/m (Mel200) is standard of care for young multiple myeloma (MM) patients. Lower doses of melphalan (MelRed) have been used to reduce toxicity, although data regarding their efficacy are not concordant. We retrospectively evaluated 313 MM patients receiving ASCT at Jena University Hospital between 2003 and 2017. Patients receiving MelRed were on average older (p < 0.001), had a worse renal function (p < 0.001) and more comorbidities (p < 0.001). No differences were seen in treatment response before ASCT between the two groups, whilst after ASCT the rate of at least very good partial responses (VGPR) was significantly higher for patients receiving Mel200 (93% vs. 76%, p < 0.001). PFS (39 vs. 20 months, p < 0.001) and OS (103 vs. 59 months, p = 0.001) were longer with Mel200. Toxicities were comparable in the two groups. After adjusting for age and clinical characteristics using the propensity score, for VGPR before and after ASCT and for double ASCT strategy in a Cox regression analysis, Mel200 was still associated with a lower risk of disease progression (HR = 0.40, 95% CI = 0.40-0.96) and of death (HR = 0.61, 95% CI = 0.35-1.07). Our results confirm that Mel200 is still the standard of care for ASCT eligible myeloma patients.
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http://dx.doi.org/10.1038/s41409-020-01170-0DOI Listing
December 2020

Correction: The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML.

Leukemia 2020 Jul;34(7):1972

Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41375-020-0706-3DOI Listing
July 2020

Frailty impairs the feasibility of induction therapy but not of maintenance therapy in elderly myeloma patients: final results of the German Maintenance Study (GERMAIN).

J Cancer Res Clin Oncol 2020 Mar 2;146(3):749-759. Epub 2019 Dec 2.

Universitätsklinikum Jena, Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie, Am Klinikum 1, 07747, Jena, Germany.

Purpose: The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients.

Methods: Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21).

Results: The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity.

Conclusion: A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients.
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http://dx.doi.org/10.1007/s00432-019-03101-zDOI Listing
March 2020

The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML.

Leukemia 2019 11 1;33(11):2628-2639. Epub 2019 Oct 1.

Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany.

To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.
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http://dx.doi.org/10.1038/s41375-019-0581-yDOI Listing
November 2019

The risk of infections in multiple myeloma before and after the advent of novel agents: a 12-year survey.

Ann Hematol 2019 Mar 24;98(3):713-722. Epub 2019 Jan 24.

Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.

Infections represent a major cause of morbidity and mortality in multiple myeloma and are linked to both therapy- and disease-related factors. Although it has been suggested that the rate of infections increased since the introduction of novel agents, controversies still exist. To better assess the risk factors associated with infections in the era of novel agents, we conducted a large retrospective analysis of 479 myeloma patients treated at Jena University Hospital over a period of 12 years. During their disease history, 65% of patients developed at least one infection, and 37% of therapies were associated with at least one infectious episode. The rate of infections was constant over the years, with no increase in infectious complications after the routine implementation of novel agents. Infections were mainly bacterial and strongly associated with high disease burden, relapsed disease, and treatment with high-dose chemotherapy. Varicella zoster virus (VZV) reactivations occurred late during treatment (median time between high-dose chemotherapy and VZV reactivation 6 months, range 0-44 months), and fewer patients developed a VZV reactivation after 2009 (p = 0.001). Infections are still one of the major causes of morbidity in myeloma patients, and prophylactic measures are urgently needed to reduce this potentially lethal complication.
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http://dx.doi.org/10.1007/s00277-019-03621-1DOI Listing
March 2019

Safety issues and management of toxicities associated with new treatments for multiple myeloma.

Expert Rev Hematol 2017 Mar 27;10(3):193-205. Epub 2017 Jan 27.

a Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie , Universitätsklinikum Jena , Jena , Germany.

Introduction: In the last decade, the availability of new drugs for the treatment of Multiple Myeloma (MM) significantly improved patients' outcomes, but also raised attention towards a new spectrum of adverse events. Recently, four novel agents with different mechanisms of action (carfilzomib, elotuzumab, daratumumab and panobinostat) have been approved for the treatment of MM. This review aims at providing physicians with the tools to recognize and handle toxicity issues related with these new treatments. Areas covered: This review focuses on the management of drug related adverse events of the latest approved drug combinations. New drug combinations under development and still in the phase of approval will be briefly discussed. PubMed was searched using the terms 'toxicity', 'carfilzomib', 'elotuzumab' 'daratumumab' and 'panobinostat'. Phase II and III clinical trials and previously published analyses on toxicities were reviewed. For new drug combination abstracts presented at the latest ASH, ASCO and EHA meetings as well as clinicaltrial.gov website was searched and reviewed. Expert commentary: With the development of newer drugs and the availability of different treatment options for MM patients, an accurate evaluation of treatment side effects, their prompt recognition and management is mandatory for all clinical hematologists.
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http://dx.doi.org/10.1080/17474086.2017.1284584DOI Listing
March 2017

First line vs delayed transplantation in myeloma: Certainties and controversies.

Authors:
Annamaria Brioli

World J Transplant 2016 Jun;6(2):321-30

Annamaria Brioli, Klinik für Innere Medizin II (Abteilung Hämatologie und internistische Onkologie), Universitätsklinikum Jena, 07740 Jena, Germany.

Since the middle of 1990s autologous stem cell transplantation has been the cornerstone for the treatment of young patients with multiple myeloma (MM). In the last decade the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI), has dramatically changed the therapeutic scenario of this yet incurable disease. Due to the impressive results achieved with IMiDs and PI both in terms of response rates and in terms of progression free and overall survival, and to the toxicity linked to high dose therapy and autologous stem cell transplantation (ASCT), a burning question nowadays is whether all young patients should be offered autotransplantation up front or if this should be reserved for the time of relapse. This article provides a review of the data available regarding ASCT in MM and of the current opinion of the scientific community regarding its optimal timing.
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http://dx.doi.org/10.5500/wjt.v6.i2.321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919736PMC
June 2016

Prognostic impact of serial measurements of serum-free light chain assay throughout the course of newly diagnosed multiple myeloma treated with bortezomib-based regimens.

Leuk Lymphoma 2016 09 14;57(9):2058-64. Epub 2016 Jan 14.

a Department of Experimental, Diagnostic and Specialty Medicine, "Seràgnoli" Institute of Hematology , Bologna University School of Medicine , Bologna , Italy.

We retrospectively investigated the role of serial serum-free light chain (sFLC) evaluations in 150 multiple myeloma (MM) patients treated with first-line bortezomib-based regimens. Baseline sFLC ratio (sFLCR) identified three groups of patients - normal, lightly abnormal (<100), and highly abnormal (≥100) - with different progression-free survival (PFS: 3-year estimate 72% versus 61% versus 44%, respectively, p = 0.03). Moreover, the achievement of a normal sFLCR correlated with extended PFS (49 versus 17 months, p < 0.0001) and overall survival (75 versus 43 months, p < 0.0001) as compared with abnormal sFLCR, a gain maintained in a multivariate analysis for PFS. At relapse, a high sFLCR was associated with earlier start of salvage therapy compared with sFLCR <100 (3-month probability: 89% versus 64%, p = 0.0426). In 20% of patients, sFLC escape preceded the conventional relapse by a median of 3.8 months. Our results highlight the role of sFLC assay in the prognosis and follow-up of MM.
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http://dx.doi.org/10.3109/10428194.2015.1124994DOI Listing
September 2016

The genetic and genomic background of multiple myeloma patients achieving complete response after induction therapy with bortezomib, thalidomide and dexamethasone (VTD).

Oncotarget 2016 Mar;7(9):9666-79

"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.

The prime focus of the current therapeutic strategy for Multiple Myeloma (MM) is to obtain an early and deep tumour burden reduction, up to the level of complete response (CR). To date, no description of the characteristics of the plasma cells (PC) prone to achieve CR has been reported. This study aimed at the molecular characterization of PC obtained at baseline from MM patients in CR after bortezomib-thalidomide-dexamethasone (VTD) first line therapy.One hundred and eighteen MM primary tumours obtained from homogeneously treated patients were profiled both for gene expression and for single nucleotide polymorphism genotype. Genomic results were used to obtain a predictor of sensitivity to VTD induction therapy, as well as to describe both the transcription and the genomic profile of PC derived from MM with subsequent optimal response to primary induction therapy.By analysing the gene profiles of CR patients, we identified a 5-gene signature predicting CR with an overall median accuracy of 75% (range: 72%-85%). In addition, we highlighted the differential expression of a series of genes, whose deregulation might explain patients' sensitivity to VTD therapy. We also showed that a small copy number loss, covering 606Kb on chromosome 1p22.1 was the most significantly associated with CR patients.
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http://dx.doi.org/10.18632/oncotarget.5718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891075PMC
March 2016

Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma.

J Clin Oncol 2015 Nov 17;33(33):3911-20. Epub 2015 Aug 17.

Brian A. Walker, Eileen M. Boyle, Christopher P. Wardell, Alex Murison, Dil B. Begum, Nasrin M. Dahir, Paula Z. Proszek, David C. Johnson, Martin F. Kaiser, Lorenzo Melchor, Lauren I. Aronson, Charlotte Pawlyn, Fabio Mirabella, John R. Jones, Annamaria Brioli, Faith E. Davies, and Gareth J. Morgan, The Institute of Cancer Research, London; Matthew Scales, The Institute of Cancer Research, Surrey; David A. Cairns, Walter M. Gregory, and Ana Quartilho, University of Leeds; Gordon Cook, St James's University Hospital, Leeds; Mark T. Drayson, University of Birmingham, Birmingham; Nigel Russell, Nottingham University Hospital, Nottingham; Graham H. Jackson, Newcastle University, Newcastle upon Tyne, United Kingdom; Aneta Mikulasova, Masaryk University, Brno, Czech Republic; and Xavier Leleu, Hôpital C. Huriez, Centre Hospitalier Régional Universitaire de Lille, Lille, France.

Purpose: At the molecular level, myeloma is characterized by copy number abnormalities and recurrent translocations into the immunoglobulin heavy chain locus. Novel methods, such as massively parallel sequencing, have begun to describe the pattern of tumor-acquired mutations, but their clinical relevance has yet to be established.

Methods: We performed whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial, for whom complete molecular cytogenetic and clinical outcome data were available.

Results: We identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3. The mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor-κB (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically. Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) are associated with a negative impact on survival. In contrast, those in IRF4 and EGR1 are associated with a favorable overall survival. We combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score that can identify a high-risk population of patients who experience relapse and die prematurely.

Conclusion: We have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation.
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http://dx.doi.org/10.1200/JCO.2014.59.1503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485456PMC
November 2015

PET/CT Improves the Definition of Complete Response and Allows to Detect Otherwise Unidentifiable Skeletal Progression in Multiple Myeloma.

Clin Cancer Res 2015 Oct 15;21(19):4384-90. Epub 2015 Jun 15.

"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy.

Purpose: To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012.

Experimental Design: All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months.

Results: Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUVmax was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUVmax >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUVmax >4.2 following first-line treatment was independently associated with exclusive PET/CT progression.

Conclusions: PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0396DOI Listing
October 2015

Bortezomib-based therapy combined with high cut-off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment.

Am J Hematol 2015 Jul;90(7):647-52

"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine Bologna, University School of Medicine, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular-interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib-based therapy combined with high cut-off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL(-1) and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was 8 mL/min/1.73 m(2) . Serum free light chain (sFLC) median concentration was 6,040 mg L(-1) . Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3-year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI.
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http://dx.doi.org/10.1002/ajh.24035DOI Listing
July 2015

Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma.

Transl Res 2015 Jun 11;165(6):641-50. Epub 2014 Dec 11.

Department of Experimental Diagnostic and Specialty Medicine (DIMES), Institute of Hematology, "L. & A. Seràgnoli," Bologna University, S. Orsola's University Hospital, Bologna, Italy. Electronic address:

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by accumulation of malignant plasma cells (PCs) within the bone marrow (BM). The PCs are in close contact with stromal cells, which secrete growth factors and cytokines, promoting tumor cell growth and survival. Despite the availability of new drugs with immunomodulatory properties targeting the neoplastic clone and its microenvironment, MM is still an incurable disease, with patients experiencing subsequent phases of remission and relapse, eventually leading to disease resistance and patient death. It is now well established that the MM BM microenvironment is hypoxic, a condition required for the activation of the hypoxia-inducible factor 1 alpha (HIF-1α). It has been shown that HIF-1α is constitutively expressed in MM even in normoxic conditions, suggesting that HIF-1α suppression might be part of a therapeutic strategy. Constitutively activated HIF-1α enhances neovascularization, increases glucose metabolism, and induces the expression of antiapoptotic proteins. HIF-1α is thought to be one of the most important molecular targets in the treatment of cancer, and a variety of chemical inhibitors for HIF-1α have been developed to date. This review examines the role of HIF-1α in MM and recent developments in harnessing the therapeutic potential of HIF-1α inhibition in MM.
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http://dx.doi.org/10.1016/j.trsl.2014.12.001DOI Listing
June 2015

Biology and treatment of myeloma.

Clin Lymphoma Myeloma Leuk 2014 Sep;14 Suppl:S65-70

Centre for Myeloma Research, Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom. Electronic address:

In recent years significant progress has been made in the understanding of multiple myeloma (MM) biology and its treatment. Current strategies for the treatment of MM involve the concept of sequential blocks of therapy given as an induction followed by consolidation and maintenance. In an age characterized by emerging and more powerful laboratory techniques, it is of primary importance to understand the biology of MM and how this biology can guide the development of new treatment strategies. This review focuses on the genetic basis of myeloma, including the most common genetic abnormalities and pathways affected and the effects that these have on MM treatment strategies. MM biology is discussed also in the light of more recent theory of intraclonal heterogeneity.
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http://dx.doi.org/10.1016/j.clml.2014.06.011DOI Listing
September 2014

Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations.

Blood 2015 Jan 26;125(5):831-40. Epub 2014 Nov 26.

Centre for Myeloma Research, The Institute of Cancer Research, London, United Kingdom;

The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and +1q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly.
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http://dx.doi.org/10.1182/blood-2014-07-584268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327151PMC
January 2015

HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment.

Exp Cell Res 2014 Nov 26;328(2):444-55. Epub 2014 Sep 26.

Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.

Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma.
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http://dx.doi.org/10.1016/j.yexcr.2014.09.018DOI Listing
November 2014

Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome.

Blood 2014 May 14;123(22):3414-9. Epub 2014 Apr 14.

Myeloma Research Centre, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom;

Intraclonal heterogeneity was recently described in multiple myeloma (MM), but its full impact on disease progression and relapse has not been entirely explored. The immunoglobulin type produced by myeloma cells provides an excellent marker to follow changes in clonal substructure over time. We have prospectively evaluated serial paraprotein and serum free light chain (FLC) measurements and found that 258 of 520 and 54 of 520 patients who presented with a whole paraprotein relapsed with paraprotein only (PO) and "FLC escape," respectively. The median overall survival of PO patients was longer, when compared with patients whose relapse manifested as an increase in FLC both alone and with a whole paraprotein, as a result of a significantly shorter survival from relapse of the latter groups. These observations fit a model in which 1 clone is able to produce a complete antibody, whereas the other secretes only FLC; the type of relapse represents the outgrowth of different clones, some of which are more resistant to therapy. To our knowledge, this is the largest series describing patients who have relapsed with FLC escape and highlights the importance of monitoring FLC when there is a suspicion of clinical relapse. This study was registered at www.isrctn.org as ISRCTN68454111.
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http://dx.doi.org/10.1182/blood-2013-12-542662DOI Listing
May 2014

The impact of long-term lenalidomide exposure on the cellular composition of bone marrow.

Leuk Lymphoma 2014 Nov 22;55(11):2665-8. Epub 2014 Apr 22.

Myeloma Research Centre, Division of Molecular Pathology, The Institute of Cancer Research , London , UK.

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http://dx.doi.org/10.3109/10428194.2014.900765DOI Listing
November 2014

The impact of intra-clonal heterogeneity on the treatment of multiple myeloma.

Br J Haematol 2014 May 2;165(4):441-54. Epub 2014 Mar 2.

Centre for Myeloma Research, Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.

It is clear that cancers comprise a mixture of clones, a feature termed intra-clonal heterogeneity, that compete for spatial and nutritional resources in a fashion that leads to disease progression and therapy resistance. This process of competition resembles the schema proposed by Darwin to explain the origin of the species, and applying these evolutionary biology concepts to cancer has the potential to improve our treatment strategies. Multiple myeloma (MM) has a unique set of characteristics that makes it a perfect model in which to study the presence of intra-clonal heterogeneity and its impact on therapy. Novel therapies have improved the outcome of MM patients, increasing both progression-free and overall survival. Current therapy comprises an induction, consolidation and maintenance phases and it is important to consider how these components of MM therapy are affected by the presence of intra-clonal heterogeneity. In this evolutionary context therapy can be considered as a selective pressure differentially acting on the myeloma clones and impacting on their chances of survival. In this review current knowledge of intra-clonal heterogeneity, as well as its impact on the different components of MM treatment is discussed.
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http://dx.doi.org/10.1111/bjh.12805DOI Listing
May 2014

Maintenance therapy in newly diagnosed multiple myeloma: current recommendations.

Expert Rev Anticancer Ther 2014 May 3;14(5):581-94. Epub 2014 Mar 3.

"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy.

The recent availability of novel agents has substantially improved the outcomes of patients with Multiple Myeloma (MM). Achieving the deepest level of complete response and maintaining a sustained remission are important steps towards MM cure. To achieve this goal, consolidation and maintenance therapies are currently incorporated into the modern therapeutic paradigm. The excellent activity shown by new drugs has led to their investigational use as maintenance therapy. However, despite promising results of continuous treatment with the novel agents, consensus regarding maintenance therapy still lacks. This review will focus on maintenance therapy, offering an overview of the different strategies available in MM. The issue of continuous treatment in the light of new biological discoveries, including intra-clonal heterogeneity, will also be addressed.
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http://dx.doi.org/10.1586/14737140.2014.884930DOI Listing
May 2014

The utility of newer imaging techniques as predictors of clinical outcomes in multiple myeloma.

Expert Rev Hematol 2014 Feb 10;7(1):13-6. Epub 2014 Jan 10.

Centre for Myeloma Research, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

The 14th International Myeloma Workshop Kyoto, Japan, 3-7 April 2013 The International Myeloma Workshop (IMW) is a biannual meeting that gathers experts in multiple myeloma (MM) from all over the world and scientists interested in clinical and biological aspects of myeloma. The 2013 IMW was held in Kyoto, Japan and presented an interesting program with an appealing section on newer imaging techniques as predictor of outcome in asymptomatic and symptomatic MM. During the meeting, the importance of newer functional imaging techniques as new ways of assessing bone disease and the extent of marrow infiltration by myeloma cells was highlighted. This short meeting report will provide a review of new and/or functional imaging techniques, such as magnetic resonance imaging (MRI), both axial and whole body (WB-MRI), dynamic contrast enhanced (DCE) MRI, diffusion weighted imaging (DWI) and PET integrated with computed tomography.
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http://dx.doi.org/10.1586/17474086.2014.873347DOI Listing
February 2014

Role of consolidation therapy in transplant eligible multiple myeloma patients.

Semin Oncol 2013 Oct;40(5):610-7

"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Italy. Electronic address:

The role of high-dose therapy and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM) has continued to evolve in recent years. The novel agents thalidomide, bortezomib, and lenalidomide have been successfully incorporated into induction therapy in preparation for ASCT and are currently being investigated also as post-ASCT consolidation and maintenance therapy. Consolidation treatment is generally short term and aims to increase the frequency and depth of response obtained with the previous treatment phases, including novel agent-based induction therapy and ASCT. This review will focus on recent trials of novel agents as post-ASCT consolidation therapy, offering an overview of pros and cons of this new treatment strategy in the ASCT sequence for MM patients.
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http://dx.doi.org/10.1053/j.seminoncol.2013.07.001DOI Listing
October 2013

The impact of response on bone-directed therapy in patients with multiple myeloma.

Blood 2013 Oct 23;122(17):2974-7. Epub 2013 Aug 23.

Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy;

Significant benefits for zoledronic acid (ZOL) over clodronate acid (CLO) were seen in the Medical Research Council Myeloma IX randomized trial. ZOL significantly reduced skeletal-related events (SREs), and improved progression-free survival and overall survival (OS), making it the bisphosphonate of choice for newly diagnosed myeloma patients. In this analysis of Myeloma IX data, we have investigated the impact of response on bone disease in 1111 transplant-eligible patients. At posttransplant day 100, complete response (CR) was seen in 48% of patients, very good partial response (VGPR) in 20%, and partial response (PR) in 23%. For patients in VGPR or less, ZOL was superior to CLO in reducing SREs (P = .048), whereas for patients in CR, both agents were equivalent (P = .83). For OS, ZOL was associated with a significant benefit in patients in PR (P = .0091). No difference in OS was seen with patients in CR (P = .91) or VGPR (P = .74). These findings indicate that response category posttransplant may influence the impact of bisphosphonate therapy.
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http://dx.doi.org/10.1182/blood-2013-04-498139DOI Listing
October 2013

Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes.

Ann Hematol 2014 Jan 18;93(1):123-8. Epub 2013 Jul 18.

"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy.

Bortezomib (bort)-dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort-dex. The median number of bort-dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was peripheral neuropathy, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort-dex a single line of prior therapy. Bort-dex was an effective salvage treatment for MM patients, particularly for those in first relapse.
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http://dx.doi.org/10.1007/s00277-013-1828-8DOI Listing
January 2014

Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms.

Leukemia 2014 Feb 2;28(2):384-390. Epub 2013 Jul 2.

Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.

The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
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http://dx.doi.org/10.1038/leu.2013.199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916874PMC
February 2014

Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma.

Blood 2013 Jul 22;122(2):219-26. Epub 2013 May 22.

Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, Cotswold Rd, Sutton, Surrey, United Kingdom.

Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach.
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http://dx.doi.org/10.1182/blood-2013-03-487884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709654PMC
July 2013