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The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. “Continuous therapy” commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients’ quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.

IMPORTANCE Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. OBJECTIVE To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. DESIGN, SETTING, AND PARTICIPANTS Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. INTERVENTIONS Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n=922) or placebo (n=924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. MAIN OUTCOMES AND MEASURES The primary end point was occurrence of confirmed herpes zoster cases. RESULTS Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P

EgeUn###, Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. Design, Setting, and Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. Main Outcomes and Measures: The primary end point was occurrence of confirmed herpes zoster cases. Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P, Cornell University University of Manchester Universitat de València University of Kansas Medical Center, KUMC University of Manchester College of Medicine, Korea University Chonnam National University, CNU North Carolina GlaxoSmithKline Foundation Università degli Studi del Piemonte Orientale, UPO Gilead Sciences Pfizer National Institute of Allergy and Infectious Diseases, NIAID Amgen Merck GlaxoSmithKline foundation, GSK National and Kapodistrian University of Athens Chung Hua University, CHU University of Melbourne Thomas Jefferson University, TJU National Center for Medical Rehabilitation Research, NCMRR Cancer Center, University of Colorado National Cancer Center Helsingin Yliopisto Hacettepe Üniversitesi Tufts Medical Center City, University of London, City Gachon University Chung Hua University, CHU Uniwersytet Jagiellonski Collegium Medicum Manchester Biomedical Research Centre, BRC China Medical University Hospital, CMUH Chonbuk National University Hospital Seoul National University Hospital, SNUH Universitair Medisch Centrum Utrecht, UMC Universiti Kebangsaan Malaysia University of Seoul, UOS University of Minnesota, UM Ankara Universitesi Cleveland Clinic Foundation, CCF City, University of London, City University of North Carolina at Chapel Hill, UNC-CH Kyungpook National University, KNU, Author Affiliations: GlaxoSmithKline, Wavre, Belgium (Bastidas, Campora, Lopez-Fauqued); Hospital Universitario 12 de Octubre, Madrid, Spain (de la Serna); GlaxoSmithKline, Rixensart, Belgium (El Idrissi); CureVac AG, Tübingen, Germany (Oostvogels); University Hospital of Montpellier, Montpellier, France (Quittet); Hospital Ramón y Cajal, Madrid, Spain (López-Jiménez); Ege University Medical School, Izmir, Turkey (Vural); Charles University Hospital, Prague, Czech Republic (Pohlreich); Rambam Health Care Campus, Haifa, Israel (Zuckerman); Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (Issa); Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy (Gaidano); Chonnam National University Hwasun Hospital, Jellanamdo, Republic of Korea (J.-J. Lee); University of Kansas Cancer Center, Westwood (Abhyankar); Hospital Clínico Universitario, School of Medicine, University of Valencia, Valencia, Spain (Solano); Centro Integral Oncológico Clara Campal (CIOCC), Universidad CEU San Pablo, Madrid, Spain (Perez de Oteyza); Weill Medical College of Cornell University, New York, New York (Satlin); Department of Hematology and Oncology, Charité University Medical Center, Berlin, Germany (Schwartz); Preventive Medicine and Epidemiology Department, University Hospital Vall d’Hebron, Barcelona, Spain (Campins); Haematology Department, Manchester University NHS Foundation Trust, Manchester Royal Infirmary, Manchester, England (Rocci); Faculty of Biology, Medicine and Health, School of Medical Science, Division of Cancer Sciences, University of Manchester, Manchester, England (Rocci); Hospital de Donostia, San Sebastián, Spain (Vallejo Llamas); Department of Internal Medicine, Seoul St Mary’s Hospital, College of Medicine, Catholic University of Korea, Seoul, South Korea (D.-G. Lee); Hospital Ampang, Selangor, Malaysia (Tan); Royal Hobart Hospital, Hobart, Australia (Johnston); Department of Clinical Haematology, Austin Health, Heidelberg, Australia (Grigg); Fred Hutchinson Cancer Research Center, Seattle, Washington (Boeckh); Halozyme Therapeutics, San Diego, California (Heineman); University of Pennsylvania, Philadelphia (Stadtmauer); Duke University Medical Center, Durham, North Carolina (Sullivan). -- reported being employed by and holding stock options in GlaxoSmithKline (GSK). Dr El Idrissi reported being employed by and holding stock options in GSK. Dr Oostvogels reported being employed by GSK during conception and/or conduct of the study and being currently employed by CureVac AG; being an inventor on a patent owned by GSK relevant to recombinant zoster vaccine; and holding stock in GSK. Dr López-Jiménez reported receipt of grants from Hospital Ramon y Cajal. Dr Vural reported receipt of grants and personal fees from GSK. Dr Issa reported receipt of grants from GSK, Merck, and Astellas and personal fees from Akros Pharma. Dr Gaidano reported receipt of trial patient fees from GSK and personal fees from Abbvie, Roche, Gilead, Janssen, and Morphosys. Dr Perez de Oteyza reported receipt of grants from GSK, Pharmacyclics, Vivia-Biotech, Morphosys, and Helsinn; grants and personal fees from Roche, Janssen, Takeda, and Celgene; and personal fees from Servier and Gilead. Dr Satlin reported receipt of grants from GSK, Allergan, Merck, Biofire Diagnostics, and Biomerieux and consulting fees from Achaogen and Shionogi. Dr Schwartz reported receipt of grants from GSK and personal fees and nonfinancial support from Amgen, Basilea Pharmaceutica, Gilead, Jazz Pharmaceuticals, Merck Sharp & Dohme, and Pfizer. Dr Campins reported receipt of grants and personal fees from GSK; participation as an investigator in clinical trials from GSK and Novartis; and participation in expert meetings and symposiums organized by Pfizer, GSK, Sanofi-Pasteur, Merck Sharp & Dohme, and Novartis. Dr Rocci reported receipt of consultancy fees from Takeda and Sanofi and honoraria from Takeda, Celgene, Novartis, Amgen, and Janssen and advisory board membership for Novartis, Amgen, and Janssen. Dr Johnston reported receipt of personal fees from Roche, Janssen Cilag, Celgene, and Merck Sharp & Dohme. Dr Grigg reports advisory board membership for Novartis, Gilead, Roche, Merck Sharp & Dohme, Takeda, and Bristol-Myers Squibb. Dr Boeckh reported receipt of grants and personal fees from GSK, Merck, and Chimerix and personal fees from Clinigen. Dr Campora reported being an employee of GSK; owning shares in GSK; and receipt of personal fees from GSK. Dr Lopez-Fauqued reported being an employee of GSK. Dr Heineman reported being an employee of GSK during conception and/or conduct of the study; holding stock and stock options in GSK; being an inventor on a patent owned by GSK relevant to recombinant zoster vaccine; being a paid consultant for GSK. Dr Stadtmauer reported receipt of grants from GSK. Dr Sullivan reported receipt of grants and personal fees from GSK; personal fees from Kiadis Pharmaceutical and Roche Genentech; and a grant from the National Institute of Allergy and Infectious Diseases awarded to his university. No other disclosures were reported. -- (Hematology Department, National and Kapodistrian University of Athens, “Laikon” General Hospital, Athens, Greece), Veli-Jukka Anttila, MD, PhD (Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland), Mickael Aoun, MD (Microbiologie Infectious Diseases, Institut Jules Bordet, Bruxelles, Belgium), Ibrahim Barista, MD (Hacettepe University Medical Faculty, Ankara, Turkey), Leanne Berkahn, MB, ChB (Department of Heamatology, Auckland City Hospital, Grafton, New Zealand), Adrian J. C. Bloor, PhD, FRCP (Haematology and Transplant Unit, Christie NHS Foundation Trust, Manchester, England), Raewyn Broady, MB, ChB (Vancouver General Hospital, Vancouver, British Columbia, Canada), Peter Brossart, MD (Universitaetsklinikum Bonn, Bonn, Germany), Francis K. Buadi, MB, ChB (Mayo Clinic, Rochester, Minnesota), Claude-Eric Bulabois, MD (Service d’Hématologie, CHU de Grenoble–Hôpital Michallon, Grenoble, France), Guy Cantin, MD (CHU de Quebec–Hopital de l’Enfant-Jesus, Quebec City, Quebec, Canada), Claudia Cellini, MD (UO di Ematologia, Ospedale Santa Maria delle Croci, Ravenna, Italy), Pranatharthi Haran Chandrasekar, MD (Karmanos Cancer Institute, Detroit, Michigan), Thomas Chauncey, MD (Veterans Administration Puget Sound Health Care System, Seattle, Washington), Antonio Cuneo, MD (Unità Operativa di Ematologia, Azienda Ospedale Universitaria Arcispedale S. Anna, Venice, Italy), Sanjeet Singh Dadwal, MD (City of Hope National Medical Center, Duarte, California) , Michael Dickinson, MBBS(hons), DMedSci, FRACP, FRCPA (Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia), HyeonSeok Eom, MD, PhD (National Cancer Center, Kyunggi-do, Korea), Albert Esquirol Sanfeliu, MD (Hospital Santa Creu i Sant Pau, Barcelona, Spain), Christelle Ferra Coll, MD, PhD (Hospital Germans Trias i Pujol, Barcelona, Spain), Phyllis R. Flomenberg, MD (Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania), Ana Pilar González-Rodríguez, MD, PhD (Hospital Central de Asturias, Oviedo, Spain), David J. Gottlieb, MD (Department of Haematology, Westmead Hospital, Westmead, Australia), Sigal Grisariu, MD (Hadassah Medical Center, Jerusalem, Israel), Andreas Guenther, MD (Universitaetsklinikum Schleswig-Holstein, Kiel, Germany), Jonathan Gutman, MD (University of Colorado Cancer Center, Aurora), Uwe Hahn, MD (Department of Haematology and Oncology, Queen Elizabeth Hospital, Woodville, Australia), Werner J. Heinz, MD (Universitaetsklinikum Wuerzburg, Wuerzburg, Germany), Inmaculada Heras, MD, PhD (Hospital General Universitario J. M. Morales Meseguer, Murcia, Spain), Takashi Ikeda, MD, PhD (Shizuoka Cancer Center, Shizuoka, Japan), Isidro Jarque, MD, PhD (Hospital Universitario y Politécnico La Fe, Valencia, Spain), Meinolf Karthaus, MD (Staedtisches Krankenhaus Muenchen, Muenchen, Germany), Tessa Kerre, MD, PhD (Hematologie, UZ Gent, Gent, Belgium), Alexander Kiani, MD (Klinikum Bayreuth, Bayreuth, Germany), Andreas K. Klein, MD (Tufts Medical Center, Boston, Massachusetts), Grzegorz Kofla, MD (Charite, Berlin, Germany), Irina V. Kryuchkova, MD, PhD (Research Institute of Clinical Immunology, Novosibirsk, Russia), Ching-Yuan Kuo, MD (Chang Gung Memorial Hospital–Kaoshiung, Kaohsiung, Taiwan), John Kuruvilla, MD (Princess -- Margaret Hospital, Toronto, Ontario, Canada), Aleksey Kuvshinov (Russian Hematology and Transfusiology Research Center, St Petersburg, Russia), Jae-Yong Kwak, MD, PhD (Chonbuk National University Hospital, Jeonju, South Korea), Jae Hoon Lee, MD, PhD (Hematology, Gachon University Gil Hospital, Incheon, South Korea), Stéphane Lepretre, MD (Département d’Hématologie, Centre Henri Becquerel, Rouen, France), Albert Kwok-Wai Lie, MBBS (Division of Hematology/Oncology and Bone Marrow Transplantation, Department of Medicine, Queen Mary Hospital, Hong Kong, China), Alessandro Lucchesi, MD (Oncologia Medica, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy), Johan Maertens, MD, PhD (Hematologie, UZ Leuven–Campus Gasthuisberg, Leuven, Belgium), Erik W. A. Marijt, MD, PhD (Leids UMC, Leiden, Netherlands), Carmen Martínez Muñoz, MD (Hospital Clinic i Provincial, Barcelona, Spain), Mariagrazia Michieli, MD (UOS Dipartimento Terapia Cellulare-Chemioter Alte Dosi, Centro di Riferimento Oncologico IRCCS, Aviano, Italy), Samuel T. Milliken, MBBS (Department of Haematology, St Vincent’s Hospital, Darlinghurst, Australia), Noël Milpied, MD (Hématologie Clinique et Thérapie Cellulaire, CHU de Bordeaux–Hôpital du Haut Lévêque, Pessac, France), Jorge Monserrat Coll, MD (Hospital Virgen de la Arrixaca, Murcia, Spain), Sherif Beniameen Mossad, MD (Department of Infectious Diseases, Cleveland Clinic Foundation, Cleveland, Ohio), John Murphy, MB, ChB (Monklands Hospital, Airdrie, Scotland), María Belén Navarro Matilla, MD (Hospital Puerta de Hierro, Madrid, Spain), Jan Novak, MD, PhD (Oddeleni Klinicke Hematologie, Fakultni Nemocnice Kralovske Vinohrady, Prague, Czech Republic), Harold J. Olney, MD, CM (Centre Hospitalier de l’Universite de Montreal, Montreal, Quebec, Canada), Raquel Oña Navarrete, MD, PhD (M. D. Anderson, Madrid, Spain), María Jesús Pascual Cascón, MD (Hospital Carlos Haya, Málaga, Spain), Andy Peniket (Oxford University Biomedical Research Centre, Oxford, England), Ganeva Penka (CTH Sofia, Sofia, Bulgaria), Beata Piatkowska-Jakubas, DSc, MD (Department of Haematology, Jagiellonian University Medical College, Krakow, Poland), Marta Polo Zarzuela, MD (Hospital Clínico San Carlos, Madrid, Spain), Dimas Quiel, MD (Complejo Hospitalario Dr Arnulfo Arias Madrid, Panama City, Panama), Scott D. Rowley, MD, FACP (John Theuer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey), Waleed Sabry, MD, MSc, PhD (Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada), Tommi Mikael Salmi, MD (Sisatautien Klinikka, Hematologian Yksikko os 015, Turun Yliopistollinen Keskussairaala, Turku, Finland), Dominik L. D. Selleslag, MD (Hematologie, AZ Sint-Jan Brugge– Oostende AV–Campus Sint-Jan, Brugge, Belgium), Thomas C. Shea, MD (Division of Hematology and Medical Oncology, University of North Carolina at Chapel Hill), Gerda Silling, MD (Universitaetsklinikum Muenster, Muenster, Germany), Ulla Marjatta Sinisalo, MD, PhD (Hematology Unit, Department of Internal Medicine, Tampere University Hospital, Tampere, Finland), Sang Kyun Sohn, MD, PhD (School of Medicine, Kyungpook National University, Daegu, South Korea), Peter Staib, MD, PhD (St Antonius Hospital, Eschweiler, Germany), Jeff Szer, MBBS (Haematology Department, Royal Melbourne Hospital, Parkville, Australia), Koen Theunissen, MD (Hematologie, Jessa Ziekenhuis–Campus Virga Jesse, Hasselt, Belgium), Pervin Topcuoglu, MD (Ankara University, Ankara, Turkey), Natalya G. Tyurina, PhD (Moscow Oncology Reserach Institute NA Herzen, Moscow, Russia), Mikhail Uvarov, MD, PhD (City Clinical Hospital No. 31, St Petersburg, Russia), Fadilah S. Abdul Wahid, PhD (Department of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia), Lucrecia Yáñez San Segundo, MD, PhD (Hospital Marqués de Valdecilla, Santander, Spain), Zeynep Arzu Yegin (Gazi University Medical Faculty, Ankara, Turkey), Su-Peng Yeh, MD (Department of Hematology, China Medical University Hospital, Taichung, Taiwan), Sze-Fai Yip, MD (Department of Medicine and Geriatrics, Tuen Mun Hospital, Tuen Mun, Hong Kong), Sung Soo Yoon, MD, PhD (Seoul National University Hospital, Seoul, South Korea), Jo-Anne H. Young, MD (University of Minnesota, Minneapolis), Pierre Zachée, MD, PhD (Hematologie-Oncologie, Ziekenhuisnetwerk Antwerpen, ZNA Stuivenberg and ZNA Middelheim, Antwerpen, Belgium), Francesco Zaja, MD (Clinica Ematologica, Azienda Ospedaliero Universitaria S. Maria Misericordia, Udine, Italy). Principal investigators and study sites are listed in eTable 9 and committees and GSK team members are listed in the eBox in Supplement 3. -- --

Constitutive NF ?B signaling promotes survival in multiple myeloma (MM) and other cancers; however current NF ?B targeting strategies lack cancer cell specificity. Here we identify the interaction between the NF ?B regulated antiapoptotic factor GADD45ß and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug discovery strategy we developed DTP3 a D tripeptide which disrupts the GADD45ß/MKK7 complex kills MM cells effectively and importantly lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard bortezomib but more than 100 fold higher cancer cell specificity in vitro. Notably DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence cancer selective targeting of the NF ?B pathway is possible and at least for myeloma patients promises a profound benefit.

The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analysed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise there was acceptable agreement on more than 1000 tests. The conclusions from the collaboration were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) Material should be part of the first draw of the aspirate; 2) Samples should be sent at suitable times that allow for the lengthy processing; 3) Most importantly PCs must be purified or specifically identified; 4) Positive cut-off levels should be the relatively conservative, 10% for fusion or break-apart probes and 20% for numerical abnormalities; 5) Informative probes should be combined to best effect; 6) In specialist laboratories a single experienced analyst is considered adequate; 7) At least 100 PC should be scored; 8) Essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) Suitable commercial probes are available for clinically relevant abnormalities; 10) The clinical report should be expressed clearly and must state the percentage of PC involved and method used for identification; 11) A retrospective European based FISH data bank linked to clinical data should be generated and 12) Prospective analysis should be centralized for upcoming trials based on the recommendations. EMN aims to build on these recommendations to establish standards for a common European database to define subgroups with prognostic significance. ispartof: Haematologica vol:97 issue:8 pages:1272-1277 ispartof: location:Italy status: published

Multiple myeloma (MM) is a hematologic tumor characterized by accumulation of monoclonal plasma cells (PCs) in the bone marrow (BM) producing antigen-specific immunoglobulins. The transcription factor X box binding protein 1 (XBP1), the interferon regulatory factor 4 (IRF4) and the transcriptional

Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45 beta/ MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.

Over the past two decades, not only treatment options, but also the diagnosis, staging, and risk assessment of multiple myeloma (MM), have undergone significant development, partially due to a deeper understanding of MM pathogenesis. Conventional cytogenetics and fluorescence in situ hybridization are routinely assessed in MM, and when combined with ISS stage may attain an even better predictive potential. In order to achieve even more effective and individualized therapies, one crucial goal is the identification of genes and gene combinations that predict for response or resistance to chemotherapy. High-dose chemotherapy with autologous stem cell transplant (SCT) still remains the standard therapy for younger patients, with novel agents now being included in both pre-transplant regimens and post-transplant consolidation/maintenance approaches. Similarly, novel agents are also being incorporated into allogeneic SCT for selected patients. In the treatment of elderly patients with MM, novel agents have been successfully incorporated into less intensive regimens, including melphalan/prednisone, low-dose dexamethasone, and cyclophosphamide/dexamethasone. While second-generation proteasome inhibitors are currently being intensively investigated, the subcutaneous administration of bortezomib, being equivalent to the established i.v. route, is now entering clinical practice. Supportive care remains a crucial aspect in the management of MM. The European Myeloma Network Trialist Group aims to address these contemporary aspects in MM.

Background: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis. Methods: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10 −5 ) and MFC (sensitivity, from 10 −4 to 10 −5 ). Results: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P =.0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P