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Stem Cell Transplantation Clinical Utility of Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Agents Christopher Parrish, 1 Charlotte Kallmeyer 2 and Gordon Cook 3 1. Clinical Research Fellow, Transplant Immunology Group, Academic Department of Haematology and Oncology, University of Leeds, Leeds, UK; 2. Consultant Haematologist, Department of Haematology, St James's Institute of Oncology, Leeds, UK; 3. Professor of Haematology and Myeloma Studies, Department of Haematology, St James's Institute of Oncology, Leeds, UK and Transplant Immunology Group, Academic Department of Haematology and Oncology, University of Leeds, Leeds, UK Abstract The adoption of high dose therapy and autologous stem cell rescue (ASCT) for multiple myeloma (MM) in the 1990s heralded a significant advance in outcomes for this incurable plasma cell malignancy. However, over the last decade, the availability of novel agents has once again radically altered the landscape of MM therapy and previously unachievable response rates have led to widespread adoption of these drugs. Clinicians now face a number of unanswered questions surrounding the role of ASCT in modern therapy and the optimal combination of ASCT and novel agents in the treatment paradigm is yet to be determined. In this review we explore the quagmire of evidence, discuss the ways in which ASCT could be employed, and delineate some of the important outstanding issues. Keywords High dose therapy, stem cell transplantation, multiple myeloma (MM), novel agents Disclosure: Gordon Cook has provided consultancy for Janssen and Celgene and has received research funding from Celgene. The remaining authors have no conflicts of interest to declare. Received: 16 June 2012 Accepted: 1 October 2012 Citation: European Oncology & Haematology, 2012;8(4):254–60 Correspondence: Christopher Parrish, Transplant Immunology Group, Level 5, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, Beckett Street, Leeds, LS9 7TF, UK. E: christopher.parrish@gmail.com The demonstration of the anti-myeloma activity of high dose melphalan in the 1980s promised a significant advance in the care of patients with this incurable malignancy. 1,2 However, it was only with the advent of autologous stem cell transplantation (ASCT) rescue that the associated prolonged myelosuppression and therapy-related morbidity and mortality could be overcome. 3 The first randomised controlled trial (RCT) reported median event-free survival (EFS) and overall survival (OS) of 28 and 57 months respectively, vs 18 and 44 months for conventional therapy. 4 Subsequent studies corroborated this data 5 and the technique was widely adopted, quickly becoming established as a mainstay of therapy for eligible patients. Nevertheless, with the emergence of, and accruing evidence for, the use of new biological therapies (‘novel’ agents – although thalidomide has now been in clinical use in MM therapy for over a decade), the role of ASCT merits regular reappraisal. This review will consider the evolving role of ASCT in the anti-myeloma armamentarium, with a particular focus on the combination of ASCT and other agents, and aims to address three important issues. Firstly, how should novel agents be incorporated to augment induction, high-dose, consolidation and maintenance therapies? Secondly, when is the optimal juncture to employ ASCT? This section will encompass a review of the evidence for early vs late ASCT and the modality’s utility for refractory disease and high-risk groups. Finally, the replacement of ASCT by novel agents will be considered, with an appraisal of the allure and perils of this approach. 254 Can Novel Agents Improve Autologous Stem Cell Transplantation? Novel Agent-based Induction Protocols Through the design of phase I/II studies, thalidomide (T), bortezomib (Velcade ® ; B or P) and lenalidomide (Revlimid ® ; R) first showed utility in the treatment of patients with refractory and relapsed disease (RRMM). With their efficacy thus demonstrated, the clinical research strategy evolved to appraise these drugs in the induction setting, generating a considerable body of evidence to support their use in the form of two-, three- and four-drug combinations prior to ASCT (summarised in Table 1). Thalidomide was the first of these agents to demonstrate efficacy, with superiority shown of both thalidomide and dexamethasone (TD) 6,7 and thalidomide, adriamycin and dexamethasone (TAD) 8,9 over vincristine, doxorubicin and dexamethasone (VAD), the previous standard of care. Cyclophosphamide, thalidomide and dexamethasone (CTD) was more recently shown to be superior to cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) in those with newly diagnosed disease. 10 Superiority to VAD has also been demonstrated for bortezomib, 11 a useful agent in view of its rapid action, utility in renal impairment, significant single agent activity and modest bone marrow toxicity. More recently, lenalidomide too has garnered evidence in the induction setting and offers a convenient oral regimen. 12 Appraisal of a variety of combination regimens soon followed. Detailed discussion of these trials and the relative merits and toxicities of the induction regimens is beyond the remit of this review (see Moreau et al., 2011 13 for a more thorough review). However, it is clear that the © TOUCH MEDICAL MEDIA 2012