Leukemia (2012) 26, 2317–2325 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu REVIEW Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis RL Comenzo1, D Reece2, G Palladini3, D Seldin4, V Sanchorawala4, H Landau5, R Falk6, K Wells7, A Solomon7, A Wechalekar8, J Zonder9, A Dispenzieri10,MGertz10, H Streicher11, M Skinner4, RA Kyle10 and G Merlini3 This manuscript summarizes the recommendations that emerged from the first Roundtable on Clinical Research in Immunoglobulin Light-chain Amyloidosis (AL), a meeting sponsored by the Amyloidosis Foundation (Clarkston, MI, USA) to develop a consensus of experts on a modern framework for clinical trial design and drug development in AL. Recent diagnostic and technical advances in AL, and updated consensus guidelines for assessing hematologic and organ responses, enable us to define study populations, appropriate end points, and other criteria for all phases of clinical research. This manuscript provides a framework for the design and conduct of systematic collaborative clinical research in AL to encourage more rapid testing of therapies and to expedite new drug development and approval. Leukemia (2012) 26, 2317–2325; doi:10.1038/leu.2012.100 Keywords: amyloidosis; free light chains; clinical trials; clinical research INTRODUCTION and directly cause organ toxicity and form amyloid deposits, leading 3 Systemic immunoglobulin light-chain amyloidosis (AL) is the most to organ failure and death, often from cardiac involvement. In some common type of systemic amyloidosis with an estimated cases, the tempo of disease can be rapid with an interval of months 4 incidence of 8–10 cases per million person-years.1,2 Although between diagnosis and death. Two-thirds of AL patients present there have been recent advances in AL, there is a major need for a with one or two major organ systems involved (heart, kidneys, liver/ framework for clinical research to encourage the development of GI tract, peripheral nervous system and soft tissues) while a third of 2 new therapies. Access to novel agents and their optimal and safe patients presents with more than two systems involved. Symptoms use are challenges for patients with this rare disease. Well-designed reflect involved organ disease. Both the clonal plasma cells and the clinical trials with multicenter collaboration will accelerate timely pathologic light chain proteins are targets for therapy in AL. testing of novel agents and combinations, will improve access and Unlike multiple myeloma, morbidity and mortality in AL are due will accelerate pharmaceutical company efforts and acceptance by to the devastating effects of the toxic monoclonal protein not payers. We in the United States are heartened by the continued to the proliferation of monoclonal plasma cells. Nonetheless, interest and support of the National Cancer Institute study groups, therapies that eliminate monoclonal plasma cells (similar to those particularly the Southwest and Eastern Oncology Groups, in employed in multiple myeloma) ameliorate AL disease because developing phase II and III trials for patients with AL, and in the they can remove the factory producing the toxic proteins. Most European Union by the collaboration of national plasma-cell patients die of complications of cardiac dysfunction due to disease networks and of the European Myeloma Network. These monoclonal light chains, and survival in AL depends upon rapid efforts should be complemented by the development of a phase I suppression of the synthesis of the monoclonal proteins and pipeline to nurture the development of phase II and III trials. stabilization or recovery of heart function.5,6 In this consensus report, we review distinctive aspects of AL that The necessity to translate hematologic response into cardiac impact trial design, recent important advances in AL, the definitions of and other organ responses to improve quality of life (QOL) and hematologic and organ response in AL and their implementation in extend survival requires the combined evaluation of both clonal clinical trials, the heterogeneity of the study populations among AL and organ responses and raises several problems unique to AL. patients and the end points relevant to the design of clinical trials. We For example, although the hematologic response is a prerequisite hope that our comprehensive detailed overview will serve to inform for improving outcome, this is dependent upon the extent of the the design and implementation of collaborative clinical trials. organ damage and its reversibility. Patients with very advanced cardiac damage at high risk of progressive heart failure and sudden death may not be rescued by effective anti-plasma cell DISTINCTIVE FEATURES OF AL therapy. Efforts should be made to identify these patients, The distinctive features of AL have significant implications for representing up to 20% of the patients in referral centers, who clinical trial design and drug development. AL involves monoclonal should then be considered for alternatives such as orthotopic plasma cells productive of immunoglobulin light chains that misfold heart transplantation.7 It is therefore necessary to stratify patients 1Division of Hematology/Oncology, Tufts Medical Center, Boston, MA, USA; 2Princess Margaret Hospital, Toronto, Ontario, Canada; 3Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy; 4Boston University School of Medicine, Boston, MA, USA; 5Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 6Brigham and Women’s Hospital, Boston, MA, USA; 7University of Tennessee Graduate School of Medicine, Knoxville, TN, USA; 8University College London, London, UK; 9Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; 10Mayo Clinic, Rochester, MN, USA and 11National Cancer Institute, Washington, DC, USA. Correspondence: Dr RL Comenzo, Division of Hematology/ Oncology, Tufts Medical Center, Blood Bank and Stem Cell Processing Laboratory, 800 Washington Street, Boston, MA 02111, USA. E-mail: [email protected] Received 24 January 2012; revised 19 March 2012; accepted 20 March 2012; accepted article preview online 5 April 2012; advance online publication, 15 May 2012 Clinical research for AL RL Comenzo et al 2318 according to the extent of cardiac damage and prioritize appro- priate investigational approaches. In AL unlike in myeloma, achieving a partial hematologic response or stable disease may not offer a clinical benefit as ongoing light chain production may result in further organ damage. Partial response (PR) should always be viewed in conjunction with organ response in the evaluation of treatment outcomes, and stable hematologic disease is not an innocuous category of response in AL because of the risk of organ-disease progression. This makes the concept of time-to-next therapy as a clinical research end point of limited utility, unlike in multiple myeloma. RECENT ADVANCES IN AL Definitive typing To diagnose amyloidosis, tissue biopsy of either an involved organ or a surrogate site (for example, abdominal fat) must demonstrate amyloid deposition by Congo red staining or by electron Figure 1. Patients in this international case series from seven micrographic identification of pathognomonic fibrils.8 Once the centers were analyzed for survival at 3 months after beginning diagnosis of amyloidosis has been made, the clinician must therapy based on metrics for hematologic response assessed determine the type of amyloidosis that is present. If the work-up at 6 months. In this series, 43.6% received oral melphalan and reveals a monoclonal protein, then the type is most probably AL; dexamethasone (MDex), 11.4% SCT, 22% immunomodulatory agent- based therapy and 3% bortezomib and dexamethasone. Response however, the possible coexistence of a monoclonal gammopathy criteria are CR (immunofixation negative and FLC normal); very and hereditary or age-related systemic amyloidosis should always 9 good PR (very good partial; reduction in the dFLC to o40 mg/l); be considered. If the work-up does not reveal a monoclonal PR (partial; reduction in the dFLC by 450%); and NR (no response; gammopathy, then the AL type is unlikely and evaluation for other less than PR).20 types should commence. Transthyretin amyloidosis (ATTR) is next most common, caused by either mutant (hereditary) variants (ATTRm) or the age-related variant due to wild-type transthyretin (ATTRwt).10 Secondary abnormalities associated with clonal plasma-cell diseases should be performed, and Congo red staining is necessary to identify amyloidosis, a type associated with inflammation, although rare 15–17 in the developed world, still occurs in association with amyloid. Use of the FLC assay has significantly changed the way that autoimmune diseases, malignancies and chronic infections. 18 Because clinical presentations are similar for the common types, patients with AL are diagnosed and monitored. The serum FLC assay is critical for evaluating patients with AL, as many patients one cannot infer the type of amyloid in a given patient. And 19 because monoclonal gammopathies of undetermined significance lack a measurable circulating intact immunoglobulin. FLC levels are increasingly common with age, the possibility that a patient and ratios are abnormal in 90% of AL patients, and the elevated with amyloidosis may have two potential precursor proteins FLC usually is the amyloid precursor protein. New criteria for needs to be appreciated.11 DNA sequencing of genes related to response