Thursday, November 21, 2024
11/21/2024
Abstract Our objective is to develop tools that improve early diagnosis of systemic light-chain (AL) amyloidosis, a disease that causes heart and kidney failure and early death, in patients with smoldering multiple myeloma, a disease in which patients make immunoglobulin free light chains but are relatively asymptomatic. Based on a retrospective study in members of the US Armed Forces who developed AL, there is a 10 to 15 year precursor period prior to patients presenting at a median age of 63 with symptoms of AL due to toxic free light chains (FLC) and amyloid deposits. In similar studies of patients with smoldering myeloma we know that 2% of them develop AL, meaning that 2% have FLC that are markedly abnormal. Over half of new AL patients present with heart involvement and it is the failure to diagnose early that underlies their 20% mortality within 6 months. In this application, we seek support to screen patients with smoldering multiple myeloma for undiagnosed AL and risk of AL using a series of criteria that will increase our knowledge of the likelihood of having undiagnosed AL or of being at risk for AL. Only efforts to diagnose AL and determine risk of AL in the precursor phase of the disease will reduce the early mortality rate. Our goal is to develop a likelihood algorithm for undiagnosed AL and risk of AL in smoldering myeloma patients and our aims in this application are to create a network to enroll 340 patients with smoldering multiple myeloma (SMM) on a collaborative study requiring marrow and blood specimens and collection of data for a training set of likelihood statistics and to plan the future validation study and to validate an next generation sequence (NGS) assay that identifies IGVL genes in clonal plasma cells. The clonal κ and λ IGVL genes in AL cases are restricted AL-related sets of genes. The likelihood algorithm will employ 5 parameters: (1) the presence of SMM; (2) a difference between involved (pathologic) and uninvolved FLC > 23mg/L; (3) clonal plasma cell cytogenetics showing t(11;14) or gain 1q, (4) AL-related κ or λ IGVL genes by NGS, and (5) NT-proBNP > 332pg/mL. All subjects will have their clonal IGVL genes identified by NGS enabling the creation and validation of a laboratory developed test in a precision medicine laboratory that is certified under regulations of the Clinical Laboratory Improvement Amendments of 1988 (CLIA). Our long-term goal is to overcome the current inability in patients with SMM to effectively assess for the presence of occult AL or to estimate the likelihood of developing AL. By determining the values of the 5 parameters we will create the training set for an algorithm to estimate the likelihood of having or progressing to AL and will be able to design the validation study. We have assembled a collaborative team of investigators at centers across the USA to pursue our aims and an expert support group to address the opportunities, challenges and patient care issues that will arise. We have put together a team of expert collaborators from over a dozen academic centers and expert consultants in myeloma, AL amyloidosis, molecular biology and protein biology, in order to pursue these aims, realizing the complexity of the endeavor and the demands of each aim.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
