assisted with study implementation and supervised laboratory procedures; P.V. Four patients had only one positive sample within 4 years before diagnosis, with all preceding sera negative. All 4 patients with light-chain/nonsecretory myeloma evolved from a light-chain M-Ig. A preexisting M-Ig is present in most multiple myeloma patients before diagnosis. Some patients progress rapidly through a premalignant phase. Light-chain detected M-Ig is a new entity that requires further study. Introduction Multiple myeloma (MM) is a mostly incurable malignant disorder of plasma cells diagnosed in approximately 20?000 patients in the United States annually.1 MM is known to evolve from premalignant plasma cell disorders, such as non Ig-M monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), in at NRC-AN-019 least one-third of patients.2 The progression to MM occurs at average rates of 1% per year for NRC-AN-019 MGUS2 and 10% per year for SMM.3 The risk of progression from these premalignant conditions to MM is affected by the level of monoclonal immunoglobulin, the presence of non-IgG gammopathy, an abnormal serum free light-chain (sFLC) ratio, the fraction of bone marrow plasma cells bearing an aberrant phenotype, increased bone marrow plasma cells, decreased levels of polyclonal immunoglobulin, and aneuploidy.2C7 However, the proportion of MM that develops from a preexisting MGUS or SMM is unknown and remains an important unresolved issue in the understanding of the pathogenesis of myeloma.8 These premalignant plasma cell disorders are asymptomatic and usually discovered during investigation for unrelated symptoms or laboratory abnormalities.9 Therefore, it is probable that previous studies have substantially underestimated the true proportion of MM patients with a preexisting plasma cell disorder. Epidemiologic studies support the notion that a preexisting plasma cell disorder is nearly always present.10 Others have suggested that a proportion of MM arises de novo without a premalignant plasma cell NRC-AN-019 disorder.11 It has also been postulated that MM that arises from a preexisting plasma cell disorder has distinct genomic features, a unique pattern of response to therapy, and a more favorable outcome.12C15 We sought to determine the proportion of patients with newly diagnosed myeloma who had a preexisting plasma cell disorder (PPCD), as manifested by an M-Ig, using serum collected before their diagnosis. We retrieved samples from the Department of Defense Serum Repository, which contains the unused sera from the mandatory, periodic blood tests performed on active duty US military service members. Methods A database of patients who underwent high-dose chemotherapy and autologous stem cell transplantation NRC-AN-019 for MM at Walter Reed Army Medical Center was cross-referenced with the Department of Defense Serum Repository by the Armed Forces Health Surveillance Agency. The Department of Defense Serum Repository prospectively collects the unused sera from periodic mandatory blood tests performed on active duty US military service members for medical surveillance purposes. The repository contains 27 million samples on more than 7 million persons who have served since 1990.16 We intentionally chose a transplantation population because these younger than average myeloma patients would have probably been serving on active duty after 1990 when the repository began. All available sera collected 2 or more years before the diagnosis of MM were retrieved. Serum samples less than 2 years before diagnosis were not ATN1 tested because these patients probably had undetected MM. Serum protein electrophoresis (SPEP) was performed using agarose gels (Helena Laboratories, Beaumont, TX) and inspected by a technician and one of the investigators (J.A.). Immunofixation electrophoresis (IFE) with antisera to immunoglobulin A (IgA), IgM, IgG, , and was performed (Helena Laboratories) on all cases, and IgD antisera for selected cases. sFLC levels were determined by automated immunoturbidimetric assays for free (normal range, 3.3-9.4 mg/L) and (normal.