Plasma Cell Neoplasms, Their Precursor States, and Their Prediction of Organ Damage
Authors: Raymond L. Comenzo
Journal: Journal of Clinical Oncology (2014)

In 1845, after testing the urine sent by a Dr Watson across London from a patient with mollities ossium (advanced lytic bone disease), 31-year-old H. Bence Jones linked the unusual urine protein that was later named for him to the patient’s bone disease. In the article that accompanies this editorial, Weiss et al add to our knowledge of the natural history of systemic light chain amyloidosis (AL), a plasma cell neoplasm in which immunoglobulin light chains cause organ disease, by linking the presence of a prediagnostic monoclonal gammopathy to the existence of AL cardiac involvement at diagnosis. In this landmark retrospective case-control study, Weiss et al use a serum free light chain (sFLC) assay that measures free immunoglobulin light chains, on the basis of sheep polyclonal antisera to human kappa and lambda light chains not bound to heavy chains, an assay that over the last 12 years has proven useful in the diagnosis and monitoring of patients with plasma cell neoplasms. With the sFLC assay and standard electrophoretic and immunofixation tests, and with access to both US Department of Defense medical records and the Department of Defense Serum Repository containing catalogued serial samples from members of the US armed forces, 20 of whom were eventually diagnosed with AL between 2000 and 2010, Weiss et al were able to assess M-protein levels in cases and matched controls. The results provide clear-cut evidence of a precursor or prediagnostic monoclonal gammopathy at less than 4 years in 100%, at 4 to 11 years in 80%, and at more than 11 years in 42% of patients. At diagnosis, 55% of the patients had AL cardiac involvement, a variant of organ damage that is fatal despite treatment in over 20% of patients within months. Using a similar approach, several years ago Weiss et al were able to demonstrate the presence of a prediagnostic monoclonal gammopathy in 90% of patients with symptomatic multiple myeloma (MM), confirming in detail the results of other investigations. Monoclonal gammopathies are common, but the challenge is to determine whether they are passengers that are linked to putative immune or autoimmune dysregulation, or true drivers of disease or, as sometime happens, both. The symptoms of plasma cell neoplasms are caused by disruption of normal organ function, whether as the result of cell mass swinging the balance of bone remodeling toward aggressive bone resorption, as in Watson’s patient, or of toxic light chains and fibrillar deposits causing restrictive cardiomyopathy and potential early death, as in 55% of the patients with AL reported by Weiss et al. The panel of tests for monoclonal gammopathies includes serum protein electrophoresis (SPEP) and urine protein electrophoresis, the more sensitive serum immunofixation (S-IFE) and urine immunofixation, and serum quantitative immunoglobulins and sFLC. All measure and/or identify immunoglobulin proteins produced by the clonal cells in addition to, in the electrophoretic studies, relative levels of decreased or increased normal proteins. The urine protein electrophoresis in AL typically can show significant albuminuria with little to no Bence Jones protein, whereas in MM it can show large amounts of Bence Jones protein and little albumin. The serum albumin level in AL can be decreased significantly by urinary losses, whereas in MM, it may be decreased by acute phase changes that influence the liver and are linked to plasma cell mass and inflammatory mediators. Although urine studies were not available, the prediagnostic profiles of the serum tests in the AL and MM cohorts reported by Weiss et al are profoundly instructive for two reasons. First, the patterns reflect typical serum M-protein distributions in both cohorts. In AL, the prediagnostic gammopathies were detected by sFLC only in 40%, S-IFE and sFLC in 15%, SPEP and S-IFE in 15%, and by all three tests in 30%, whereas in MM they were detected by sFLC only in 22%, S-IFE and sFLC in 4%, S-IFE alone in 7%, SPEP and S-IFE in 19%, and by all three in 51%. Interestingly, immediately before diagnosis, 80% of the MM cohort was noted to be low or low-intermediate risk by criteria for progression to MM from monoclonal gammopathy of undetermined significance (MGUS). Second, the prediagnostic time frames and tempos of increasing M-protein levels were similar. Although the number of patients in each cohort was small (AL, n 20; MM, n 30), the overall distribution of prediagnostic temporal intervals in MM was comparable with AL, with prediagnostic monoclonal gammopathies present in 90% for less than 4 years, and in 77% for 4 to 15 years, whereas 10% of patients had apparent de novo MM. The tempo of increasing M-protein levels in both cohorts also displays two patterns with either a steadily increasing or a steadily then steeply increasing M-protein level before diagnosis. In both AL and MM, steep increases of involved sFLC levels and changes in kappato-lambda ratio can be seen in the years just before diagnosis. Notably, in this regard, the next-generation sFLC assay that uses beads coated with antilight chain monoclonal antibodies may provide a technical advance over the current assay because of greater reliability in patients with antigen excess. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 25 SEPTEMBER 1 2014