Therneau, Terry M.

Abstract Motivation: Our goal was to develop a normalization technique that yields results similar to cyclic loess normalization and with speed comparable to quantile normalization. Results: Fastlo yields normalized values similar to cyclic loess and quantile normalization and is fast; it is at least an order of magnitude faster than cyclic loess and approaches the speed of quantile normalization. Furthermore, fastlo is more versatile than both cyclic loess and quantile normalization because it is model-based. Availability: The Splus/R function for fastlo normalization is available from the authors.

AbstractPrimary systemic amyloidosis (AL) is a fatal plasma cell disorder. Pilot data suggest survival is better in patients undergoing peripheral blood stem cell transplantation (PBSCT), but the selection process makes the apparent benefit suspect. We have reported that circulating cardiac biomarkers are the best predictors of survival outside of the transplantation setting. We now test whether cardiac troponins (cTnT and cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are prognostic in transplant recipients. In 98 patients with AL undergoing PBSCT, serum cardiac biomarkers were measured (cTnT, 98 patients; cTnI, 65 patients; and NT-proBNP, 63 patients). Elevated levels of cTnT, cTnI, and NT-proBNP were present in 14%, 43%, and 48% of patients, respectively. At 20 months median follow-up, median survival has not been reached for patients with values below the thresholds; in patients with values above the thresholds, median survival is 26.1 months, 66.1 months, and 66.1 months, respectively. Our previously reported risk systems incorporating these markers were also prognostic, notably the cTnT/NT-proBNP staging. Using this system, 49%, 38%, and 13% of patients were in stage I, stage II, and stage III, respectively. Determining levels of circulating biomarkers may be the most powerful tool for staging patients with AL undergoing PBSCT.

AbstractPrimary systemic amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem failure and death. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has been associated with higher response rates and seemingly higher overall survival than standard chemotherapy. Selection bias, however, confounds interpretation of these results. We performed a case-match-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Matching criteria included age, sex, time to presentation, left ventricular ejection fraction, serum creatinine, septal thickness, nerve involvement, 24-hour urine protein, and serum alkaline phosphatase. According to design, there was no difference between the groups with respect to sex (57% males), age (median, 53 years), left ventricular ejection fraction (65%), number of patients with peripheral nerve involvement (17%), cardiac interventricular septal wall thickness (12 mm), serum creatinine (1.1 mg/dL [97.24 μmol/L]), and bone marrow plasmacytosis (8%). Sixty-six patients have died (16 cases and 50 controls). For PBSCT and control groups, respectively, the 1-, 2-, and 4-year overall survival rates are 89% and 71%; 81% and 55%; and 71% and 41%. Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL.

AbstractLittle effort has been made to quantitate adverse outcomes of monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin M (IgM) class, which progresses to lymphoma or Waldenström macroglobulinemia, whereas IgA and IgG MGUS progress to multiple myeloma, primary amyloidosis (AL), or a related plasma cell disorder. From 1960 to 1994, IgM MGUS was diagnosed in 213 patients in southeastern Minnesota. The end point was progression to lymphoma or a related disorder, as assessed with the Kaplan-Meier method. The 213 patients were followed up for 1567 person-years (median, 6.3 years per patient). Lymphoma developed in 17 patients (relative risk [RR], 14.8), Waldenström macroglobulinemia in 6 (RR, 262), primary amyloidosis in 3 (RR, 16.3), and chronic lymphocytic leukemia in 3 (RR, 5.7). The relative risk of progression was 16-fold higher in the patients with IgM MGUS than in the white population of the Iowa Surveillance, Epidemiology, and End Results Program. Cumulative incidence of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years. On multivariate analysis, the serum monoclonal protein and serum albumin concentrations at diagnosis were the only risk factors for progression to lymphoma or a related disorder. Risk for progression to lymphoma or a related disorder at 10 years after the diagnosis of MGUS was 14% with an initial monoclonal protein concentration of 0.5 g/dL or less, 26% with 1.5 g/dL, 34% for 2.0 g/dL, and 41% for more than 2.5 g/dL. (Blood. 2003;102:3759-3764)

The POEMS syndrome (coined to refer to polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) remains poorly understood. Ambiguity exists over the features necessary to establish the diagnosis, treatment efficacy, and prognosis. We identified 99 patients with POEMS syndrome. Minimal criteria were a sensorimotor peripheral neuropathy and evidence of a monoclonal plasmaproliferative disorder. To distinguish POEMS from neuropathy associated with monoclonal gammopathy of undetermined significance, additional criteria were included: a bone lesion, Castleman disease, organomegaly (or lymphadenopathy), endocrinopathy, edema (peripheral edema, ascites, or effusions), and skin changes. The median age at presentation was 51 years; 63% were men. Median survival was 165 months. With the exception of fingernail clubbing (P = .03) and extravascular volume overload (P = .04), no presenting feature, including the number of presenting features, was predictive of survival. Response to therapy (P < .001) was predictive of survival. Pulmonary hypertension, renal failure, thrombotic events, and congestive heart failure were observed and appear to be part of the syndrome. In 18 patients (18%), new disease manifestations developed over time. More than 50% of patients had a response to radiation, and 22% to 50% had responses to prednisone and a combination of melphalan and prednisone, respectively. We conclude that the median survival of patients with POEMS syndrome is 165 months, independent of the number of syndrome features, bone lesions, or plasma cells at diagnosis. Additional features of the syndrome often develop, but the complications of classic multiple myeloma rarely develop.

Abstract The plasma cell labeling index (PCLI) is a measure of plasma cell proliferative activity and is an important prognostic factor in newly diagnosed multiple myeloma (MM). Occasionally patients have been observed with stable, plateau phase MM with minimal numbers of residual light-chain–restricted monoclonal plasma cells, but a high PCLI. No data are available on the outcomes for such patients. Data from 57 patients with plateau phase MM and a marrow PCLI of more than 1.0% were compared with 105 matched control patients with MM with a marrow PCLI of less than 1.0%. All patients had less than 10% total plasma cells on marrow aspirate and biopsy. The median time to progression and overall survival were 8 months and 20 months, respectively, in the high PCLI group versus 39 months and 56 months, respectively, in the low PCLI group (P &lt; .0001). These findings suggest that a high PCLI in patients with apparently stable, plateau phase MM is an adverse parameter that may predict a short time to disease progression and death.