Faculty Bibliography

The manifestations of bone involvement in patients with multiple myeloma (MM) can have devastating clinical effects and increase mortality. Recent studies demonstrate that patients with the precursor conditions smoldering MM (SMM) and monoclonal gammopathy of undetermined significance (MGUS) show evidence of bone disease and increased risk of fractures. The understanding of the pathogenesis of bone disease in MM has expanded in recent years. The traditional skeletal survey will probably be replaced by newer and more sensitive imaging techniques, which may have a prognostic impact and change our definition of MGUS and SMM. Bisphosphonates are recommended to prevent skeletal events in patients with MM, and have also been studied in SMM and MGUS. This article summarizes the current knowledge of bone disease in plasma cell disorders, and discusses the current standard and future role of novel imaging techniques, as well as the evidence and current guidelines for bisphosphonates in MM, SMM and MGUS.

Using population-based data from Sweden, we identified all multiple myeloma (MM) patients (n = 8740) and 5652 monoclonal gammopathy of undetermined significance (MGUS) patients diagnosed between 1986 and 2005. We calculated standardized incidence rates (SIRs) for all subsequent hematologic and nonhematologic malignancies for MM patients diagnosed before/after 1995 (introduction of high-dose melphalan/autologous stem cell transplantation [HDM-ASCT]) and 2000 (introduction of immunomodulatory drugs [IMiDs]), respectively. MM patients had an 11.51-fold (95% confidence interval: 8.19-15.74) increased risk of acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS); risk was very similar before/after 1995 and 2000, respectively. MGUS patients had an 8.01-fold (5.40-11.43) increased risk of AML/MDS. Risk was confined to IgG/IgA, while no IgM MGUS patients developed AML/MDS; patients with monoclonal-protein (M-protein) concentrations > 1.5 g/dL (SIR = 11.12; 3.61-25.96) had higher risk than those < 1.5 g/dL (SIR = 4.67; 1.71-10.16). An excess risk of nonmelanoma skin cancer was observed subsequent to both MM (SIR = 2.22; 1.74-2.80) and MGUS (SIR = 3.30; 2.76-3.90). Our novel observations of an excess risk for AML/MDS following IgG/IgA (but not IgM) MGUS, and the highest risk associated with M-protein concentrations > 1.5 g/dL, support a role for nontreatment-related factors in plasma cell dyscrasias. AML/MDS risk following MM was the same before/after the introduction of HDM-ASCT. Longer follow-up is needed to characterize second tumor risks in the IMiD era.

Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias, with a propensity to progress to symptomatic MM. In recent years there have been improvements in risk stratification models (involving molecular markers) of both disorders, which have led to better understanding of the biology and probability of progression of MGUS and SMM. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS and SMM represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. In this review we discuss the current standard of care of patients with MGUS and SMM, the use of risk models, including flow cytometry and free-light chain analyses, for predicting risk of progression. Emerging evidence from molecular studies on MGUS and SMM, involving cytogenetics, gene-expression profiling, and microRNA as well as molecular imaging is described. Finally, future directions for improving individualized management of MGUS and SMM patients, as well as the potential for developing early treatment strategies designed to delay and prevent development of MM are discussed.

Traditionally, the skeletal survey has been the standard modality for the detection of osteolytic bone disease in multiple myeloma. In addition to its poor sensitivity for the detection of osteolytic lesions, this modality is not able to identify extramedullary lesions and focal bone marrow involvement, nor measure response to therapy. The application of novel imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and molecular imaging such as fluorine-18 fluorodeoxyglucose positron emission tomography CT ((18)F-FDG PET/CT) and fluorine-18 sodium fluoride positron emission tomography CT ((18)F-NaF PET/CT) has the potential to overcome these limitations as well as provide prognostic information in precursor states and multiple myeloma. Also promising is the use of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to measure vascular permeability, an important feature of myelomagenesis. This review summarizes the current status and possible future role of novel imaging modalities in multiple myeloma and its precursor states.

Plasma cell neoplasms result from the clonal expansion of terminally differentiated, immunoglobulin heavy-chain class switched B cells that typically secrete a monoclonal immunoglobulin. The 2008 World Health Organization (WHO) classification of plasma cell neoplasms encompasses a broad spectrum of disorders, from the precursor disorder monoclonal gammopathy of undetermined significance (MGUS) to plasma cell leukemia. The classification includes, in addition to precursor lesion MGUS, plasma cell myeloma, plasmacytoma, immunoglobulin deposition diseases, and osteosclerotic myeloma. Plasma cell myeloma is further divided into symptomatic plasma cell myeloma or multiple myeloma (MM), asymptomatic smoldering myeloma (SMM), non-secretory myeloma, and plasma cell leukemia. Although histopathologic cut-off criteria are incorporated into the classification schema, distinction between MGUS, SMM, and MM depends primarily on the presence or absence of end-organ damage, as defined by "CRAB" criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions, or a combination of these). Systematic evaluation of pathogenetic differences between MGUS and MM should offer invaluable insights into early myelomagenesis. Given the complex, intertwined nature of the malignant plasma cell and its surroundings, multiple pathogenetic mechanisms play a critical role in interactions between neoplastic cells and their microenvironment. Understanding the events leading to end-organ damage, like anemia and bone remodeling, is a critical part of investigating early myelomagenesis and should provide us with better tools for early identification and treatment of these patients.

A number of cyclohexenyl chalcone Diels-Alder natural products possess promising biological properties including strong cytotoxicity in various human cancer cells. Herein, we show that natural products in this class including panduratin A and nicolaioidesin C inhibit cysteine cathepsins as indicated by protease profiling assays and cell-free cathepsin L enzyme assays. Owing to the critical roles of cathepsins in the biology of human tumor progression, invasion, and metastasis, these findings should pave the way for development of novel antitumor agents for use in clinical settings.

The level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of adverse events in patients with heart failure. We examined the relation between acute changes in NT-proBNP during a single hospitalization and subsequent mortality and readmission. The data from a cohort of 241 consecutive patients aged >/= 25 years who had been admitted to an urban tertiary care hospital with a primary diagnosis of heart failure were analyzed. Creatinine and NT-proBNP were measured at admission and at discharge of the first admission. The patient demographics, co-morbidities, and length of stay were collected. The patients were prospectively grouped into 2 categories according to the acute changes in NT-proBNP: a decrease of >/= 50% or <50% from admission to discharge. The primary composite outcome was readmission or death within 1 year of the first hospital admission. The unadjusted hazard ratio of readmission/death was 1.40 (95% confidence interval 0.97 to 2.01; p = 0.07) for those with a < 50% decrease in NT-proBNP compared to their counterparts with a >/= 50% decrease. After adjustment for age, gender, race, and admission creatinine and NT-proBNP, the risk of readmission/death was 57% greater for those with a < 50% decrease (hazard ratio 1.57, 95% confidence interval 1.08 to 2.28; p = 0.02). An adjustment for co-morbidity, length of stay, and left ventricular ejection fraction did not significantly change this relation. Reductions in NT-proBNP of < 50% during an acute hospitalization for heart failure might be associated with an increased hazard of readmission/death, independent of age, gender, race, creatinine, admission NT-proBNP, co-morbidities, left ventricular ejection fraction, and length of stay. In conclusion, patients with a < 50% reduction in NT-proBNP might benefit from more intensive medical treatment, monitoring, and follow-up.

CONTEXT: Atherosclerotic cardiovascular diseases, including coronary heart disease (CHD), carotid artery stenosis (CAS), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA), affect millions of U.S. adults and are leading causes of morbidity and mortality. There is some uncertainty regarding the utility of certain screening tests for prevention of cardiovascular morbidity and mortality. EVIDENCE ACQUISITION: Current guidelines and studies pertaining to CHD, CAS, PAD, and AAA screening in the adult population were reviewed. EVIDENCE SYNTHESIS: CHD risk can be estimated by the Framingham Risk Score (FRS), which is valuable in identifying high-risk asymptomatic adults who may benefit from preventive treatments. There is moderate certainty that the benefits of screening do not outweigh the harms for individuals with asymptomatic CAS. The potential harms associated with routine PAD screening in asymptomatic adults are also likely to exceed benefits. Ultrasonography is a safe, noninvasive, and reliable screening test used to identify AAAs for treatment in men aged >65 years who have ever smoked. CONCLUSIONS: American College of Preventive Medicine (ACPM) recommends CHD risk assessment using the FRS to guide risk-based therapy. ACPM does not recommend routine screening of the general adult population using electrocardiogram, exercise-stress testing, computed tomography scanning, ankle-brachial index, carotid intima medial thickness, or emerging risk factors, including high-sensitivity C-reactive protein (hs-CRP). ACPM does not recommend routine screening of the general adult population for CAS or PAD. ACPM recommends one-time AAA screening in men aged 65-75 years who have ever smoked. Routine AAA screening in women is not recommended.