Citations

AbstractBackgroundWe aimed to determine the feasibility of monitoring viral delivery and initial distribution to solid tumors using iodinated contrast agent and micro‐computed tomography (CT).MethodsHuman BxPC‐3 pancreatic tumor xenografts were established in nude mice. An oncolytic measles virus with an additional transcriptional unit encoding the sodium iodide symporter (NIS), as a reporter for viral infection, was mixed with a 1:10 dilution of Omnipaque 300 (GE Healthcare, Milwaukee, WI, USA) contrast agent and injected directly into tumors. Mice were imaged with micro‐CT immediately before and after injection to determine the location of contrast agent/virus mixture. Mice were imaged again on day 3 after injection with micro‐single‐photon emission CT/CT to determine the location of NIS‐mediated 99mTcO4 transport.ResultsA 1:10 dilution of Omnipaque had no effect on viral infectivity or cell viability in vitro and was more than adequate for CT imaging of the intratumoral injectate distribution. The volume of tumor coverage with initial CT contrast agent and the 3‐day postinfection measurement of virally infected tumor volume were significantly correlated. Additionally, regions of the tumor that did not receive contrast agent from the initial injection were largely devoid of viral infection at early time points.ConclusionsContrast‐enhanced viral delivery enables a rapid and accurate prediction of the initial viral distribution within a solid tumor. This technique should enable real‐time monitoring of viral propagation from initially infected tumor regions to adjacent tumor regions. Copyright © 2012 John Wiley & Sons, Ltd.

Abstract Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).

Abstract Immunoglobulin light-chain (AL) amyloidosis is a rare, incurable plasma cell disorder. Its therapy has benefited immensely from the expanding drug armamentarium available for multiple myeloma. Pomalidomide in combination with weekly dexamethasone (Pom/dex) is active among patients with relapsed myeloma. In the present study, we explored the Pom/dex combination in patients with previously treated AL. Patients were eligible for this prospective phase 2 trial if they had had at least one prior regimen and if they had reasonably preserved organ function. Patients were treated with oral Pom/dex. Thirty-three patients were enrolled. The median age was 66 years. Median time from diagnosis to on-study was 37 months. Eighty-two percent had cardiac involvement. The confirmed hematologic response rate was 48%, with a median time to response of 1.9 months. Organ improvement was documented in 5 patients. The median overall and progression-free survival rates were 28 and 14 months, respectively; the 1-year overall and progression-free survival rates were 76% and 59%, respectively. There was a discordance between the hematologic response and the N-terminal pro-brain natriuretic peptide response. The most common grade 3-5 adverse events, regardless of attribution, were neutropenia and fatigue. We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896.

Purpose Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification. Patients and Methods We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials. Results We examined the prognostic value of plasma cell–related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β 2 microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets. Conclusion Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.

Abstract Routine incorporation of FISH into multiple myeloma (MM) diagnostic testing has led to a better appreciation of the heterogeneity of genetic abnormalities associated with this disease. We studied a group of 484 patients with newly diagnosed symptomatic MM to better understand the prevalence of the various abnormalities and the prognostic significance of the overlapping abnormalities. A translocation involving the IgH locus and 1 of the 5 recurrent partner chromosomes was seen in 161 (33%) patients, and 275 (57%) had trisomy of at least 1 odd-numbered chromosome. High-risk FISH, defined as the presence of t(4;14), t(14;16), t(14;20), or loss of P53, was seen in 115 (24%) patients; the median overall survival for this group was 3.9 years, compared with “not reached” for standard-risk patients (P < .001). Among the patients with high-risk FISH, 49 patients who also had at least 1 trisomy had a median overall survival that was not reached, compared with 3 years for high-risk patients without a concurrent trisomy (P = .01). Based on the current findings, we conclude that the presence of trisomies in patients with t(4;14), t(14;16), t(14;20), or p53 deletion abnormalities in MM ameliorates the usual adverse impact associated with these prognostic markers.

Abstract IgD monoclonal gammopathies are uncommon. They are seen rarely as a monoclonal gammopathy of undetermined significance and are present in 1%-2% of patients with multiple myeloma. In light-chain amyloidosis, IgD monoclonal proteins are found in ap-proximately 1% of patients. When an IgD monoclonal protein is found, amyloidosis is often omitted from the differential diagnosis. In the present study, we reviewed the natural history of IgD-associated amyloidosis among 53 patients seen over 41 years. The distribution of clinical syndromes suggests that these patients have a lower frequency of renal and cardiac involvement. The overall survival of these patients does not appear to be different from that of patients who have light-chain amyloidosis associated with another monoclonal protein.

Abstract The POEMS syndrome is associated with elevated vascular endothelial growth factor (VEGF) levels. Several studies have compared serum VEGF levels between POEMS patients and other disease entities showing higher serum VEGF in POEMS syndrome; however, it is unknown whether serum levels are reliable and reproducible given variable platelet release of VEGF. We therefore compared plasma levels of VEGF in 29 patients with POEMS syndrome with those of other disorders (n = 76). We demonstrated that plasma VEGF levels are useful in differentiating POEMS from other plasma cell dyscrasias, neuropathic processes, and multisystem illnesses. Plasma VEGF is also useful in monitoring disease activity after treatment and correlates with clinical improvements better than hematologic response.