Dingli, David

AbstractSymptomatic hyperviscosity is a well‐established phenomenon in Waldenström macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity‐related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre‐empt hyperviscosity‐related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate‐analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time‐to‐initial therapy was 6.9 years and only 15% developed hyperviscosity‐related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity‐related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM‐directed therapy.

Abstract The use of replication-competent viruses as oncolytic agents is rapidly expanding, with several oncolytic viruses approved for cancer therapy. As responses to therapy are highly variable, understanding the dynamics of therapy is critical for optimal application of virotherapy in practice. Although mathematical models have been developed to understand the dynamics of tumor virotherapy, a scarcity of in vivo data has made difficult parametrization of these models. To tackle this problem, we studied the in vitro and in vivo spread of two oncolytic measles viruses that induce expression of the sodium iodide symporter (NIS) in cells. NIS expression enabled infected cells to concentrate radioactive isotopes that could be reproducibly and quantitatively imaged using SPECT/CT. We observed a strong linear relationship in vitro between infectious virus particles, viral N and NIS gene expression, and radioactive isotope uptake. In vivo radioisotope uptake was highly correlated with viral N and NIS gene expression. Similar expression patterns between viral N and NIS gene expression in vitro and in vivo implied that the oncolytic virus behaved similarly in both scenarios. Significant titers of viable virus were consistently isolated from tumors explanted from mice that had been injected with oncolytic measle viruses. We observed a weaker but positive in vivo relationship between radioisotope uptake and the viable virus titer recovered from tumors; this was likely due to anisotropies in the viral distribution in vivo. These data suggest that methods that enable quantitation of in vivo anisotropies are required for continuing development of oncolytic virotherapy. Significance: These findings address a fundamental gap in our knowledge of oncolytic virotherapy by presenting technology that gives insight into the behavior of oncolytic viruses in vivo. Cancer Res; 78(20); 5992–6000. ©2018 AACR.

AbstractDetection of myeloma progression (PD) relies on serial 24‐h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24‐h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55‐312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase ≥ 25%, 94% had absolute increase in dFLC > 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC (n = 118), 89% had increase in dFLC ≥ 25%, 97% had dFLC increase of > 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24‐h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of >10 mg/dL from the nadir, a 24‐h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria.

Much remains unknown about how TREX1 influences HIV-1 replication: whether it targets full-length viral DNA versus partial intermediates, how intracellular TREX1 protein levels correlate with ISG induction, and whether TREX1 digestion of cytoplasmic DNA and subsequent cGAS pathway activation affects both initial and subsequent cycles of infection. To answer these questions, we experimentally varied the intracellular level of TREX1 and showed that this strongly determines the innate immunogenicity of HIV-1. In addition, several lines of evidence, including time-of-addition experiments with drugs that impair reverse transcription or capsid integrity, showed that the pathogen-associated molecular patterns sensed after viral entry contain DNA, are TREX1 and cGAS substrates, and are derived from incomplete reverse transcriptase (RT) products. In contrast, the experiments demonstrate that full-length integration-competent viral DNA is immune to TREX1. Treatment approaches that reduce TREX1 levels or facilitate release of DNA intermediates may advantageously combine enhanced innate immunity with antiviral effects.

Background: Heart involvement is the most important prognostic determinant in AL amyloidosis patients. Echocardiography is a cornerstone for the diagnosis and provides important prognostic information. Methods and Results: We studied 754 patients with AL amyloidosis who underwent echocardiographic assessment at the Mayo Clinic, including a Doppler-derived measurement of stroke volume (SV) within 30 days of their diagnosis to explore the prognostic role of echocardiographic variables in the context of a well-established soluble cardiac biomarker staging system. Reproducibility of SV, myocardial contraction fraction, and left ventricular strain was assessed in a separate, yet comparable, study cohort of 150 patients from the Pavia Amyloidosis Center. The echocardiographic measures most predictive for overall survival were SV index <33 mL/min, myocardial contraction fraction <34%, and cardiac index <2.4 L/min/m 2 with respective hazard ratios (95% confidence intervals) of 2.95 (2.37–3.66), 2.36 (1.96–2.85), and 2.32 (1.91–2.80). For the subset that had left ventricular strain performed, the prognostic cut point was −14% (hazard ratios, 2.70; 95% confidence intervals, 1.84–3.96). Each parameter was independent of systolic blood pressure, Mayo staging system (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and troponin), and ejection fraction on multivariable analysis. Simple predictive models for survival, including biomarker staging along with SV index or left ventricular strain, were generated. Conclusions: SV index prognostic performance was similar to left ventricular strain in predicting survival in AL amyloidosis, independently of biomarker staging. Because SV index is routinely calculated and widely available, it could serve as the preferred echocardiographic measure to predict outcomes in AL amyloidosis patients.

SummaryThe optimal duration of induction therapy (IT) in transplant‐eligible multiple myeloma (MM) patients in not well defined, resulting in a wide variation in clinical practice. The objective of our study was to determine whether the duration of IT in patients undergoing upfront autologous stem cell transplantation (ASCT) has an impact on progression‐free survival (PFS) in the era of proteasome inhibitors and immunomodulatory drugs. A total of 596 patients who underwent ASCT at Mayo Clinic between 2007 and 2014 were included. The patients were divided into two cohorts based on the duration of IT: IT ≤ 4 and IT > 4 months. At a median follow‐up of 54·5 months from ASCT, the median PFS in the IT ≤ 4 group was 28 months [95% confidence interval (CI), 25–33], compared to 26 months in the IT > 4 group (95% CI, 24–31) [P = 0·605]. There was no significant difference in overall survival (OS) in the two groups (P = 0·904). The lack of impact of IT duration on PFS and OS was consistent in subgroups with high‐risk features at diagnosis (International Staging System III or high‐risk cytogenetics) and different depths of pre‐transplant response [≥very good partial response (VGPR) and <VGPR]. In conclusion, prolonging the duration of IT beyond 4 months does not impact survival in patients with newly diagnosed MM who complete a single line of IT followed by consolidation with ASCT.

Key Points λ Light chain AL amyloidosis is associated with a shorter PFS and OS compared with κ. Light chain type predicts likelihood of organ involvement in AL amyloidosis.

Purpose Autologous stem-cell transplantation (ASCT) has been used in patients with immunoglobulin light chain (AL) amyloidosis for more than two decades. Early experience raised concerns regarding safety with high early-mortality rates. Patients and Methods We report 20 years of experience with ASCT for AL amyloidosis at the Mayo Clinic Rochester. In all, 672 consecutive patients receiving ASCT for AL amyloidosis were divided into three cohorts on the basis of date of transplantation (cohort 1, 1996-2002 [n = 124]; cohort 2, 2003-2009 [n = 302]; and cohort 3, 2010-2016 [n = 246]). Results The median age for the entire cohort was 59 years, with patients in cohort 3 being slightly older than those in the other two cohorts (60 v 58 v 54 years for cohorts 3, 2, and 1, respectively; P < .001). Fewer patients in cohort 3 had more than two organs involved (9% v 18% v 19% for cohorts 3, 2, and 1, respectively; P < .001). More patients received pretransplantation therapy in cohort 3 compared with earlier time periods (49% v 38% v 42% for cohorts 3, 2, and 1, respectively; P = .02). Hematologic response was higher in cohort 3 (84% v 79% v 69% for cohorts 3, 2, and 1, respectively; P = .002). Median overall survival for the entire cohort was 122 months and improved over time (not reached v 120 months v 75 months for cohorts 3, 2, and 1, respectively; P < .001). Treatment-related mortality declined over time (2.4% v 8.6% v 14.5% for cohorts 3, 2, and 1, respectively; P < .001). On multivariable analysis, conditioning dose, Mayo stage 2012, and hematologic response were independent predictors of survival. Conclusion ASCT is a highly effective therapy for AL amyloidosis. The improved survival and markedly reduced treatment-related mortality in eligible patients indicate that this will remain an important first-line option even in the era of treatment approaches that use novel agents.

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.