Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis.

Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL). This retrospective cohort includes 43 patients with previously treated AL, from 14 centers in the US and Europe. Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown. Patients received a venetoclax-containing regimen for at least one 21- or 28-day cycle; the median prior treatments was three. The hematologic response rate for all patients was 68%; 63% achieved VGPR/CR. t(11;14) patients had higher hematologic response (81% vs. 40%) and higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02-0.62) than non-t(11;14) patients. For the unsegregated cohort, median progression-free survival (PFS) was 31.0 months and median OS was not reached (NR). For t(11;14), median PFS was NR and for non-t(11;14) median PFS was 6.7 months (HR: 0.14, 95% CI 0.04-0.53). Multivariate analysis incorporating age, sex, prior lines of therapy, and disease stage suggested a risk reduction for progression or death in t(11;14) patients. Median OS was NR for either subgroup. The organ response rate was 38%; most responders harbored t(11;14). Grade 3 or higher adverse events occurred in 19% with 7% due to infections. These promising results require confirmation in a randomized clinical trial.

Modern Treatments and Future Directions for Relapsed/Refractory Multiple Myeloma Patients.

Since the introduction of proteasome inhibitors, immunomodulators, and monoclonal antibodies, the longevity of a patient with multiple myeloma has greatly improved. Although prognosis is improving, multiple myeloma remains an incurable disease and most patients will inevitably relapse. With new studies and prospective trials being published every few months, the landscape of multiple myeloma treatment is changing and sequencing treatments remains complex. In this review, we discuss the current data and approaches to treating a patient with relapsed/refractory multiple myeloma.

Use of daratumumab in high risk multiple myeloma: A meta-analysis.

Daratumumab is approved for use in newly diagnosed and relapsed/refractory multiple myeloma (MM), however the patients most likely to benefit from its addition to standard anti-myeloma therapy is unclear. This meta-analysis included 2340 newly diagnosed MM patients (1982 with standard risk and 358 with high risk cytogenetics) and 673 patients with relapsed/refractory MM (513 with standard risk and 160 with high risk cytogenetics) to assess which cytogenetic subgroups derived PFS benefit from Daratumumab. Studies included were the CASSIOPEIA, MAIA and ALCYONE (for newly diagnosed MM) and the CASTOR and POLLUX trials (for relapsed/refractory MM). Daratumumab's addition led to a clear benefit in standard risk newly diagnosed MM (HR 0.43; 95% CI, 0.35-0.53; P < .05) and both high and standard risk relapsed/refractory disease (HR 0.28; 95% CI, 0.21-0.36; P < .05 and HR 0.48; 95% CI, 0.30-0.76; P < .05, respectively). No clear benefit was seen in newly diagnosed high risk MM. These findings fail to demonstrate PFS benefit from Daratumumab's addition in high risk newly diagnosed MM. Data forthcoming from the GRIFFIN and MASTER trials may increase the power of the study and provide a definitive answer. Daratumumab remains important in standard risk upfront and relapsed/refractory MM and high risk relapsed/refractory MM.

Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.

The system L neutral amino acid transporter (LAT; LAT1, LAT2, LAT3, or LAT4) has multiple functions in human biology, including the cellular import of S-nitrosothiols (SNOs), biologically active derivatives of nitric oxide (NO). SNO formation by haemoglobin within red blood cells (RBC) has been studied, but the conduit whereby a SNO leaves the RBC remains unidentified. Here we hypothesised that SNO export by RBCs may also depend on LAT activity, and investigated the role of RBC LAT in modulating SNO-sensitive RBC-endothelial cell (EC) adhesion. We used multiple pharmacologic inhibitors of LAT in vitro and in vivo to test the role of LAT in SNO export from RBCs and in thereby modulating RBC-EC adhesion. Inhibition of human RBC LAT by type-1-specific or nonspecific LAT antagonists increased RBC-endothelial adhesivity in vitro, and LAT inhibitors tended to increase post-transfusion RBC sequestration in the lung and decreased oxygenation in vivo. A LAT1-specific inhibitor attenuated SNO export from RBCs, and we demonstrated LAT1 in RBC membranes and LAT1 mRNA in reticulocytes. The proadhesive effects of inhibiting LAT1 could be overcome by supplemental L-CSNO (S-nitroso-L-cysteine), but not D-CSNO or L-Cys, and suggest a basal anti-adhesive role for stereospecific intercellular SNO transport. This study reveals for the first time a novel role of LAT1 in the export of SNOs from RBCs to prevent their adhesion to ECs. The findings have implications for the mechanisms of intercellular SNO signalling, and for thrombosis, sickle cell disease, and post-storage RBC transfusion, when RBC adhesivity is increased.

Primary large B-cell cardiac lymphoma.

Primary cardiac lymphomas are rare. They can be detected incidentally during echocardiography or cardiac operation. They can have various clinical manifestations. We report a case of primary cardiac large B-cell lymphoma in a 66-year-old man with symptoms of chest pain and light-headedness who was found to have a right atrial mass with echocardiography and without right ventricular outflow tract obstruction or pericardial involvement.