A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.

Pericardial Effusion and Cardiac Tamponade Following Percutaneously Inserted Central Line Insertion in an Extremely Low-birth-weight Baby: Case Report and Successful Management.

Pericardial effusion and cardiac tamponade are rare complications of percutaneously inserted central lines (PICLs), in extremely low-birth-weight babies. This particular complication carries a high degree of mortality, if not suspected and diagnosed. Bedside echocardiography proves not only diagnostic but also can be lifesaving in these conditions. Here, we wish to report such a baby who suddenly deteriorated and showed cardiovascular instability 2 days after the insertion of PICL. Immediate bedside echocardiography helped pick up the effusion which was drained using a subxiphoid percutaneous approach.

Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With ≥3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD.

BACKGROUND: This retrospective study evaluated the treatment patterns in and overall survival (OS) of multiple myeloma (MM) patients who were refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or who had received three or more prior lines of therapy (LOTs) including a PI and an IMiD. METHODS: Electronic health records in the IMS LifeLink and OPTUM databases were screened for indexing periods of 2000-2014 and 2007-2014, respectively. Patients who were refractory to both a PI and an IMiD (criterion 1) or who received three or more prior LOTs (including a PI and an IMiD) and showed disease progression within 60 days of their most recent regimen (criterion 2) comprised the eligible population. Median OS from time of last LOT was assessed for the full cohort, cohorts meeting criteria 1 and 2, and clinically important subgroups. RESULTS: Of 3,929 and 3,837 patients with MM diagnoses evaluated in the IMS LifeLink and OPTUM databases, 500 and 162 met the eligibility criteria, respectively. Similar median OS was observed for eligible patients in the IMS LifeLink and OPTUM databases (7.9 vs. 7.9 months; p = .5358). In subgroup analyses of the IMS LifeLink data set, median OS was longer in patients <65 years of age than it was for those ≥65 years at eligibility (9.5 vs 6.7 months; p < .01) and in patients with good or unreported versus poor performance status at last claim (7.8 or 8.8 vs. 2.9 months; p < .0001). CONCLUSION: The findings of this survival analysis suggest that outcomes for these patients remain poor despite the availability of newer agents. IMPLICATIONS FOR PRACTICE: This real-world retrospective study of electronic health records examines the survival outcomes of patients with multiple myeloma who are heavily pretreated or highly refractory to currently approved treatments, including recently approved proteasome inhibitors and immunomodulatory drugs. This survival analysis showed that outcomes for these patients remain poor despite the availability of newer agents, with median overall survival of approximately 8 months. These findings highlight a critical need to develop novel therapies for these patients and also serve as a reference point against which emerging agents for heavily pretreated or highly refractory disease may be evaluated.

Bortezomib cumulative dose, efficacy, and tolerability with three different bortezomib-melphalan-prednisone regimens in previously untreated myeloma patients ineligible for high-dose therapy.

Substantial efficacy has been demonstrated with bortezomib-melphalan-prednisone in phase III studies in transplant-ineligible myeloma patients using various twice-weekly and once-weekly bortezomib dosing schedules. In VISTA, the regimen comprised four 6-week twice-weekly cycles, plus five 6-week once-weekly cycles. In the GIMEMA MM-03-05 study, the bortezomib-melphalan-prednisone regimen was either per VISTA ('GIMEMA twice-weekly'), or comprised nine 5-week once-weekly cycles ('GIMEMA once-weekly'). In the GEM2005MAS65 study, the regimen comprised one 6-week twice-weekly cycle, plus five 5-week once-weekly cycles. We evaluated the cumulative bortezomib dose administered during bortezomib-melphalan-prednisone, as well as efficacy and tolerability, using patient-level study data. Over all bortezomib-melphalan-prednisone cycles (nine in VISTA/GIMEMA; six in GEM2005MAS65), the median cumulative bortezomib dose administered was 38.5, 42.1, 40.3, and 32.9 mg/m(2) in VISTA, GIMEMA twice-weekly, GIMEMA once-weekly, and GEM2005MAS65, respectively, and the respective proportions of planned bortezomib dose actually delivered were 57.0%, 62.3%, 86.1%, and 90.4%. Response rates following bortezomib-melphalan-prednisone were 74-87% and appeared generally similar between studies. Three-year survival rates were 67.9-75.7% across studies. Grade 3/4 peripheral neuropathy rates were 13% in VISTA and 14% in GIMEMA twice-weekly, but were lower at 2% in GIMEMA once-weekly and 7% in GEM2005MAS65. Discontinuations and bortezomib dose reductions due to peripheral neuropathy were reduced in GIMEMA once-weekly versus VISTA and GIMEMA twice-weekly. Exclusive or predominant use of once-weekly bortezomib dosing in GIMEMA once-weekly and GEM2005MAS65 resulted in high efficacy, comparable with that demonstrated in VISTA, and similar cumulative bortezomib dose with reduced toxicity. Trials are registered with ClinicalTrials.gov: VISTA (Identifier:00111319), GIMEMA MM-03-05 (Identifier:01063179), and GEM2005MAS65 (Identifier:00443235).

Photophysical behavior of a new cholesterol attached coumarin derivative and fluorescence spectroscopic studies on its interaction with bile salt systems and lipid bilayer membranes.

A new fluorescent-cholesterol (Cum-Chl) molecule has been synthesized by attaching 3-acetyl-7-(diethylamino)-2H-chromen-2-one (Cum) to cholesterol via cholesterol bound ß-keto ester. The ß-keto ester was synthesized from the corresponding nitrile by applying the Blaise reaction. The molecule forms H-aggregates in solutions. The efficiency of aggregation is high in water. The H-aggregates are non-fluorescent in non-aqueous solvents but fluorescent in water. Aqueous bile salt media suppress the formation of H-aggregates, this effect being more pronounced for sodium deoxycholate (NaDC) which is more hydrophobic. With increasing bile salt concentration, the enhancement of monomeric fluorescence intensity of Cum-Chl generally follows the progressive miceller aggregation of bile salts. Incorporation of Cum-Chl into the dimyristoylphosphatidylcholine (DMPC) lipid bilayer membrane results in a significant enhancement of monomeric fluorescence intensity. The variation of fluorescence intensity is also sensitive to the thermotropic phase transition of the bilayer. It is seen that in such aqueous micro- and nanoscale organized media like bile salts and lipid bilayer membranes the monomer-to-aggregate fluorescence intensity ratio reflects the state of organization of the medium.

Randomized Phase III SIERRA Trial of 131I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML.

PURPOSE: Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate 131I-apamistamab with conventional care. METHODS: SIERRA (ClinicalTrials.gov identifier: NCT02665065) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an 131I-apamistamab-led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the 131I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive 131I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population. RESULTS: The ITT population included 153 patients (131I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received 131I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with 131I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring 131I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the 131I-apamistamab and conventional care groups, respectively. CONCLUSION: The 131I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. 131I-apamistamab was well tolerated and could address an unmet need in this population.

Efficacy of Antenatal Magnesium Sulfate for Neuroprotection in Extreme Prematurity: A Comparative Observational Study.

Background: Survival of preterm infants has improved drastically. In addition to significant contribution to neonatal mortality, impact of prematurity among survivors may continue through life impairing long-term physical life through neuro-disability and increased risk of cerebral palsy. Maternal administration of magnesium sulfate prior to impending preterm birth is an effective strategy to reduce neuromorbidity. Aim: To investigate the effectiveness of antenatal magnesium sulfate for neuroprotection in preterm infants between 26 and 34 weeks in preventing early neonatal morbidity and mortality. Secondary objective was to assess any adverse events with the use of magnesium sulfate on the mother and neonate. Method: This was a prospective observational comparative study for 2 years at our tertiary care hospital of 100 pregnant women who gave preterm births. Fifty infants each were born to mothers who were either not given MgSO4 (Group 1) or given 4gm intravenous loading dose MgSO4 (Group 2), preferably 4 h prior to preterm birth. Results: Among all the preterm in our study, 81% delivered between 30 and 34 weeks. There was no significant difference in terms of maternal mortality or serious morbidity including postpartum hemorrhage, caesarian section rates or length of hospital stay among women receiving MgSO4 versus no MgSO4. Mild maternal side effects secondary to magnesium sulfate were experienced in 8% cases. There were no significant differences between both groups for low 5 min APGAR, need for NICU admission, neonatal convulsions, hyperbilirubinemia, necrotizing enterocolitis, periventricular leukomalacia and septicemia. There was a trend toward reduced risk in the magnesium sulfate group for need for mechanical ventilation and ongoing respiratory support, intraventricular hemorrhage, neonatal hypotension, hypothermia, length of NICU stay. IVH was less frequent and less severe in babies exposed to antenatal MgSO4 (8%) as compared to non-MgSO4 group (16%). Neonatal morbidities were more when antenatal MgSO4 was given less than 4 h from delivery. Conclusion: MgSO4 is a safe drug to use in antenatal women at risk for impending preterm. Antenatal magnesium sulfate given to women in established preterm labor conferred significant neuroprotective advantage to the neonate. MgSO4 also has protective effect on the need of invasive ventilatory support in preterm infants. Given the breadth of evidence in its favor, it is time for us to start using MgSO4 in clinical practice for neuroprotective intent in all our extreme preterm births.

Squalamine lactate for exudative age-related macular degeneration.

Squalamine lactate inhibits angiogenesis by a long-lived, intracellular mechanism of action. The drug is taken up into activated endothelial cells through caveolae, small invaginations in the cellular membrane. Subsequently, the drug binds to and "chaperones" calmodulin to an intracellular membrane compartment and blocks angiogenesis at several levels. A series of basic investigations, preclinical studies, and human clinical trials have begun to establish the proof of concept, efficacy, and safety parameters for use of squalamine lactate as a therapeutic agent for exudative age-related macular degeneration and several types of malignancies.

A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical response, and pharmacokinetics of squalamine when administered as a 5-day continuous infusion in conjunction with standard chemotherapy every 3 weeks in patients with stage IIIB (pleural effusion) or stage IV non-small cell lung cancer. EXPERIMENTAL DESIGN: Patients with chemotherapy-naive non-small cell lung cancer were treated with escalating doses of squalamine in combination with standard doses of paclitaxel and carboplatin. Paclitaxel and carboplatin were administered on day 1, followed by squalamine as a continuous infusion on days 1-5, every 21 days. RESULTS: A total of 45 patients were enrolled (18 patients in the Phase I dose escalation arm and 27 in the Phase IIA arm). The starting dose of squalamine was 100 mg/m(2)/day and escalated to 400 mg/m(2)/day; two of three patients at 400 mg/m(2)/day had dose-limiting toxicity that included grade 3/4 arthralgia, myalgia, and neutropenia. On the basis of safety and toxicity, 300 mg/m(2)/day was selected as the Phase II dose of squalamine in this combination regimen. An additional 27 patients (a total of 33) were enrolled according to the protocol treatment schema at 300 mg/m(2)/day. There was no pharmacokinetic evidence of drug interactions for the combination of squalamine, carboplatin, and paclitaxel. Forty-three patients were evaluable for response. Partial tumor responses were observed in 12 (28%) of these patients; an additional 8 evaluable patients (19%) were reported to have stable disease. For all of the patients treated, the median survival was 10.0 months; and 1-year survival was 40%. CONCLUSIONS: The combination of squalamine given continuously daily for 5 days, with paclitaxel and carboplatin given on day 1, is well tolerated. Patient survival data and the safety profile of this drug combination suggests that the use of squalamine given at its maximum tolerated dose with cytotoxic chemotherapy should be explored further as a potentially effective therapeutic strategy for patients with stage IIIB or IV non-small cell lung cancer.

Use of a claims database to characterize and estimate the incidence rate for Castleman disease.

Castleman disease (CD) is a rare lymphoproliferative disorder affecting single (unicentric; UCD) or multiple (multicentric; MCD) lymph nodes. The incidence of this difficult to diagnose disease is poorly understood, as no International Classification of Diseases, Ninth Revision (ICD-9) code is available. This study utilized a unique strategy to estimate its incidence using two commercial claims databases, IMS LifeLink™ and Truven Health Analytics MarketScan(®). Patients with an index diagnosis of lymphadenopathy (ICD-9 code 785.6) were followed longitudinally for 1 year prior to and 2 years post-index diagnosis date. An algorithm that identifies potential patients with CD was developed to determine the incidence rate in person-years. The incidence rate for CD was calculated as 21 (IMS LifeLink™) and 25 (MarketScan(®)) per million person-years. Additionally, 23% of patients with CD were identified as potentially suffering from MCD. These results are consistent with the definition of an orphan disease, and the low incidence of the disease estimated in the literature.

Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials.

PURPOSE: To characterize efficacy and safety of bortezomib-based versus nonbortezomib-based induction regimens through an integrated analysis of data from phase III studies in transplantation-eligible patients with previously untreated myeloma. PATIENTS AND METHODS: Patient-level data from the IFM 2005-01 (bortezomib-dexamethasone v vincristine-doxorubicin-dexamethasone [VAD] induction), HOVON-65/GMMG-HD4 (bortezomib-doxorubicin-dexamethasone v VAD), and PETHEMA GEM05MENOS65 (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) studies were pooled in an integrated analysis of efficacy and safety. Study-level data from the GIMEMA MM-BO2005 study (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) supplemented the integrated patient-level analysis. Key efficacy end points were post-transplantation complete plus near-complete response (CR+nCR) rate and progression-free survival (PFS). RESULTS: Patient-level data for 1,572 patients (bortezomib-based induction, n = 787; nonbortezomib-based induction, n = 785) were included. Post-transplantation CR+nCR rate was significantly higher following bortezomib-based versus nonbortezomib-based induction (38% v 24%; odds ratio, 2.05; P < .001); the benefit remained similar (pooled odds ratio, 1.96) when GIMEMA MM-BO2005 data were included. Median PFS was 35.9 months versus 28.6 months with bortezomib-based versus nonbortezomib-based induction, respectively (hazard ratio, 0.75; P < .001); 3-year overall survival (OS) rates were 79.7% and 74.7%, respectively (hazard ratio for OS, 0.81; P = .0402). Median duration of induction treatment was 11 weeks in both treatment groups. Rates of peripheral neuropathy during induction were 34% versus 17% (grade ≥ 3, 6% v 1%). Overall, 3% and 4% of patients died during bortezomib-based and nonbortezomib-based induction, respectively. CONCLUSION: Bortezomib-based induction results in significant improvements in response and PFS/OS compared with nonbortezomib-based induction and is generally well tolerated, with a higher rate of peripheral neuropathy but no apparent increase in risk of death during induction.