Herpesviral encephalitis associated with bortezomib use in a patient with multiple myeloma and associated light-chain amyloidosis.

INTRODUCTION: Bortezomib is proteasome inhibitor used in multiple myeloma treatment. The reactivation of herpes simplex virus (HSV) and varicella-zoster virus (VZV) during bortezomib-based therapy is a well-known adverse event. Antiviral prophylaxis is mandatory. Nevertheless, reports of herpesviral encephalitis are scarce. CASE REPORT: A 57-year-old multiple myeloma patient who during CyBorD protocol (Bortezomib, cyclophosphamide, and dexamethasone), after a transient suspension of antiviral prophylaxis presented progressive headaches unresponsive to conventional analgesics, asthenia, fever, episodic visual hallucinations, and vesicular lesions in the right supraorbital and frontal region. Herpetic encephalitis was diagnosed after detecting herpes zoster in cerebrospinal fluid. MANAGEMENT & OUTCOME: The patient was treated with acyclovir 500mg every 6 hours for 21 days, and subsequent valacyclovir prophylaxis achieving an excellent clinical evolution. Anti-myeloma treatment was changed to lenalidomide and dexamethasone achieving a durable complete response. Herpesviral encephalitis is a rare but severe complication associated with the use of Bortezomib, especially when patients did not receive acyclovir prophylaxis. However, a rapid detection based on the clinical suspicion, and the prompt start of treatment, may lead to overcome this adverse event.

"Protocol for a phase 2, randomized, double-blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-myocardial infarction": study protocol for a randomized controlled trial.

BACKGROUND: Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Previous trials using bone marrow cells, selected stem cell populations, or cardiac stem cell progenitors require invasive procedures and had so far inconclusive results. A less invasive approach utilizes granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to circulating blood and induce neovascularization and differentiation into endothelial cells and cardiomyocytes. Stromal cell-derived factor 1 alpha (SDF-1α) is an important chemokine for initiating stem cell migration and homing to ischemic myocardium. SDF-1α concentrations can be increased by inhibition of CD26/DPP4. Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model. METHODS: We test the safety and tolerability and efficacy of dutogliptin in combination with filgrastim (G-CSF) in patients with STEMI (EF < 45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect > 3.8% improvement in left ventricular ejection fraction (LV-EF) compared to placebo. One hundred forty subjects will be randomized to filgrastim plus dutogliptin or matching placebos. DISCUSSION: The REC-DUT-002 trial is the first to evaluate dutogliptin in combination with G-CSF in patients with STEMI. Results will lay the foundation for an appropriately powered cardiovascular outcome trial to test the efficacy of this combined pharmacological strategy. TRIAL REGISTRATION: EudraCT no.: 2018-000916-75 . Registered on 7 June 2018. IND number: 123717.

An Update on Existing and Emerging Data for Meropenem-Vaborbactam.

PURPOSE: The search for new agents to treat multidrug-resistant gram-negative bacterial infections has been ongoing. Specifically, carbapenem-resistant Enterobacteriaceae (CRE) infections often exhibit multiple resistance mechanisms, including alterations in drug structure, bacterial efflux pumps, and drug permeability. Vaborbactam, a cyclic boronic acid pharmacophore, has the highest potency in vitro with meropenem as an inhibitor of class A carbapenemases, including Klebsiella pneumoniae carbapenemase (KPC). This combination product was approved by the US Food and Drug Administration for complicated urinary tract infections (cUTIs) in August 2017, and recent Phase III trial data have expanded the literature available. This article aimed to describe the literature regarding spectrum of activity, dosing and administration, including pharmacokinetic and pharmacodynamics properties, safety profile, and efficacy end points. METHODS: The terms meropenem, vaborbactam, RPX7009, and meropenem-vaborbactam were used to search for literature via PubMed, ClinicalTrials.gov, and published abstracts from 2013 to July 2019. Abstracts from IDWeek 2019 were also searched via these terms. Results were limited to availability in English. FINDINGS: Meropenem-vaborbactam covers a spectrum of gram-negative bacterial pathogens, including K pneumoniae, Escherichia coli, and Enterobacter cloacae complex. Although the addition of vaborbactam to meropenem results in MIC lowering for KPC-positive Enterobacteriaceae, in vitro data reveal limited activity against resistant strains of Acinetobacter species and Pseudomonas aeruginosa. Data from 2 Phase III studies compare the drug with available therapies for the following indications: cUTIs, acute pyelonephritis, hospital-acquired and ventilator-acquired bacterial pneumonia, bacteremia, and complicated intra-abdominal infections. Outcomes include an improvement in clinical success when compared with piperacillin-tazobactam (98.4% vs 94%; 95% CI, 0.7%-9.1%; P < 0.001 for noninferiority) for overall treatment of cUTIs and acute pyelonephritis and clinical cure (64.3% vs 33.3%; P = 0.04) when compared with best available therapy for CRE infections in various sites of infection. Adverse events have been described as mild to moderate, with few events requiring discontinuation of the drug therapy. IMPLICATIONS: Currently, meropenem-vaborbactam is approved for treatment of cUTIs and acute pyelonephritis; however, off-label use, in particular for CRE infections, appears beneficial. Clinical trials to date have found an improvement in clinical cure and potentially an improved tolerability compared with standard therapies. Most of the evidence for meropenem-vaborbactam activity and the role in therapy focuses on KPC-producing organisms; however, because in vitro activity has been found with some non-KPC-producing CRE, its role may be further described from upcoming in vivo cases and postmarketing research.

Safety, tolerability, pharmacokinetics and pharmacodynamics of parenterally administered dutogliptin: A prospective dose-escalating trial.

AIMS: Animal studies suggest that inhibition of dipeptidyl peptidase 4 (DPP-IV) may improve heart function and survival after myocardial infarction by increasing cardiac myocytes' regenerative capacity. Parenterally administered dutogliptin may provide continuous strong DPP-IV inhibition to translate these results into humans. This trial investigated the safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of parenterally administered dutogliptin after single and repeated doses. METHODS: In an open-label trial, volunteers received dutogliptin at increasing doses of 30-120 mg subcutaneously or 30 mg intravenously in the single-dose cohorts. Subjects in the multiple-dose cohort received 60, 90 or 120 mg dutogliptin subcutaneously once daily on 7 consecutive days. RESULTS: Forty healthy males were included in the trial. No related serious adverse events occurred. Mild local injection site reactions with no requirement for intervention comprised 147 of 153 (96%) related adverse events. Subcutaneous bioavailability was approximately 100%. Multiple injections at daily intervals did not lead to the accumulation of the study drug. The accumulation ratios based on AUC0-24h range from 0.90 to 1.03, supporting this argument. All subjects receiving ≥60 mg dutogliptin yielded a maximum DPP-IV inhibition >90%. The duration of DPP-IV inhibition over time increased in a dose-dependent manner and was highest in the 120-mg multiple-dosing cohort with a maximum AUEC0-24h of 342 h % (standard deviation: 73), translating into 86% DPP-IV inhibition 24 hours after dosing. CONCLUSION: Parenteral injection of dutogliptin was safe and subcutaneous bioavailability is excellent. DPP-IV inhibition increased dose dependently to >86% over 24 hours after multiple doses of 120 mg dutogliptin.

Chemical proteasome inhibition as a novel animal model of inner retinal degeneration in rats.

Chemical proteasome inhibition has been a valuable animal model of neurodegeneration to uncover roles for the ubiquitin-proteasome system in the central nervous system. However, little is known about the effects of chemical proteasome inhibitors on retinal integrity. Therefore, we characterized the effects of structurally different chemical proteasome inhibitors on the retinal morphology and the mechanisms of their action in the normal adult rat eyes. Intravitreal injection of MG-262 and other proteasome inhibitors led to inner retinal degeneration. MG-262-induced inner retinal degeneration was accompanied by reduced proteasome activity, increased poly-ubiquitinated protein levels, and increased positive immunostaining of ubiquitin, 20S proteasome subunit and GADD153/CHOP in the retina. Its retinal degenerative effect was also associated with reduced retinal neurofilament light chain gene expression, reflecting retinal ganglion cell death. MG-262-induced neurofilament light chain downregulation was largely resistant to pharmacological modulation including endoplasmic reticulum stress, apoptosis or MAP kinase inhibitors. Thus, this study provides further evidence of roles for the ubiquitin-proteasome system in the maintenance of the retinal structural integrity. Chemical proteasome inhibition may be used as a novel animal model of inner retinal degeneration, including retinal ganglion cell loss, which warrants further analysis of the molecular mechanisms underlying its retinal degenerative effect.

Meropenem-vaborbactam for adults with complicated urinary tract and other invasive infections.

INTRODUCTION: Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat among uropathogens with significant morbidity and mortality. Meropenem-vaborbactam is a novel carbapenem and cyclic boronic acid-based beta-lactamase inhibitor combination with potent activity against subtypes of CRE. Areas covered: This article reviews mechanisms of carbapenem resistance, existing treatment options for CRE, and the current evidence to support the use of meropenem-vaborbactam for the treatment of infections caused by subtypes of CRE including complicated urinary tract infections. Expert commentary: Meropenem-vaborbactam is a superior treatment option for infections secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. It is associated with higher rates of treatment success and lower rates of toxicity than traditional agents and demonstrates a potentially higher barrier to acquired antimicrobial resistance than ceftazidime-avibactam. At present, meropenem-vaborbactam should be regarded as a preferred treatment option for invasive infections secondary to KPC-producing CRE.

Meropenem-vaborbactam: a new weapon in the war against infections due to resistant Gram-negative bacteria.

Meropenem-vaborbactam is a fixed-dose combination product of a carbapenem and a cyclic boronic acid ß-lactamase inhibitor with potent in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE). The efficacy of meropenem-vaborbactam for the treatment of complicated urinary tract infections and acute pyelonephritis was demonstrated in a Phase III trial (TANGO I). Preliminary data from TANGO II, a separate Phase III study, support the efficacy of meropenem-vaborbactam for the treatment of infections caused by CRE. Overall, meropenem-vaborbactam appears to be safe and well tolerated. It has favorable toxicity, pharmacokinetic and pharmacodynamic profiles compared with other antibiotics with activity against CRE. Meropenem-vaborbactam is an important addition to the current armamentarium of antimicrobial agents with activity against K. pneumoniae carbapenemase-producing CRE.

Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial.

Importance: Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. Objective: To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. Design, Setting, and Participants: Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (≥18 years) with complicated UTI, stratified by infection type and geographic region. Interventions: Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. Main Outcomes and Measures: Primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was -15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95% CIs were calculated. Results: Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, -0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, -4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam. Conclusions and Relevance: Among patients with complicated UTI, including acute pyelonephritis and growth of a baseline pathogen, meropenem-vaborbactam vs piperacillin-tazobactam resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Further research is needed to understand the spectrum of patients in whom meropenem-vaborbactam offers a clinical advantage. Trial Registration: clinicaltrials.gov Identifier: NCT02166476.

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects.

Meropenem-vaborbactam is a fixed combination of the novel ß-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.).

Meropenem/vaborbactam fixed combination for the treatment of patients with complicated urinary tract infections.

On August 29, 2017, the United States Food and Drug Administration (FDA) approved meropenem/ vaborbactam fixed combination for the treatment of adults with complicated urinary tract infections (cUTI). The decision was based on substantial preclinical and clinical data, including two recent trials involving hundreds of adults with cUTI. Meropenem/ vaborbactam represents a powerful new treatment option to address antibiotic-resistant pathogens, including Klebsiella pneumoniae carbapenemase-producing bacteria. In this paper, we examine the work that led to FDA approval, with special emphasis on molecular pharmacology, pharmacokinetics, metabolism, efficacy and drug safety. We also look ahead, to explore how this promising new antimicrobial agent might be used in the near future to confront other drug-resistant infections..

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (ß5/ß1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the ß-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects.

Vaborbactam (formerly RPX7009) is a member of a new class of ß-lactamase inhibitor with pharmacokinetic properties similar to those of many ß-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmax and area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0-∞) was 144.00 ± 13.90 mg · h/liter, and the Vss was 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistant Enterobacteriaceae (CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.).

Hydrogen sulfide in posthemorrhagic shock mesenteric lymph drainage alleviates kidney injury in rats

Posthemorrhagic shock mesenteric lymph (PHSML) is a key factor in multiple organ injury following hemorrhagic shock. We investigated the role of hydrogen sulfide (H2S) in PHSML drainage in alleviating acute kidney injury (AKI) by administering D,L-propargylglycine (PPG) and sodium hydrosulfide hydrate (NaHS) to 12 specific pathogen-free male Wistar rats with PHSML drainage. A hemorrhagic shock model was established in 4 experimental groups: shock, shock+drainage, shock+drainage+PPG (45 mg/kg, 0.5 h prehemorrhage), and shock+drainage+NaHS (28 µmol/kg, 0.5 h prehemorrhage). Fluid resuscitation was performed after 1 h of hypotension, and PHMSL was drained in the last three groups for 3 h after resuscitation. Renal function and histomorphology were assessed along with levels of H2S, cystathionine-γ-lyase (CSE), Toll-like receptor 4 (TLR4), interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-α in renal tissue. Hemorrhagic shock induced AKI with increased urea and creatinine levels in plasma and higher H2S, CSE, TLR4, IL-10, IL-12, and TNF-α levels in renal tissue. PHSML drainage significantly reduced urea, creatinine, H2S, CSE, and TNF-α but not TLR4, IL-10, or IL-12. PPG decreased creatinine, H2S, IL-10, and TNF-α levels, but this effect was reversed by NaHS administration. In conclusion, PHSML drainage alleviated AKI following hemorrhagic shock by preventing increases in H2S and H2S-mediated inflammation.

Measurement of Proteasome Activity in Peripheral Blood Mononuclear Cells as an Indicator of Susceptibility to Bortezomib-Induced Severe Neurological Adverse Events in Patients with Multiple Myeloma.

AIMS: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells. METHODS: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate. RESULTS: Bortezomib injection resulted in a dramatic decrease in proteasome activity, reaching 32.4 ± 18.79% (mean ± SD) of the pretreatment level at 1 h, but it generally recovered at the end of the first course. In total, 6 patients manifested with severe bortezomib-induced peripheral neuropathy (sBIPN) in the second-third course. There was a nonsignificant trend for these patients to have lower levels of the relative proteasome activity at the end of the first course than those without sBIPN (median: 74.03 vs. 103.2%, p = 0.052). Moreover, in all of them, proteasome activity did not recover to the pretreatment level, whereas no patients with complete recovery manifested with sBIPN. Analysis with Fisher's exact test demonstrated that incomplete recovery of proteasome activity is a significant risk factor for sBIPN (p = 0.014). CONCLUSION: Patients with incomplete recovery of proteasome activity are at high risk for developing sBIPN, and the susceptible patients can be indicated by monitoring proteasome activity.

Bortezomib-induced peripheral neurotoxicity in human multiple myeloma-bearing mice.

The proteasome inhibitor bortezomib is an antineoplastic drug mainly used for the treatment of multiple myeloma (MM). Despite its effectiveness, bortezomib clinical use is often limited by the onset of peripheral neuropathy (BiPN). To better understand the mechanisms of BiPN several rat and mice models have been proposed, but no studies in MM-bearing animals allowing to test the antitumor activity of the selected schedules and the role of MM by itself in peripheral nervous system damage have been reported to date. Here, we carried out a study using immunodeficient C.B-17/Prkdcscid (SCID) mice injected with RPMI8266 human MM cells and treated with bortezomib 1 mg/kg once a week for five weeks. Animals were assessed with neurophysiological, behavioral and pathological methods and tumor volume measurement was performed along the study. At the end of the study BiPN was evident in bortezomib-treated animals, and this neurotoxic effect was evident using a schedule able to effectively prevent tumor growth. However, neurophysiological and pathological evidence of MM induced peripheral nervous system damage was also reported. This model based on MM-bearing animals is more reliable in the reproduction of the clinical setting and it is, therefore, more suitable than the previously reported models of BiPN to study its pathogenesis. Moreover, it represents an optimal model to test the efficacy of neuroprotective agents and at the same time their non-interference with bortezomib antineoplastic activity.

Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma.

BACKGROUND: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma. METHODS: In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival. RESULTS: After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group. CONCLUSIONS: VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).

[Bortezomib-associated acute congestive heart failure in a patient with multiple myeloma].

We report an 81-year-old woman with multiple myeloma who developed acute cardiac injury after receiving bortezomib. The patient received weekly intravenous bortezomib. She developed shortness of breath and bilateral pedal edema on day 19. Electrocardiography showed no ST-T changes but the cardio-thoracic ratio was increased, the ejection fraction was decreased, the ventricular septum showed hypokinesis and mitral regurgitation was noted. We stopped bortezomib and started acute congestive heart failure treatment. ST-T changes were detected after the patient's condition improved. There was no evidence of coronary stenosis on CT angiography. Acute cardiac injury is rare during bortezomib administration, but patients should be monitored carefully during treatment.

Treatment-related symptom management in patients with multiple myeloma: a review.

PURPOSE: Recent therapeutic advancements have significantly improved overall survival of patients with multiple myeloma (MM). As a result, the impact of disease- and treatment-related symptoms must be managed effectively to improve patient quality of life, given prolonged survival after diagnosis. This review discusses current MM treatment options, effective symptom management approaches, and practical strategies for supportive care. METHODS: A literature search was performed using MEDLINE/PubMed and scientific congress databases, focusing on clinical trials, review articles, clinical practice guidelines, and other guidance documents on treatment paradigms and supportive care strategies in MM. Additionally, clinical practice worksheets were developed from published sources, and nursing "pearls of wisdom" were gathered from practical experience in the clinic. RESULTS: Current therapeutic regimens for relapsed/refractory MM include proteasome inhibitors (i.e., bortezomib, carfilzomib) and immunomodulatory agents (i.e., thalidomide, lenalidomide, pomalidomide), alone or in combination with chemotherapy or corticosteroids. Toxicities associated with agents and combination regimens used in the treatment of MM include myelosuppression, venous thromboembolism, peripheral neuropathy, infections, fatigue, gastrointestinal disorders, and/or cardiac events. Treatment-specific tools and clinical assessments can be useful for optimizing dosing and schedule adjustments to increase therapy duration, and implementing supportive care strategies (e.g., growth factors, transfusional support, intravenous hydration, bisphosphonates, antiviral therapies) to manage treatment-related symptoms. CONCLUSIONS: Improved survival after MM diagnosis has led to increased patient susceptibility to other diseases and comorbidities due to advanced age. In addition to appropriate drug dosing and administration, effective supportive care and health maintenance are crucial for maximizing quality of life and disease control.