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Marizomib ( MRZ) is an irreversible, pan-subunit proteasome inhibitor ( PI) in clinical development for relapsed/refractory multiple myeloma ( RRMM) and glioma. This study analysed MRZ, pomalidomide ( POM) and low-dose dexamethasone (Lo- DEX) [ PMD] in RRMM to evaluate safety and determine the maximum tolerated dose ( MTD) and/or recommended Phase 2 dose ( RP2D). Intravenous MRZ (0·3-0·5 mg/m2) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo- DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities ( DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients. [ABSTRACT FROM AUTHOR]

Background The objective of this review was to determine the impact of immunomodulatory drugs (IMiDs) and proteasome inhibitor (PI)–based therapy on infection risk in patients with myeloma across three treatment periods: induction, maintenance therapy and relapse/refractory disease (RRMM). Methods A systematic review and meta-analysis of randomised controlled trials (RCT) of IMiD and PI-based therapy versus conventional therapy from 1990 to 2015 using MEDLINE, EMBASE and CENTRAL was conducted. Study methods, characteristics, interventions, outcomes and rate of infection were extracted using a standardised tool. Findings Thirty RCTs of 13,105 patients fulfilled inclusion criteria. The rate of severe infection with the use of IMiD-based therapy was 13.4%, 22.4%, 10.5% and 16.6% for induction therapy for non-transplant- and transplant-eligible patients, maintenance therapy and therapy for RRMM, respectively. Rate of severe infection with PI-based induction in transplant-eligible patients was 19.7%. Compared to conventional therapy, use of IMiD-based induction therapy was associated with reduced risk for transplant patients (RR 0.76, p < 0.01). There was no significant difference with PI-based therapy. For maintenance therapy and RRMM, use of IMiD-based therapy was significantly associated with 74% and 51% increased risk of severe infection, respectively. Compared to thalidomide, bortezomib-based induction therapy and lenalidomide maintenance therapy were associated with increased risk of severe infection (RR 2.03, p < 0.01; RR 1.95, p = 0.03). Interpretation The differential impact of myeloma therapies on risk for infection and the effect of treatment phases upon risk have now been established. Thalidomide is associated with the lowest risk of severe infection when used for induction and maintenance therapy. Funding Fight Cancer Foundation . [ABSTRACT FROM AUTHOR]

Introduction: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma. The epidemiology, risk factors and outcomes of viral respiratory tract infections (vRTI) are not well described in patients with multiple myeloma managed with novel agents, the current standard of care. Methods: Patients with myeloma from 2009 to 2012 who tested positive on respiratory virus multiplex polymerase chain reaction had clinical, radiological and microbiological records reviewed. The Fourth European Conference on Infections in Leukaemia (ECIL-4) definitions of RTI were applied. Univariate and multivariate regression analysis of risk factors was performed using vRTI as the evaluable outcome. Results: Of 330 patients, 75 (22.7 %) tested positive for a total of 100 vRTI episodes. All patients received thalidomide, lenalidomide or bortezomib in combination with myeloma therapies (median of three treatment regimens). vRTI occurred most commonly in patients with progressive disease, and receipt of more than three lines of myeloma therapy was associated with an increased risk of vRTI ( p < 0.01). Amongst key respiratory pathogens, influenza was associated with the highest hospital admission rate (66.7 %), ICU admission rate (41.6 %) and mortality (33.3 %) whilst RSV was associated with prolonged hospital stay. Conclusion: Patients with multiple myeloma and advanced disease managed with multiple lines of therapy are at risk for vRTI, and targeted interventions for prevention/treatment are required. [ABSTRACT FROM AUTHOR]

In multiple myeloma (MM), it remains unclear whether the depth of response correlates with progression-free survival (PFS) and overall survival (OS). We updated long-term follow-up data on the two previously published multi-centre phase-II trials in patients with relapsed or refractory MM using thalidomide ± IFNα-2B (n = 75, median follow-up 6.1 years) celecoxib-thalidomide combination (n = 66, median follow-up 4.0 years), and assessed the predictors of durable response and impact of depth of response. Twenty-seven of the 141 (19%) patients remained progression-free beyond 24 months. The most significant baseline predictor for durable PFS and OS was a serum β2-microglobulin ≤3.0 mg/L. The median PFS for patients who achieved complete remission/very good partial remission, partial remission and stable disease were 69.4, 13.6 and 4.1 months, respectively (p < 0.001). The OS for these groups were >69.8, 35.4 and 11.7 months, respectively (p < 0.001). These findings support the therapeutic goal of achieving 'maximum depth of response' in patients with relapsed myeloma. [ABSTRACT FROM AUTHOR]

The article offers recommendations from the National Institue for Health and Clinical Excellence (NICE) for the management of the lower urinary tract dysfunction in neurological disease. Initial assessment should include a clinical history of urinary tract system, hand and cognitive function and a urine dipstick test. Referral for further care is indicated in people with haematuria, loin pain, and recurrent catheter blockages. Treatment for impaired bladder storage,stress incontinence and impaired bladder emptying is mentioned. The burden of infections should be managed effectively without the development of antibiotic resistance. If possible the underlying cause of infection should be determined.

Preclinical evidence supports the investigation of histone deacetylase inhibitors for the treatment of myeloma. Results from early studies demonstrate clinical activity and further studies investigating combination strategies should be explored. [ABSTRACT FROM AUTHOR]

The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL- 1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractoryMM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800mgin safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], and nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66);42% achieved very good partial response or better (≥VGPR). Mediantime to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥ VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% [17/18]) than patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractoryMM.This trialwas registered atwww.clinicaltrials.gov as#NCT01794507 [ABSTRACT FROM AUTHOR]