Renal impairment at diagnosis in myeloma: Patient characteristics, treatment, and impact on outcomes. Results trom the Australia and New Zealand myeloma and related diseases registry

Background: Renal impairment (RI) is a common complication of multiple myeloma (MM) and remains a poor prognostic factor despite improved survival with newer therapies. Patients and Methods: We evaluated baseline characteristics, treatment, and outcomes of newly diagnosed MM patients with RI at diagnosis in the Australia and New Zealand Myeloma and Related Diseases Registry over 5 years to April 2018; we compared patients with RI (estimated glomerular filtration rate [eGFR

Isatuximab in combination with lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma: Updated safety run-in results from the randomized phase 3 ithaca study

Background: Results from a randomized, Phase 3 study by the Spanish Myeloma Group (PETHEMA/GEM) previously showed that treatment with lenalidomide plus dexamethasone (Rd) may delay progression to active disease in patients (pts) with high-risk smoldering multiple myeloma (SMM), compared with observation. To further improve outcomes, addition of the anti-CD38 antibody isatuximab (Isa) to lenalidomide and dexamethasone (Isa-Rd) for the treatment of pts with high-risk SMM is being evaluated in the ongoing, randomized, multi-center, Phase 3 ITHACA study (NCT04270409). Initial findings from the safety run-in analysis of this trial have shown a manageable safety profile and encouraging, preliminary anti-myeloma activity. We now report updated safety and efficacy results from the safety run-in part of ITHACA at a median follow-up of 19.4 months. Methods: Pts were included in the study if they had been diagnosed within 5 years with SMM (per the International Myeloma Working Group [IMWG] criteria) and had high-risk SMM according to the Mayo '20-2-20' and/or updated PETHEMA model criteria. Pts who had received prior anti-myeloma treatment were not eligible. Enrolled pts received Isa 10 mg/kg IV on day (D) 1, 8, 15, and 22 in cycle (C) 1, D1 and D15 C2-12, D1 C13-36; plus R D1-21 (25 mg C1-9; 10 mg C10-24) and d weekly (40 mg, 20 mg for ≥75 yr-old pts C1-9; 20 mg C10-24). Cycle duration was 28 days. Safety evaluations included treatment-emergent AEs (TEAEs)/serious AEs and laboratory parameters, graded by NCI-CTCAE v5.0. Response was determined by IMWG criteria (2016). Mandatory imaging by MRI and/or low-dose whole-body CT/PET-CT, and assessments of minimal residual disease (MRD, by next-generation sequencing in pts with very good partial response [VGPR] or better), were performed at protocol-defined time points. The primary study objective for the safety run-in was to confirm the recommended dose of Isa in combination with Rd. Overall response rate (ORR) and MRD negativity rate at 10-5 sensitivity were included as secondary endpoints.Sanof

Daratumumab plus lenalidomide and dexamethasone for untreated myeloma

This is an accepted manuscript of an article published by Massachusetts Medical Society in New England Journal of Medicine on 30/05/2019, available online: https://doi.org/10.1056/NEJMoa1817249 The accepted version of the publication may differ from the final published version.Copyright © 2019 Massachusetts Medical Society. Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. METHODS We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. RESULTS At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).Published versio

The clinical role of novel biological agents and the in vivo immunological effects of immunomodulatory drugs (IMiDs) in the management of multiple myeloma

© 2010 Dr. Hang Ai QuachOver the last decade, the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib has revolutionised the treatment and outlook of multiple myeloma (MM), an incurable plasma cell malignancy with significant morbidity. Our experience with these novel agents has yet to improve however, with regards to the optimal scheduling and combination therapy that would maximise response duration and survival. Furthermore, the exact anti-myeloma mechanisms of these agents are poorly understood, and many of the proposed mechanisms in vitro have yet to be corroborated in vivo. The work presented in this thesis aims to improve our current understanding of the in vivo immune modulation by lenalidomide in patients with MM, and to fine tune current treatment regimens based on our matured experience with these novel therapeutic agents, so as to minimise toxicity and maximise response and survival outcome. The first chapter (1A) reviews the current treatment paradigm of MM, and the current accepted role of thalidomide, lenalidomide, bortezomib and histone-deacetylase inhibitors. The current understanding of MM pathophysiology and the mechanism of actions of novel agents is reviewed in chapter 1B, providing a background for the correlative immunological studies in chapter 3B. The work from chapters 1A and 1B have culminated in 2 published review manuscript in Drugs and Aging 2007 and Leukemia 2009, respectively (see preface). The second chapter explores the long-term outcome to thalidomide-based treatment to show that depth of response to thalidomide correlates to survival outcome. This chapter highlights the importance complete remissions in the quest for durable responses in the era of novel therapeutic agents. The work from this chapter has been published as a manuscript in Leukemia & Lymphoma 2009. The following chapters (3,5,6) are a series of investigator-driven phase II trials exploring optimal scheduling of lenalidomide or bortezomib with dexamethasone in the treatment of relapsed or refractory MM, as well as the safety and preliminary efficacy of a novel bortezomib-romidepsin combination therapy. To enable the ongoing optimisation of treatment schedules or combinations of novel-agent, an understanding of their individual in vivo effects is important. Correlative immunological studies were therefore performed, as outlined in chapter 3B, to investigate the in vivo immunological changes in patients treated with immunomodulators, and how immune stimulation can be optimised to further improve clinical outcome. Indeed it was found that the concurrent use of dexamethasone abrogates lenalidomide-induced NK cell stimulation, and may subvert the full immune stimulatory capacity of lenalidomide. These findings have been submitted as a manuscript to Blood at the time of this thesis submission, and have been presented at several international scientific meetings. The insight that was gained from this correlative immunological study also resulted in a review manuscript on drug-mediated and cellular immunotherapy in MM, was published in Immunotherapy 2010. Overall, the work from this thesis aims to contribute to the shaping of optimal treatment strategies for MM, as well as an improved understanding of the in vivo effects of lenalidomide. We remain in an era of exploration of the role of novel therapeutic agents in the treatment of MM, and how to best manipulate sequential or combination therapy with the ultimate aim of cure, if not durable disease control

Gluconic Acid Pretreatment of Wheat Straw and Fermentation to Ethanol

Gluconic acid was evaluated to be a promising pretreatment agent on wheat straw. The pretreatment was tested at different gluconic acid concentrations (0.125-1M), temperatures (160-190°C), and reaction times (30-120 minutes). After each pretreatment, the slurries were separated into hemicellulose hydrolysate and pretreated solid residue. The sugar yields in stage 1 (hemicellulose hydrolysate) and stage 2 (enzymatic hydrolysis of pretreated solid residue) were reported. The highest overall xylose achieved 89.6±3.4% yield that was observed at the pretreatment condition of 0.125M gluconic acid concentration, 170°C pretreatment temperature, and 30-minutes reaction time. The highest overall glucose achieved 91.5±2.0% yield at the pretreatment condition of 0.5M gluconic acid concentration, 190°C pretreatment temperature, and 30-minutes reaction time. The overall sugar (glucose and xylose combined) yield of 83.5±2.4% was achieved at the pretreatment condition of 0.5M gluconic acid concentration, 170°C pretreatment temperature, and 30-minutes reaction time. Preference of utilizing lower gluconic acid concentration was also evaluated. The overall sugar yield of 81.1±0.2% was achieved at the pretreatment condition of 0.125M gluconic acid concentration, 170°C pretreatment temperature, and 60-minutes reaction time.The evaluation for ethanol production utilized the hemicellulose hydrolysate and pretreated solid residue generated from the pretreatment condition of 0.125M gluconic acid concentration, 170°C pretreatment temperature, and 60-minutes reaction time because of lower gluconic acid concentration consumption and high overall sugar yield. Roughly 4.2±0.14% of the gluconic acid was lost during the pretreatment process and a portion may be lost from being stuck to pretreated solid residue. The remaining 75.6±0.59% of gluconate in the detoxified hemicellulose hydrolysate was fermented to ethanol along with other hemicellulose sugars (glucose, xylose, and arabinose). The engineered microorganisms such as Escherichia coli AH003 and E. coli SL100 were evaluated for ethanol production in the detoxified hemicellulose hydrolysate. The theoretical maximum yield obtained from the detoxicated hemicellulose hydrolysate fermentation was 107.5±1.2% from E. coli AH003 using Luria-Bertani (LB) media and 90.4±1.8% from E. coli SL100 using low-salt (AM1) media. Additionally, E. coli AH003 and Saccharomyces cerevisiae D5A were used as the ethanologens to convert the pretreated solid residue to ethanol via simultaneous saccharification and fermentation (SSF) with cellulase loading of 20 FPU and ?-glucosidase loading of 20IU/g cellulose. The ethanol yield obtained from E. coli AH003 in LB media from SSF was unclear since glucose, xylose, and a small amount of gluconate could be hydrolyzed from the pretreated solid residue. Meanwhile, S. cerevisiae D5A exclusively consumed glucose in lean media and the ethanol yield was 92.8±2.0% with cellulose conversion of 70.8±0.8%. Overall, evaluation of fermentation suggests that casamino acids in LB media could promote high cell growth and ethanol yield