Citations

Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells. It is the second most common hematologic cancer, affecting nearly 30,000 people in the United States annually. Substantial progress has been made in the past fifteen years in the treatment of MM due to the approval of several new classes of drugs. However, patients inevitably relapse and become refractory to existing therapies. Hence, there is an immediate unmet need to develop novel therapies for MM based on a better understanding of the disease biology. Mutations in RAS have been found to occur in about 40% of newly diagnosed MM patients, with the frequency increasing to around 70% in relapsed/refractory patients. Such mutations are absent in patients with the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Clearly, RAS mutations contribute to both disease progression and relapse. However, targeting the MEK/ERK pathway has been unsuccessful in MM patients to date. Given the high frequency of RAS mutations in MM, we hypothesized that targeting this pathway could still be a promising strategy when combined with existing agents that have multifaceted mechanisms to promote tumor cell death, such as the recently approved histone deacetylase (HDAC) inhibitor LBH589 (panobinostat). Our results clearly demonstrate that low doses of LBH589 in combination with the MEK inhibitor AZD6244 induce BIM-dependent synergistic cell death in several MM cell lines and patient cells. Our studies also suggest that mutations in RAS/RAF could serve as a predictive biomarker for sensitivity to AZD6244/LBH589. RAS/RAF mutations appear to confer Mcl-1 dependence in MM cells, in part by driving up the phosphorylation of Mcl-1. The AZD6244/LBH589 combination is able to decrease the phosphorylation of Mcl-1 at several sites, which dissociates BIM-Mcl-1 complexes, ultimately leading to activation of the intrinsic apoptosis pathway. Additionally, we identified that wild-type RAS/RAF cells have relatively lower levels of phospho-Mcl-1, as well as higher levels of Bcl-2 and phospho-Bcl-2 when compared to mutated RAS/RAF cells. This seems to confer functional Bcl-2 dependence. Consequently, we found that wild-type RAS/RAF cells are sensitive to the BH3-mimetic ABT199 (venetoclax) when combined with LBH589. Through ongoing experiments, we hope to further confirm the mechanism of action of both these combinations, identify the particular HDAC that is required to be inhibited for the observed synergy, and validate RAS/RAF mutational status as a biomarker for predicting sensitivity to either combination. Our findings have broad therapeutic potential given the prevalence of RAS mutations in MM. Moreover, the ABT199/LBH589 combination could emerge as a targeted therapy for wild-type RAS patients, perhaps broadening the scope and capacity of Bcl-2 inhibition in MM. Citation Format: Kevin C. Miller, Jessica Haug, Teresa Kimlinger, Sanjay Kumar, Wilson Gonsalves, S. Vincent Rajkumar, Shaji K. Kumar, Vijay Ramakrishnan. HDAC inhibition in combination with MEK or BCL-2 inhibition as novel therapeutic strategies in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3909.

Nonalcoholic steatohepatitis (NASH) is projected to become the leading indication for liver transplantation (LT) in the next decade in the United States. Strategies to treat the underlying etiology of NASH, which is almost always obesity, are being pursued. One such strategy is the utilization of bariatric surgery (BS) in the peritransplant period. The use of BS prior to LT could prevent the progression of NASH and abrogate the need for LT. BS at the time of LT or postoperatively has the potential to not only improve obesity‐associated conditions such as diabetes, but also the potential to influence the incidence of NASH in the post‐LT setting. However, there continues to be no consensus on the use and timing of BS in this patient population. This review aims to discuss the current literature and possible future action.

Background Interest in the use of telehealth interventions to increase access to healthcare services is growing. Group-based interventions have the potential to increase patient access to highly needed services. The aim of this study was to systematically review the available literature on group-based video teleconference services. Methods The English-language literature was searched using Ovid MEDLINE, PubMed, PsycINFO and CINAHL for terms related to telehealth, group therapy and support groups. Abstracts were reviewed for relevance based on inclusion criteria. Multiple study types were reviewed, including open-label, qualitative and randomised controlled trial study designs. Data were compiled regarding participants, study intervention and outcomes. Specific areas of interest were the feasibility of and satisfaction with telehealth technology, as well as the effect of video teleconference delivery on group dynamics, including therapeutic alliance. Results Forty published studies met the inclusion criteria and were included in the review. Six were randomised controlled trials. Among the studies, there was a broad range of study designs, participants, group interventions and outcome measures. Video teleconference groups were found to be feasible and resulted in similar treatment outcomes to in-person groups. However, few studies were designed to demonstrate noninferiority of video teleconference groups compared with in-person groups. Studies that examined group process factors showed small decreases in therapeutic alliance in the video teleconference participants. Conclusions Video teleconference groups are feasible and produce outcomes similar to in-person treatment, with high participant satisfaction despite technical challenges. Additional research is needed to identify optimal methods of video teleconference group delivery to maximise clinical benefit and treatment outcomes.

Key PointsCoexisting psychiatric comorbidities are associated with greater increased health care utilization and cost of care in patients with MM. Clinical complications of MM are seen more frequently in patients with coexisting psychiatric conditions.