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Purpose Drug development in oncology is resource intensive, time consuming, and frequently unsuccessful. Here, we hypothesized that therapeutic benefit of published phase I studies of antimyeloma investigational agents was associated with advancement to phase II and future regulatory approval. Patients and Methods Seventy four phase I trials that treated patients with multiple myeloma (n = 2,408) conducted from 2004 to 2015 were analyzed to assess drug safety, efficacy, phase advancement, and regulatory approval. Results The median overall response rate (ORR) for all single-agent trials evaluated was 13.2%. However, the ORR in trials that advanced to phase II was 19%, whereas it was only4%in trials that failed to advance. The median ORR was 23% for trials testing agents that were ultimately approved by the US Food and Drug Administration compared with only 8% for trials testing agents that were not approved (hazard ratio, 2.21; 95%CI, 2.01 to 2.61; P = .012). Importantly, the absolute number of phase I trials in multiple myeloma, but not the success rate, significantly increased over the period studied. The proportion of industry-sponsored trials also steadily increased over that same period. The ratio of initial dose to maximum tolerated dose was 0.29, suggesting that many patients were undertreated. Conclusion Investigational agents with higher ORRs in phase I trials were more likely to advance to phase II trials and achieve US Food and Drug Administration approval. Our results suggest that designing phase I trials to maximize the antimyeloma efficacy of a given compound may lead to more successful and costeffective drug development. [ABSTRACT FROM AUTHOR]

While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib, carfilzomib, or ixazomib. Genome-wide profiling identified lncRNAs that were significantly deregulated in all three PI-resistant cell lines relative to the drug-sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI-resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic cell transplant (HCT) is frequently used to treat Multiple Myeloma (MM). Metabolic abnormalities have been reported in patients (pts) undergoing this modality of therapy contributing to catheter requirement and prolonged hospital admission. Incidence and timing of electrolyte imbalances have not thoroughly been investigated. Methods All consecutive MM pts underwent autologous stem cell transplant from Jan 2012 to July 2016 were included. Patient charts were reviewed for the laboratory results of the first four weeks following HCT. Calcium level was corrected for the albumin level. Time to nadir of these abnormalities was recorded as days after stem cell infusion. engraftment speed (ES) was calculated as the period between the first rise in absolute neutrophil count (ANC) and the full engraftment defined as the first day of ANC>500 for three consecutive days. To define impact of oral intake on the electrolyte drop we assess degree of oral mucositis and nauseas using CTCAE v4.0. Results The study included 118 MM pts received transplant. Median age was 60.9 years old (range: 34-78), 65 pts were male (55%) and the rest female. Ninety pts were Caucasian (76%) and 20 were African-American (19%). Eighty two pts had IgG (69%), 24 IgA (21%) and 11 (9%) had light chain myeloma. Sixty pts (51%) achieved Very Good Partial Response, 29 pts (24%) Partial Response and 25 pts (21%) Complete Response before HCT. Twenty pts (22%) were on Lasix, 62 pts (52%) were on PPI, 3 pts (2%) on H2 blocker at the time of HCT. Conditioning regimen included Melphalan 200 and 140 mg/m2 in 108 pts (91%) and 10 pts (9%), respectively, with pre-melphalan amifostine infusion for all pts. Filgrastim daily started on the day after stem cell infusion. The pre-SCT and post-SCT nadir values are listed in Table-1. Median ES was 2 days (range: 0-5) and 40 pts (36%) had ES<2 days. The engraftment occurred at median of 10 days, standard deviation (SD): 1.50 days, after HCT. The median time-to-nadir for both phosphorus and potassium was 10 days, SD: 3.10 days and 4.28 days for phosphorous and potassium, respectively. The drop in P was statistically higher in the group with ES<2 days in comparison to the group with ES ≥ 2 days (median: 1.4 vs. 0.9 mg/dL, p-value: 0.000) as well as the drop in potassium (median: 1.1 vs. 0.7 mmol/L, p-value: 0.039). There was no difference in the calcium or Magnesium drop between two groups based on ES (Figure-1). There was no statistically significant difference between the drop in phosphorus and potassium based on severity of nausea or oral mucositis (Figure-2 and -3). Conclusion Here we defined a correlation between magnitude of the drop in potassium and phosphorous and a steep rise in neutrophil counts around the engraftment period. It can indicate the "genesis syndrome", a massive transfer of electrolytes into rapidly proliferating cells that was described in high grade lymphoma and leukemia before. [ABSTRACT FROM AUTHOR]

We conducted a prospective study to determine the longitudinal microbial profile in patients undergoing HCT for multiple myeloma (MM), and whether changes in microbial composition correlate with HCT outcomes and/or toxicities. Samples were collected from 15 patients at baseline (T-2), during marrow aplasia (T+7) and after engraftment (T+30). Ion-Torrent PGM workflow was used. Amplicons generated from 16s rRNA and the ITS genes were sequenced for bacterial and fungal identification, respectively. Relative abundance, diversity and richness were determined at the phylum and genus levels at each time point, in oral and fecal microbiome. Diversity and richness of the oral mycobiome decreased at T+7 from baseline with further decrease noted at T+30. Fecal mycobiome diversity (T-2 vs T+7, p=0.05) and richness decreased from baseline to T+7, and richness trended towards significance (p=0.06) with further decrease at T+30. In fecal samples, lower bacterial diversity at T+7 associated with more severe diarrhea (p= 0.03). Anaerobic targeting antibiotic exposure on or before T+7 affected the bacterial genus diversity (p=0.015) and richness at T+7 (p=0.014). The bacterial genus richness at baseline (p=0.03) and the diversity/richness at T+7 (p=0.01) were associated with fever development on or after T+7. Exposure to anaerobic depleting antibiotics correlated with oral mycobiome genus richness at T+30 (p=0.04). At the bacterial phylum level, the oral community composition changed at T+30 compared to baseline (Bray-curtis p=0.046) and T+7 (Bray-curtis p=0.025). When examining the changes in the mycobiome composition, test for dissimilarity showed a significant difference in the fecal fungal genus between baseline and T+30 (BrayPA p=0.025). In fecal samples, a higher abundance of Bacteriodetes present at T+7 was associated with the severity of diarrhea experienced (p=0.03). Blautia and Ruminococcus , both belonging to the Firmicutes phylum and Clostridium Class, when detected at T+7 were associated with a higher severity of vomiting (p=0.05). In oral samples, the presence of the genus Glomerella at T+7 was negatively associated with rates of neutrophil engraftment (p=0.03). Our results show that oral and fecal microbiota undergo dynamic changes in diversity, composition and relative abundance during the course of transplantation. Bacterial and fungal microbiota present specifically at count nadir could be important players. The relative abundance of particularly the anaerobic bacterial phyla, Bacteroidetes and Firciumtes during marrow aplasia, correlated with post transplant toxicities. We identified a correlation between exposure to anaerobic organism depleting antimicrobials and changes in genus diversity and richness. Baseline microbial diversity/richness and changes coinciding with marrow aplasia correlate with the incidence and severity of post transplant toxicities. [ABSTRACT FROM AUTHOR]

Multiple Myeloma (MM) are often treated with high-dose melphalan and autologous stem cell transplant (ASCT). Cardiac toxicity, including Supraventricular tachyarrhythmias (SVT), is a fairly common complication which may be related to Melphalan, the transplanted stem cells or effects of para-proteinemia on the conduction system. Here, we sought to determine the incidence of SVT and its predisposing factors in this setting. Methods We reviewed the 100-day post-ASCT clinical course of all MM patients treated from 2007 to 2017 that had undergone ASCT at our institution. Clinical data, EKG and Echocardiography data were extracted. QRS amplitude was measured in the V2 precordial lead as the distance from the R peak to S peak. Both atrial fibrillation and atrial flutter were classified as SVT. Results A total of 222 patients were included in the study population. Amifostine was used before all ASCT to reduced oral mucositis. Patient median age was 60.6 (range: 36-79), 110 patients (49%) were male and the 112 female (51%). Median pre-ASCT QRS amplitude was 1.7 millivolt (mV) (range: 0.3-4.4). Median QRS duration was 90 millisecond (mS, range: 60-208). Only 166 patients received a pre-ASCT ECHO. Median time of pre-ASCT and post-ASCT ECHO were 38 days (range: 1-333 days) and 55 days (range: 4-118), respectively. Seventeen patients (8%) developed SVT during or after ASCT with a median time of 12 days post-ASCT (range: 1-97 days). Median time of the length of hospital stay between patients without SVT and with SVT was different, 15 vs. 19 days (p-value < 0.001). There was no statistically significant between average melphalan dose utilized as the conditioning regimen, infused CD34 dosage, transplant-associated weight loss, time from diagnosis or length of pre-ASCT exposure to proteasome inhibitors between two cohorts (Table-1 and 2). Also, there was no association between pre-ASCT use of anti-lipid lowering agents, beta-blockers, angiotensin-converting enzyme inhibitor or angiotensin receptor inhibitors. Out of all pre-ASCT comorbidities renal insufficiency (9% vs. 41%, p-value: 0.017) and HTN (49% vs. 76%, p-value: 0.045) were predictor, of SVT occurrence in the univariate analysis. Multivariate analysis indicated that renal insufficiency at baseline (OR: 3.6, 95% CI: 2.1-4.8, p-value < 0.001), left ventricular systolic dysfunction (LVSD, OR: 3.0, CI: 1.1-5.1, p-value: 0.003), and hypertension (OR: 2.5, CI: 1.2-4.6, p-value: 0.028), were significantly associated with the development of SVT after ASCT (Fig. 1). Conclusion Taken together, our results suggest that SVT represents an important cause of morbidity and is associated with longer hospital stay for MM patients undergoing ASCT. The presence of abnormal renal function, LVSD, or hypertension at baseline identifies patients at greater risk of developing SVT following ASCT. [ABSTRACT FROM AUTHOR]