Abstract: Background Intestinal microbiome disruption is a risk factor for poor outcomes after allogeneic hematopoietic cell transplantation (allo-HCT), but the factors that contribute to microbiome injury are not well understood. We hypothesized that nutrition contributes to microbiome composition during allo-HCT. Methods Along with 16S profiling of collected fecal samples, we monitored daily inpatient nutritional intake using a customized real-time survey instrument. Data were quality-controlled by a dietitian and matched to the Food and Nutrient Database for Dietary Studies (FNDDS). Results 97 adult patients received conditioning regimens that were 68% ablative, 22% reduced, and 10% nonmyeloablative; 35% patients had acute myeloid leukemia and 35% had myelodysplastic/myeloproliferative neoplasms, while 10% had non-Hodgkin's lymphoma. Grafts were T-cell depleted in 49% and cord blood in 7%. The remaining had unmodified bone marrow or peripheral blood stem cell. 5 patients had enteral nutrition during the treatment. 22,614 food entries from 5,230 meals were collected during inpatient admissions. Among 800 sequenced stool samples, 329 were collected following exposure to an empiric antibiotic. The hierarchical organization of the FNDDS vocabulary facilitated application of alpha and beta diversities to diet data, as well as analysis of food items (e.g., chicken), which have been reported to more closely associate with microbiome composition than macronutrients (e.g., fat). Nutritional diversity declined from admission until day 3 (A). Clusters of dietary patterns were revealed by ordination with unweighted UniFrac distance applied, in which highly diverse diets clustered together (B). We observed a correlation between total calories consumed and fecal alpha diversity (r = 0.23, P & lt; 0.001) and the relative fecal abundance of the genus Blautia (r = 0.31, P & lt; 0.001), which we have previously associated with protection from lethal graft versus host disease (GVHD). In contrast, calorie intake was inversely associated with the fecal relative abundance of genus Enterococcus (r = -0.15, P & lt; 0.001), a genus we have reported exacerbates GVHD. Similar associations with microbiome features were observed for fiber. To gain insight into which types of foods are associated with microbiome injury, we constructed a Bayesian multilevel model to evaluate relationships between microbiota diversity and the amount consumed of different food groups in the two days preceding each stool sample. This model controlled for conditioning intensity, exposure to empiric antibiotics, enteral nutrition, and total parenteral nutrition. Empiric antibiotics refer to the ones for neutropenic fever such as piperacillin/tazobactam, carbapenems, cefepime, linezolid and for C. difficile such as oral vancomycin, and metronidazole. A random intercept term per patient to accommodate repeated measurements from the same patient and a random intercept term for each week relative to HCT were incorporated in the model. Intake of sugars, sweets and beverages was associated with low fecal microbiota alpha diversity (C). The model predicts that, on average, consumption of 100g sugars and sweets over two days would result in a biologically meaningful decline of diversity by 1.13-fold in inverse Simpson units. Interestingly, fruits, a food type enriched in simple sugars, trended toward associations with lower diversity as well. Conclusion Consumption of sugars and sweets is associated with lower fecal microbiota alpha diversity in allo-HCT. We hypothesize that initial insults to diverse microbial communities are exacerbated by simple sugars, which can be exploited by the remaining organisms as readily available nutrients. These results highlight the importance of developing evidence-based nutritional recommendations in allo-HCT. Figure 1 Figure 1. Disclosures Adintori: Vidafuel Inc.: Current holder of stock options in a privately-held company. Buchan: Savor Health: Current Employment. Gomes: Xbiome: Current Employment. Johnson: Diversigen: Consultancy. Knights: Diversigen: Consultancy. Jenq: Microbiome DX: Consultancy; Merck: Consultancy; Prolacta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kaleido: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seres: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; LisCure: Consultancy, Membership on an entity's Board of Directors or advisory committees; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karius: Consultancy. Giralt: GSK: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Perales: NexImmune: Honoraria; Servier: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Medigene: Honoraria; Takeda: Honoraria; Sellas Life Sciences: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Cidara: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Omeros: Honoraria. van den Brink: Priothera: Research Funding; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Jazz Pharmaceuticals: Honoraria; Pharmacyclics: Other; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Wolters Kluwer: Patents & Royalties; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Amgen: Honoraria; Frazier Healthcare Partners: Honoraria; Forty-Seven, Inc.: Honoraria; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Kite Pharmaceuticals: Other; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Juno Therapeutics: Other; MagentaTherapeutics: Honoraria; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Rheos: Honoraria; DKMS (nonprofit): Other; Therakos: Honoraria; Merck & Co, Inc: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards ; WindMILTherapeutics: Honoraria. Schluter: Postbiotics Plus LLC: Other: cofounder. Peled: MaaT Pharma: Consultancy; CSL Behring: Consultancy; DaVolterra: Consultancy; Seres Therapeutics: Research Funding.

Abstract: Chemical gustometry (taste testing) was feasible in patients with multiple myeloma undergoing autologous hematopoietic cell transplantation. Dysgeusia and symptom burden are highest and caloric intake is lowest during the blood count nadir but improved to near‐normal levels by three months after transplantation.

Abstract: The intestinal microbiota undergoes major perturbations during allogeneic hematopoietic stem cell transplantation (allo-HCT), and low microbiota diversity during this period is associated with an increased risk of graft-versus-host disease and mortality. Identifying the environmental variables that might impact intestinal microbiota could inform strategies to maintain and restore a healthy microbiota state. However, understanding microbial dynamics is challenging due to the high-dimensional nature of microbiota data. Here, we simplified complex microbiota communities into clusters and investigated the dynamics under different conditions in terms of transition probabilities in a large dataset of allo-HCT fecal specimens (Fig. a). The bacterial compositions of 7,930 samples from 1,076 allo-HCT patients were determined by 16S rRNA deep-sequencing. Samples were then clustered into 10 distinct states by k-means clustering of a Bray-Curtis β-diversity matrix (Fig. b). These clusters captured variations in diversity and microbiota compositions (Fig. c-d). Cluster 1 represented a high-diversity state, and Lachnospiraceae and other Clostridiales were the most commonly observed taxa in this cluster. The low-diversity clusters 9 and 10 consisted mostly of Streptococcus-dominated and Enterococcus-dominated samples, respectively. We utilized a regression-based predictive approach to model cluster transition probabilities in terms of a weight for remaining in the same cluster over time (self-weight) and a weight for attracting transitions from other clusters over time (attractor-weight). Controlling for the effect of time, the weights measured the contribution of different environmental exposures to intestinal microbial behaviors. A negative parameter coefficient indicates cluster destabilization or decreased cluster transition likelihood in the case of self-weights and attractor-weights, respectively. We evaluated the impact of the 3 most commonly used non-prophylactic antibacterial drugs using 2359 daily samples from 385 allo-HCT patients collected between day -14 to 7 relative to transplant. High-diversity cluster 1 was significantly destabilized by piperacillin-tazobactam (pip-tazo) exposure (β = -0.87, P & lt; 0.05). Meanwhile, exposure to cefepime and meropenem did not have a significant effect on cluster 1 stability (Fig. e). Exposure to pip-tazo also increased the transition probability to the Streptococcus-dominated cluster 9 (β = 1.83, P & lt; 0.001), while cefepime (β = 2.69, P & lt; 0.05) and meropenem (β = 1.96, P & lt; 0.01) exposure favored transitions to the Enterococcus-dominant cluster 10. These results suggest that antibiotic exposures are associated with different composition outcomes depending on patient microbiota states during transplant period. In a small subset of 242 daily samples from 46 allo-HCT patients with detailed daily dietary information, we observed that an increase in total protein intake (range = 0-137.4g; median = 36g) was associated with low self-maintenance of cluster 1 (β = -1.29, P & lt; 0.05), while an increase in total fat intake (range = 0-183.3g; median = 34.5g) improved cluster 1 stability (β = 1.44, P & lt; 0.05). Overall, dietary intakes could also modulate transition probabilities between microbial communities in allo-HCT patients. While prior studies have assessed specific bacterial taxa or diversity indices as biomarkers of clinical outcomes, here we considered the entire intestinal communities and demonstrated that various environmental exposures were associated with changes in microbiota composition during allo-HCT. Using a regression-based approach that predicts cluster transitions in response to environmental conditions, we found that pip-tazo exposure was associated with destabilization of a high-diversity state and increased transitions to a Streptococcus-dominated state, while cefepime and meropenem exposure did not disrupt high-diversity microbial community. Furthermore, increased protein intake was also associated with disruption to the high-diversity cluster, while increased fat intake strengthened the maintenance of a diverse and healthy microbial community. Ultimately, this computation framework aims to inform strategies to optimize treatment plans for allo-HCT patients to maximize a healthy gut microbiota state and clinical outcomes. Disclosures Gomes: Seres Therapeutics: Other: Part of Salary. Peled:Seres Therapeutics: Research Funding. Slingerland:Seres Therapeutics: Other: Salary supported by Seres funding. Clurman:Seres Therapeutics: Research Funding. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Perales:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees. Pamer:MedImmune: Honoraria; Seres Therapeutics: Honoraria, Patents & Royalties; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Ferring Pharmaceuticals: Honoraria. van den Brink:Acute Leukemia Forum (ALF): Consultancy, Honoraria; Seres Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Flagship Ventures: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Evelo: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Therakos: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Merck & Co, Inc.: Consultancy, Honoraria; Juno Therapeutics: Other: Licensing; Magenta and DKMS Medical Council: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background and Scientific Rationale: Multiple myeloma (MM) is often preceded by the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Obesity, low adiponectin levels, and diets high in inflammatory, insulinemic foods or lacking plant-based foods are known risk factors for the development of MGUS/SMM, as well as for progression to MM. Therefore, there is an opportunity to study a dietary intervention in cancer progression among patients with MGUS/SMM, for which the standard of care is observation even though some patients will eventually progress to MM. This is a pilot nutrition-based intervention study of a whole food, plant-based diet (WFPBD) in overweight and obese MGUS and SMM patients to enable weight loss, assess associated changes in disease biomarkers, epigenetics, and the gut microbiome. We expect that the findings will enable larger lifestyle-based studies of prevention and survivorship in plasma cell disorders. Study Design and Methods: This is a single-arm, single-center pilot study of a WFPBD for 12 weeks and nutrition counseling for 24 weeks which will enroll 20 patients (Figure). Clinical trial registry number: NCT04920084, actively recruiting. Study Population and Inclusion Criteria i) SMM or MGUS ii) Body mass index ≥25 iii) Monoclonal protein spike ≥0.2 g/dL or abnormal free light chain ratio with increased level of the appropriate involved light chain iv) ECOG performance status 0-3 v) Willingness to comply with study-related procedures Statistical Methods: The average weight loss from baseline at 12 weeks will be reported as sample mean along with 95% confidence interval. Adherence will be estimated by sample proportion, with confidence intervals based on exact binomial distribution. Patients who have completed evaluation at 12 weeks will be evaluable for the weight loss outcome. All patients who have received at least one WFPBD intervention will be evaluable for adherence assessment. We will consider this intervention promising if 1) we detect weight loss at 12 weeks and 2) estimated adherence to the intervention is ≥70%. Study Treatment: For 12 weeks, patients will receive two premade meals per day, for lunch and dinner for 6 days per week, prepared and shipped by Plantable. The meals will have a low glycemic index and contain vegetables, whole grains, and plant-based fats that have undergone minimal processing. Detailed recommendations for snacks and breakfasts meeting the standard of a WFPBD will also be given to supplement their daily calorie needs with access to an online portal or phone application from Plantable which contains education materials and access to a coach daily for 24 weeks. Patients will receive dietary education and counseling from a research dietitian every 2 weeks for the 12-week intervention period. Endpoints: Primary: - To determine the feasibility of a WFPBD, as measured by weight loss and adherence at 12 weeks. Secondary: - To determine the feasibility of a WFPBD, as measured by safety, and quality of life. - To assess weight loss at 24, and 52 weeks. - To assess alterations in metabolic, and myeloma markers. Exploratory: - To assess alterations in T cell and plasma cell epigenetic markers - To assess alterations in the fecal microbiome - To assess changes in body composition as determined by PET imaging and correlate with weight change as well as disease markers. Figure 1 Figure 1. Disclosures Shah: Janssen: Research Funding; Celgene/BMS: Research Funding. Adintori: Vidafuel Inc.: Current holder of stock options in a privately-held company. Mailankody: Jansen Oncology: Research Funding; Physician Education Resource: Honoraria; Bristol Myers Squibb/Juno: Research Funding; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Takeda Oncology: Research Funding; Allogene Therapeutics: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Curio Science LLC: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. D'Souza: Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Janssen, Prothena: Consultancy. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees. Iyengar: Novartis: Consultancy; Seattle Genetics: Consultancy; Novartis: Research Funding. Landgren: Janssen: Other: IDMC; Janssen: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. van den Brink: Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Forty-Seven, Inc.: Honoraria; MagentaTherapeutics: Honoraria; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Wolters Kluwer: Patents & Royalties; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Notch Therapeutics: Honoraria; DKMS (nonprofit): Other; Pharmacyclics: Other; Kite Pharmaceuticals: Other; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards ; Nektar Therapeutics: Honoraria; Rheos: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Amgen: Honoraria; Therakos: Honoraria; WindMILTherapeutics: Honoraria; Juno Therapeutics: Other; Merck & Co, Inc: Honoraria; Frazier Healthcare Partners: Honoraria; Priothera: Research Funding; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Jazz Pharmaceuticals: Honoraria. Lesokhin: pfizer: Consultancy, Research Funding; Genetech: Research Funding; Trillium Therapeutics: Consultancy; Behringer Ingelheim: Honoraria; Serametrix, Inc: Patents & Royalties; bristol myers squibb: Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy.