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2112 Gut Microbiome Composition Is Associated with Engraftment Syndrome in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Program: Oral and Poster Abstracts
Session: 731. Autologous Transplantation: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Biological therapies, adult, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies, Adverse Events, Biological Processes, microbiome, Study Population, Human, Transplantation
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Rena Feinman, PhD1, Ariel A. Aptekmann, PhD1*, Iriana Colorado, MSc1*, Samuel Roy, BSc1*, Joshua Zenreich, BA2*, Sophia H. Dar, MD1*, Adolfo Aleman, MD, CCRC3*, Rashmi Unawane, MD2*, Margaret Zhuang, Undergraduate Student1*, Megan Korkoleo, BA1*, Mariefel Vendivil, RN, BSN, OCN, CCRC4*, Andrea Ricourt, BSN, RN4*, Andrew McConnell, BA4*, Phyllis McKiernan, APN, MSN, OCN4*, Anqi Dai, MS5*, Andrew L. Pecora, MD2*, Noa Biran, MD3, David Samuel Siegel, MD, PhD6, Jonathan U. Peled, MD, PhD7 and Michele L. Donato, MD4*

1Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ
2John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ
3Division of Multiple Myeloma, John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ
4Stem Cell Transplantation and Cellular Therapy Program, John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ
5Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY
6Division of Multiple Myeloma, John Theurer Cancer Center, Hackensack Meridian Health and Center for Discovery and Innovation, Hackensack, NJ
7Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Engraftment syndrome (ES) is a pro-inflammatory complication often seen during neutrophil recovery in MM patients treated with high-dose melphalan conditioning chemotherapy and autologous stem cell transplantation (ASCT). The varied incidence of ES (5-70%) reported by different transplant centers is due to stringent diagnostic criteria and a myriad of symptoms (e.g. diarrhea, non-infectious fever, skin rash, capillary leak). Most ES cases are mild whereas a subset of patients is at higher risk of morbidity, longer hospital stay, infection, and occasional death. The etiology of ES remains elusive and probable mechanisms include proinflammatory cytokines, endothelial dysfunction, and activation of self-reactive T cells, all reminiscent of graft-versus host disease. Current induction regimens consisting of IMiDs and proteasome inhibitors have been associated with the increased the incidence of ES in MM patients. Gut microbiome composition is associated with immune-related adverse events and response to immune checkpoint blockade, allogeneic stem cell transplantation, ASCT and CAR T cell therapy. In MM, loss of gut microbiota (GM) diversity and domination of Enterococcus and Streptococcus during engraftment predicted inferior outcomes post-ASCT. A higher abundance of butyrate-producing Eubacterium hallii was associated with minimal residual disease negativity. In this prospective observational study, we hypothesize that depletion of healthy gut commensals and mono-domination of facultative pathogens may influence the development of ES.

Methods and Results: We serially collected stools samples from 53 MM patients at time of melphalan conditioning (pre-ASCT), engraftment (72hrs of absolute neutrophil count ≥ 500/mcL), and 60-120 days post-ASCT. Taxonomic profiling was performed using 16S rRNA sequencing of the V4-V5 region and amplicon sequence variants (ASV) were annotated against the NCBI 16S database using BLAST. We found lower alpha-diversity at neutrophil engraftment from pre-ASCT, using inverse Simpson diversity index (p=0.0001, Wilcoxon matched pairs signed rank test, n=45). Recovery of diversity to pre-ASCT levels was attained 60-120 days post-ASCT (p=0.001, n=41). However, we did not observe any significant differences in alpha-diversity of patients with ES and without ES at each timepoint tested (Fig.1A). The domination taxa profiles (defined as the relative abundance of a single taxon >30%) differed between patients with and without ES at each timepoint (Fig. 1B). The domination of Enterococcus was only evident in ES patients (pre-ASCT, engraftment) whereas Streptococcus was unique to non-ES patients (engraftment, post-ASCT). Blautia had a higher frequency of domination in non-ES patients compared to ES patients prior to ASCT, during engraftment and post-ASCT. Using Random Forest, a supervised machine-learning algorithm, Streptococcus, Ruminococcus, Coprococcus, and Enterococcus had the highest variable significant features at engraftment.

Conclusions: We found that domination of Enterococcus prior to conditioning and ASCT and further increasing during engraftment is associated with increased risk of ES. Our findings suggest that GM may impact immune-related adverse events and outcomes in MM patients undergoing ASCT and provide the rationale for microbiota-centered interventions.

Disclosures: Feinman: BMS: Honoraria; Takeda: Honoraria; GSK: Honoraria; Janssen: Honoraria; Merck: Other: Consulting; Cellularity: Membership on an entity's Board of Directors or advisory committees. Biran: Amgen, Janssen, Karyopharm, Merck, BMS, Sanofi: Consultancy, Research Funding. Siegel: BMS: Honoraria, Speakers Bureau; COTA: Current equity holder in private company, Current holder of stock options in a privately-held company; GSK: Honoraria, Speakers Bureau; Takeda: Honoraria; Janssen: Honoraria; Merck: Honoraria; Celularity: Membership on an entity's Board of Directors or advisory committees. Peled: Hanson Wade Limited: Other: Speaking; French National Cancer Institute (INCa): Consultancy; HayMatick Meetings & Events: Other: Speaking; University of Nebraska Medical Center: Other: Speaking; William Blair & Company, L.L.C.: Other: Speaking; Parker Institute for Cancer Immunotherapy: Other: Attending a conference , Research Funding; University Hospital Regensburg: Other: Speaking; University of Pennsylvania: Other: Lecture/Speaking; Clinical Immunology Society: Other: Lecture/Speaking; KongresKompagniet A/S: Other: Speaking; apanese Society of Hematology: Other: Speaking; Arjun Pai: Consultancy; Seres Therapeutics: Other: Memorial Sloan Kettering Cancer Center (MSK) has financial interest relative to Seres Therapeutics ; intellectual property applications related to the microbiome: Other: He has filed intellectual property applications related to the microbiome (reference numbers #62/843,849, #62/977,908, and #15/756,845). ; MaaT Pharma: Consultancy; Postbiotics Plus Research: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; DaVolterra: Consultancy; Seres Therapeutics: Other: Intellectual Property Fees & Travel Funding , Research Funding.

*signifies non-member of ASH