{
  "abstract": "Background The gut microbiota plays a critical role in regulating immune homeostasis and modulating responses to cancer immunotherapies. However, the impact of antibiotic-induced dysbiosis in patients with multiple myeloma (MM) treated with bispecific antibodies (BsAbs) remains unexplored. This multicenter, international study investigated whether antibiotic exposure prior to BsAb initiation alters the gut microbiome and affects clinical outcomes in patients with relapsed or refractory MM.Methods We retrospectively analyzed 237 adult patients with MM treated with CD3-engaging BsAbs across six academic institutions. Antibiotic exposure was defined as the administration of any broad-spectrum, non-prophylactic antibiotic within 30 days before BsAb initiation. Clinical outcomes included overall survival (OS), progression-free survival (PFS), and cumulative incidence of relapse, evaluated using Kaplan-Meier estimates, log-rank tests, and multivariable Cox and competing-risk regression models. Additionally, in a subset of 24 patients, peripheral blood samples were collected prior to BsAb infusion for immunophenotyping, cytokine profiling, and serum short-chain fatty acid (SCFA) quantification, while stool samples for 16S ribosomal RNA (rRNA) sequencing were collected in a subset of 19 patients.Results Broad-spectrum antibiotic exposure prior to BsAb therapy was associated with significantly inferior 1-year OS (60% (95% CI 44% to 81%) vs 77% (95% CI 71% to 83%), p=0.004) and PFS (26% (95% CI 14% to 47%) vs 53% (95% CI 46% to 61%), p<0.001), and higher relapse incidence (68% (95% CI 48% to 82%) vs 43% (95% CI 36% to 50%), p=0.004). In multivariable analyses, antibiotic exposure remained independently associated with poorer OS, PFS, and higher relapse risk. These associations were also observed within the subgroup of patients treated with CD3/B-cell maturation antibody-targeted BsAbs (n=155). Immunoprofiling revealed lower CD4 + T-cell counts (p=0.017) and reduced circulating cytokine levels among antibiotic-exposed patients. 16S rRNA sequencing demonstrated a marked depletion of SCFA-producing genera, including Roseburia and Eubacterium, accompanied by lower serum SCFA concentrations. Moreover, microbiota composition before BsAb treatment correlated with therapy response and treatment-related toxicity.Conclusions Antibiotic-induced dysbiosis prior to BsAb therapy is associated with impaired immune reconstitution and inferior clinical outcomes in MM. These findings underscore the importance of antibiotic stewardship and suggest that microbiota-preserving strategies could enhance the efficacy of BsAb therapy in MM.",
  "authors": [
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain",
        "Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain"
      ],
      "name": "Magdalena Corona"
    },
    {
      "affiliations": [
        "Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain"
      ],
      "name": "Roberto García-Vicente"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"
      ],
      "name": "Adolfo Jesús Saez-Marin"
    },
    {
      "affiliations": [
        "Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain",
        "Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, Madrid, Spain"
      ],
      "name": "Raquel Ancos-Pintado"
    },
    {
      "affiliations": [
        "Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain"
      ],
      "name": "Alba Rodríguez-Garcia"
    },
    {
      "affiliations": [
        "Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain"
      ],
      "name": "Andrés Arroyo"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"
      ],
      "name": "Alberto Blanco"
    },
    {
      "affiliations": [
        "Hematology Department, University of California San Francisco, San Francisco, California, USA"
      ],
      "name": "Ajai Chari"
    },
    {
      "affiliations": [
        "Hematology Department, University of California San Francisco, San Francisco, California, USA"
      ],
      "name": "Thomas Martin"
    },
    {
      "affiliations": [
        "Hematology Department, University of California San Francisco, San Francisco, California, USA"
      ],
      "name": "Jeffrey Wolf"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Clinico Universitario de Salamanca, Salamanca, Spain"
      ],
      "name": "Beatriz Rey-Bua"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Clinico Universitario de Salamanca, Salamanca, Spain"
      ],
      "name": "Maria-Victoria Mateos"
    },
    {
      "affiliations": [
        "Hematology Department, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "K Martin Kortüm"
    },
    {
      "affiliations": [
        "Hematology Department, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Christine Riedhammer"
    },
    {
      "affiliations": [
        "Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain"
      ],
      "name": "Luis E Tamariz-Amador"
    },
    {
      "affiliations": [
        "Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain"
      ],
      "name": "Evelyn Valencia"
    },
    {
      "affiliations": [
        "Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain"
      ],
      "name": "Paula Rodríguez-Otero"
    },
    {
      "affiliations": [
        "Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain"
      ],
      "name": "Jesús San Miguel"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Germans Trias i Pujol, Badalona, Spain"
      ],
      "name": "Gladys Ibarra"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Germans Trias i Pujol, Badalona, Spain"
      ],
      "name": "Albert Oriol"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"
      ],
      "name": "Maria Teresa Cedena"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"
      ],
      "name": "Nieves López-Muñoz"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"
      ],
      "name": "Rafael Alonso"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"
      ],
      "name": "Maria Calbacho"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"
      ],
      "name": "Jose María Sanchez-Pina"
    },
    {
      "affiliations": [
        "Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain",
        "Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, Madrid, Spain"
      ],
      "name": "María Linares"
    },
    {
      "affiliations": [
        "Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain",
        "Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain",
        "Department of Medicine, Medicine School, Universidad Complutense de Madrid, Madrid, Spain"
      ],
      "name": "Joaquín Martínez-López"
    }
  ],
  "title": "Antibiotic-associated dysbiosis and bispecific antibody outcomes in multiple myeloma",
  "uid": "1ff342bf-9f92-5320-92d6-a32b0df5bd82"
}