Antibiotic-associated dysbiosis and bispecific antibody outcomes in multiple myeloma.

Broad-spectrum antibiotic exposure prior to bispecific antibody therapy was associated with significantly inferior 1-year overall survival in multiple myeloma patients.

• 1-year OS was 60% (95% CI 44% to 81%) in antibiotic-exposed patients versus 77% (95% CI 71% to 83%) in unexposed patients (p=0.004).
• Study included 237 adult patients with MM treated with CD3-engaging BsAbs across six academic institutions.
• Antibiotic exposure was defined as administration of any broad-spectrum, non-prophylactic antibiotic within 30 days before BsAb initiation.
• Antibiotic exposure remained independently associated with poorer OS in multivariable Cox regression analyses.

Antibiotic exposure prior to bispecific antibody therapy was associated with significantly inferior 1-year progression-free survival.

• 1-year PFS was 26% (95% CI 14% to 47%) in antibiotic-exposed patients versus 53% (95% CI 46% to 61%) in unexposed patients (p<0.001).
• Antibiotic exposure remained independently associated with poorer PFS in multivariable analyses.
• These associations were also observed within the subgroup of patients treated with CD3/BCMA-targeted BsAbs (n=155).

Antibiotic exposure prior to bispecific antibody therapy was associated with higher cumulative incidence of relapse.

• Relapse incidence was 68% (95% CI 48% to 82%) in antibiotic-exposed patients versus 43% (95% CI 36% to 50%) in unexposed patients (p=0.004).
• Higher relapse risk remained independently associated with antibiotic exposure in multivariable competing-risk regression models.
• The association was also observed in the CD3/BCMA-targeted BsAb subgroup (n=155).

Antibiotic-exposed patients demonstrated lower CD4+ T-cell counts and reduced circulating cytokine levels.

• Immunophenotyping was performed on peripheral blood samples collected prior to BsAb infusion in a subset of 24 patients.
• CD4+ T-cell counts were significantly lower in antibiotic-exposed patients (p=0.017).
• Reduced circulating cytokine levels were observed among antibiotic-exposed patients.
• Findings suggest impaired immune reconstitution associated with antibiotic-induced dysbiosis.

16S rRNA sequencing demonstrated marked depletion of short-chain fatty acid-producing gut microbial genera in antibiotic-exposed patients.

• Stool samples for 16S rRNA sequencing were collected in a subset of 19 patients prior to BsAb treatment.
• Depletion of SCFA-producing genera including Roseburia and Eubacterium was observed in antibiotic-exposed patients.
• Lower serum SCFA concentrations accompanied the depletion of these genera.
• Microbiota composition before BsAb treatment correlated with therapy response and treatment-related toxicity.