Antibiotic-associated dysbiosis and bispecific antibody outcomes in multiple myeloma

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.

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.

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.

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.