Antibiotic Exposure Affecting Bortezomib Efficacy in Multiple Myeloma: A Systematic Review
Introduction/Background/Significance: Bortezomib, a proteasome inhibitor, has significantly improved survival outcomes in multiple myeloma (MM). However, resistance remains a major barrier to durable remission. Emerging evidence suggests that antibiotic exposure may contribute to reduced efficacy or delayed response to therapy. Antibiotics can disrupt the gut microbiome, alter systemic immune tone, and shift bone marrow cytokine signaling—particularly IL-6/STAT3 and TNF-α pathways—known to support MM cell survival and drug resistance. Additionally, loss of microbiome-derived short-chain fatty acids (SCFAs) and related epigenetic regulators may impair apoptotic priming in MM cells, potentially blunting proteasome inhibitor activity. This review evaluates clinical and mechanistic evidence linking antibiotic exposure to altered bortezomib efficacy
Materials and Methods/Case Presentation/Objective: We performed a systematic literature search (2005–2025) in PubMed, EMBASE, and Web of Science using “bortezomib,” “antibiotic,” “microbiome,” and “multiple myeloma.” Studies examining antibiotic exposure, microbiome alterations, and proteasome inhibitor responses were included. Data were extracted regarding antibiotic type, timing, treatment outcomes, and mechanistic findings. Due to heterogeneity, a narrative synthesis approach was used.
- Microbiome and immune effects: Broad-spectrum antibiotics depleted commensal bacteria, reducing SCFA production and leading to increased IL-6 and TNF-α signaling, both known mediators of drug resistance.
- Metabolic and proteasome adaptations: Murine models demonstrated that antibiotic-conditioned dysbiosis preserved proteasome activity and reduced bortezomib-induced cytotoxicity, effects partially reversed by butyrate supplementation.
- Clinical observations: Retrospective analyses of MM cohorts suggested a trend toward inferior partial response rates when antibiotics were administered within two weeks of bortezomib initiation (p values 0.06–0.09). Additional case-based observations reported delayed or suboptimal responses associated with prolonged antibiotic exposure.
- Mechanistic convergence: Evidence implicated SCFA depletion, cytokine-driven survival pathways, and possible alterations in proteasome subunit composition as potential mediators.
Conclusions: Antibiotic exposure may adversely influence bortezomib efficacy in MM through microbiome disruption and downstream effects on immune and metabolic homeostasis. Although existing evidence is limited and primarily hypothesis-generating, mechanistic plausibility is supported by converging clinical and preclinical data. Prospective studies integrating microbiome profiling and antibiotic exposure tracking are warranted to establish causal relationships and guide supportive care strategies, including antibiotic stewardship and microbiome-preserving interventions, during proteasome inhibitor therapy.
