CXCR4/CXCL12 antagonism to disrupt microenvironment-mediated resistance for autologous transplant conditioning in multiple myeloma: A systematic review and mechanistic synthesis.

e19523 Background: Despite advances in therapy, multiple myeloma remains incurable, with relapse driven by residual disease protected within the bone marrow microenvironment. The CXCR4/CXCL12 axis regulates myeloma cell homing and retention in stromal niches, promoting survival and limiting therapeutic efficacy. Although CXCR4 antagonists are routinely used for stem cell mobilization, pathway disruption also mobilizes malignant plasma cells and attenuates stromal resistance. Melphalan conditioning for autologous stem cell transplantation represents a key opportunity for MRD eradication, yet stromal protection remains a barrier. While CXCR4/CXCL12 antagonism has been explored with established anti-myeloma therapies, its role in chemosensitization and relevance to transplant conditioning have not been systematically synthesized. This review evaluates whether CXCR4/CXCL12 disruption enhances therapeutic sensitivity in myeloma and its rationale as an adjunct to transplant conditioning. Methods: We conducted a systematic review following PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science were searched from inception through January 10, 2026 using terms related to multiple myeloma, CXCR4/CXCL12 antagonism, stromal interactions, and chemosensitization. After deduplication, records were independently screened. Eligible studies included preclinical, translational, and clinical investigations of CXCR4/CXCL12 blockade combined with anti-myeloma therapies; reviews and non-myeloma malignancies were excluded. Findings were narratively synthesized due to heterogeneity; formal risk-of-bias assessment was not performed. Results: Of 348 screened records, 22 studies met inclusion criteria. Preclinical studies showed that CXCR4/CXCL12 disruption significantly reduced stromal protection and enhanced sensitivity to melphalan, proteasome inhibitors, and immunomodulatory drugs. Early-phase clinical trials combining CXCR4 antagonists with standard regimens demonstrated significant biological activity and acceptable safety but were not powered for survival outcomes. Reported effects included increased circulating myeloma cells, response signals, and manageable hematologic toxicity. No randomized studies directly evaluated CXCR4/CXCL12 antagonism in autologous transplant conditioning. Conclusions: Across preclinical and early clinical studies, CXCR4/CXCL12 disruption increases myeloma cell vulnerability by limiting microenvironment-driven drug resistance. Although interpretation is constrained by heterogeneity and preclinical predominance, the convergence of chemosensitization and mobilization supports further investigation of CXCR4/CXCL12 blockade during melphalan conditioning to enhance cytoreduction in autologous transplantation.