Kidney-Tonifying, Phlegm-Resolving, and Blood Stasis-Removing Therapy for Multiple Myeloma: Protocol for a Randomized Controlled Trial on Epigenetic and Immune Modulation.

Background: Multiple myeloma (MM) is characterized by kidney deficiency, phlegm, and blood stasis as core findings, specifically in Traditional Chinese Medicine (TCM), and the kidney-tonifying, phlegm-resolving, and blood stasis-removing (KPR) method is a fundamental therapeutic approach for MM in TCM. Western medicine primarily focuses on targeted immunotherapy or chemotherapy for MM treatment, whereas TCM characterizes MM through distinct pathological patterns that directly correspond to immune microenvironment dysregulation. Emerging evidence implicates the PHD finger protein 19 (PHF19)/enhancer of zeste homolog 2 (EZH2)/trimethylated histone H3 at lysine 27 (H3K27me3) epigenetic axis in immune microenvironment dysregulation and MM progression. Notably, TCM "blood stasis" correlates with hypoxia-induced immune gene silencing in MM bone marrow, and KPR (a clinically validated TCM decoction with 16 herbs) acts on this axis via its active components that regulate EZH2 and epigenetic function, merging TCM syndrome differentiation with modern epigenetics. We have designed a randomized controlled trial (RCT) to investigate the mechanism of action and safety of the KPR method in MM. Objective: This RCT aims to assess whether a KPR herbal formula combined with standard bortezomib-based therapy improves the immune microenvironment via the PHF19-EZH2-H3K27me3 epigenetic axis to restore immune function in MM, providing a mechanistic basis for integrating TCM into evidence-based oncology care in relapsed or refractory patients. Methods: This is a single-center, prospective RCT involving patients with MM. It has been designed to test the hypothesis that the KPR formula epigenetically regulates the PHF19-EZH2-H3K27me3 axis to improve the immune microenvironment. Patients are randomly assigned in a 1:1:1 ratio to 3 groups (blank control group, Western medicine control group, and integrated TCM and Western medicine treatment group). All patients undergo 12 weeks of treatment and a 6-month follow-up. The primary outcome is the CD3+ T-cell ratio in bone marrow/peripheral blood, which is detected by flow cytometry. The secondary outcomes include quantified TCM syndrome scores, Western medicine efficacy evaluation criteria, complete blood count, bone marrow morphology, blood and urine immunoglobulin levels, quantitative M protein levels, free light chain levels, β2-microglobulin levels, and whole-body imaging findings. Statistical analysis involves linear mixed models for longitudinal data and Bonferroni correction to verify KPR's immunomodulatory effects via the targeted epigenetic axis. Results: This study was funded in November 2023. Recruitment was initiated in March 2025 and is expected to be completed in February 2026. As of October 2025, 41 patients have been enrolled. Data collection is projected to end in October 2026. Data analysis has not yet been initiated, and the results are expected to be published in 2027. Conclusions: This unique mechanistic RCT evaluating a TCM formula targeting the PHF19-EZH2-H3K27me3 axis in patients with MM will establish a biomarker-driven framework for integrating TCM with immunotherapy, offering novel strategies for treatment-refractory patients.