Calcium silicate/bortezomib combinatory therapy for multiple myeloma.

Area of Science:

• Hematologic Malignancies
• Bioceramics
• Drug Resistance

Background:

• Multiple myeloma (MM) is a prevalent hematologic malignancy with bortezomib (BOR) as a primary treatment.
• BOR resistance and side effects like peripheral neuropathy limit its long-term efficacy, leading to refractory relapsed multiple myeloma (RRMM).
• Developing strategies to enhance BOR sensitivity and mitigate resistance is crucial for improving patient outcomes.

Purpose of the Study:

• To investigate the potential of calcium silicate (CS), a Si-releasing bioceramic, to enhance the anti-myeloma effects of bortezomib (BOR).
• To evaluate the efficacy of the combination therapy in overcoming BOR resistance in multiple myeloma (MM) models.
• To elucidate the underlying mechanisms by which Si ions (SI) modulate BOR's anti-myeloma activity.

Main Methods:

• In vitro studies using human myeloma cell lines (HMCLs), including BOR-resistant U266/BOR cells.
• Assessment of anti-myeloma effects in primary MM cells from patients.
• In vivo evaluation in MM xenograft mouse models.
• Mechanistic studies involving cell cycle analysis and pathway inhibition (NF-κB).

Main Results:

• Calcium silicate (CS) significantly enhanced the anti-myeloma activity of BOR in vitro, including in BOR-resistant cell lines.
• The combination therapy demonstrated efficacy in primary MM cells and in MM xenograft mouse models.
• Mechanistically, SI promoted G2/M cell cycle arrest and augmented BOR-induced inhibition of the NF-κB pathway.

Conclusions:

• The combination of Si ions (SI) and BOR (SI/BOR) is a promising strategy to overcome BOR resistance in multiple myeloma (MM) and refractory relapsed multiple myeloma (RRMM).
• CS, as a SI delivery system, offers a potential approach to reduce toxicity and improve treatment outcomes.
• Future development of CS nanomaterials for BOR delivery presents a promising clinical application for MM treatment.