Lenalidomide in combination with an activin A-neutralizing antibody: preclinical rationale for a novel anti-myeloma...

Area of Science:

• Oncology
• Bone Biology
• Pharmacology

Background:

• Multiple myeloma (MM) frequently causes osteolytic bone disease, necessitating therapies targeting the bone microenvironment.
• Activin A has been identified as a key mediator in MM-induced osteolysis.
• Lenalidomide is an established treatment for relapsed MM, but its effects on bone metabolism require further investigation.

Purpose of the Study:

• To investigate the mechanism by which lenalidomide affects osteoblastogenesis in the context of MM.
• To evaluate the therapeutic potential of combining lenalidomide with an activin A-neutralizing antibody to counteract MM-induced osteolysis.

Main Methods:

• Investigated the effect of lenalidomide on activin A secretion in bone marrow stromal cells.
• Utilized Akt- and Jun N-terminal kinase (JNK)-dependent signaling pathways to elucidate the mechanism of action.
• Assessed the impact of combining lenalidomide with an activin A-neutralizing antibody on osteoblast function and MM cell cytotoxicity in vitro.

Main Results:

• Lenalidomide treatment directly increased activin A secretion from bone marrow stromal cells via Akt/JNK signaling, inhibiting osteoblastogenesis.
• Co-administration of an activin A-neutralizing antibody abrogated lenalidomide-induced activin A secretion.
• The combination therapy restored osteoblast function and inhibited MM-induced osteolysis without compromising lenalidomide's cytotoxic effects on malignant cells.

Conclusions:

• Lenalidomide's mechanism involves increased activin A secretion, which impairs osteoblast function.
• Combining lenalidomide with an anti-activin A antibody offers a promising strategy to manage MM-induced bone disease while maintaining therapeutic efficacy against myeloma cells.
• This approach provides a rationale for ongoing clinical trials investigating this combination therapy.