Emerging precision medicine in multiple myeloma: clinical and preclinical landscape of T cell, natural killer cell, and macrophages engaging multi-specific antibodies

Multiple Myeloma (MM) is the third most common hematological malignancy worldwide. Despite advancements in available therapies, MM remains incurable for most patients, mainly due to the early relapse and eventual resistance to therapy, underlining the need for novel drugs. Among these, multi-specific antibodies (MsAbs) have emerged as promising agents. Multi-specific immune cell-engaging antibodies, such as bi-specific, and tri-specific are designed to recognize two or more antigens on the same or distinct cells. These antibodies could promote cancer cell clearance by engaging both myeloma cells and cytotoxic immune cells such as T and Natural killer (NK) cells and macrophages (M). Currently, four bi-specific T cell engagers (teclistamab, elranatamab, talquetamab and linvoseltamab) are approved for refractory or relapsed MM patients (RRMM). While these therapies have demonstrated promising results in achieving deep remissions in RRMM, primary resistance occurs in about one-third of patients. Initially, immune engager research focused only on T cells due to their crucial anti-cancer role, but more recently, interest has expanded to NK cells and M for broader therapeutic potential. To date, several NK and M engaging MsAbs with mainly bi-specific and tri-specific formats are in clinical or preclinical evaluation for improving MM patients’ response and reduce treatment related toxicity. This review discusses the recent advancement in T, NK and M engaging MsAbs in treating MM, including immunological background, mechanisms of action, relevant clinical and preclinical advancements and challenges. Moreover, we discuss the advantages and drawbacks of the different immune cell engagers. Furthermore, we review recent studies investigating the clinical and molecular determinants of resistance along with the latest predictive or prognostic biomarkers of response to MsAbs. Finally, we explore novel strategies to enhance MsAbs efficacy and reduce their toxicity, providing long-term disease control and improving survival in MM patients.