Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf

Abstract

The impressive improvement of overall survival in multiple myeloma (MM) patients in the last years has been mostly related to the availability of new classes of drugs with different mechanisms of action, including proteasome inhibitors (PI), immunomodulating agents (IMiDs), and monoclonal antibodies. However, even with this increased potence of fire, MM still remains an incurable condition, due to clonal selection and evolution of neoplastic clone. This concept underlines the importance of immunotherapy as one of the most relevant tools to try to eradicate the disease. In line with this concept, active and passive immunotherapies represent the most attractive approach to this aim. Antibody-drug conjugate(s) (ADCs) and bispecific antibodies (BsAbs) include two innovative tools in order to limit neoplastic plasma cell growth or even, if used at the time of the best response, to potentially eradicate the tumoral clone. Following their promising results as single agent for advanced disease, at the recent 62nd ASH meeting, encouraging data of several combinations, particularly of ADC(s) with PI or IMiDs, have been reported, suggesting even better results for patients treated earlier. In this paper, we reviewed the characteristics, mechanism of action, and clinical data available for most relevant ADC(s) and BsAbs.

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma

“…Other BCMA-targeting ADCs include AMG-224, CC-99712, SG1-auristatin, MEDI228, and HDP-101, as summarized in very recent comprehensive reviews (172,(185)(186)(187).…”

Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome‐scale CRISPR‐Cas9 screening in myeloma cells

“…5 Several innovative targeted therapies, such as monoclonal antibodies, CAR-Tcell therapy, antibody-drug conjugates and bispecific antibodies, have made rapid progress in MM. [6][7][8] Furthermore, with the continuous improvement of new technologies and treatment methods, research on biomarkers for MM is steadily developing and is continuously being applied to risk stratification, prognosis assessment and the small-molecule inhibitor selection of subsequent treatment for MM patients. 9 However, the recurrence of MM is still common, and therefore, deeper research into the molecular mechanisms underlying the occurrence and development of MM is needed.…”

“…Despite some progress in treatment strategies for MM, including the use of novel drugs such as proteasome inhibitors, immunomodulatory agents and monoclonal antibodies for younger patients, as well as autologous stem cell transplantation for eligible individuals, MM still remains a challenge 5 . Several innovative targeted therapies, such as monoclonal antibodies, CAR‐Tcell therapy, antibody–drug conjugates and bispecific antibodies, have made rapid progress in MM 6–8 . Furthermore, with the continuous improvement of new technologies and treatment methods, research on biomarkers for MM is steadily developing and is continuously being applied to risk stratification, prognosis assessment and the small‐molecule inhibitor selection of subsequent treatment for MM patients 9 .…”

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

“… 3 , 5 T-cell bispecific antibodies in development include CC-93269 (BCMA-CD3 trivalent), teclistamab (BCMA-CD3) and talquetamab (GPCR5D-CD3). 6 Despite therapeutic advances, MM remains incurable for the majority of patients due to the selection of unresponsive, drug-resistant tumor cells, making relapse imminent.…”