UCSF

Multiple myeloma is one of the most common blood cancers. Many drugs have been developed to treat multiple myeloma, yet refractory and relapsed disease remain prevalent. The recent identification of CD46, an antigen overexpressed on multiple myeloma cells, has led to new development of antibody-based immunotherapies, including the antibody-drug conjugate CD46 ADC and the radioimmunotherapy [225Ac]Ac-Macropa-PEG4-YS5. The structures of both drugs include the CD46-binding monoclonal antibody YS5, and both have shown high tumor binding and antitumor efficacy in pre-clinical models for multiple myeloma. A Phase 1 clinical trial is also underway to evaluate CD46 ADC in multiple myeloma. While initial results are promising, both drugs have noted drawbacks, with blood cancers like multiple myeloma known to develop resistance to ADCs over time and [225Ac]Ac-Macropa-PEG4-YS5 studies displaying nephrotoxicity at higher doses. Hypothesizing that the use of the two drugs in tandem could improve therapeutic efficacy, this study investigated the performance of RIT & ADC combined treatment across preclinical multiple myeloma models in-vitro and in-vivo. Results of initial cell-based assays demonstrated a high cell killing ability of combination treatment, with evidence of a synergistic interaction between drugs at select combination concentrations. A pilot xenograft mouse model comparing combination treatment to RIT & ADC monotherapies showed a widespread reduction in tumor burden with animal body weight remaining stable, potentially indicating reduced off-target toxicity. Future work will monitor the antitumor efficacy of RIT & ADC combination therapy over a longer time scale and measure organ damage ex-vivo to further compare against prior monotherapy results. This encouraging initial data provides guidance on combination dosing regimens for future preclinical research and suggests that RIT & ADC combination therapy may be a valuable clinical option for treating multiple myeloma.