Therapy-induced senescence as a driver of immune activation and myeloid plasticity in multiple myeloma

Abstract Multiple myeloma (MM) is an incurable plasma cell malignancy. Despite therapeutic advances, nearly all MM patients are expected to relapse and develop refractory disease, underscoring the need to improve the efficacy of first line therapy to prevent disease relapse. The current standard of care for newly diagnosed MM includes a myeloablative dose of the cytotoxic agent melphalan prior to autologous stem cell transplant (ASCT). Cytotoxic drugs are known to trigger therapy induced senescence (TIS) in normal cells. Several solid tumors have been shown to exhibit features of TIS following chemotherapy, and these markers in tumor cells are associated with superior progression free survival (PFS). One potential mechanism for this benefit is the activation of anti-tumor immune responses through the senescence associated secretory phenotype (SASP), which recruits and stimulates immune cells. Consistent with the findings in solid tumors, our analysis of longitudinal MM patient bone biopsies revealed a significant increase in senescence in MM cells in patients with PFS ≥2.5 years following ASCT. In contrast, patients that relapsed in