Multiple Myeloma (MM) is an incurable disease characterized by a clonal evolution across the course of the diseases and multiple lines of treatment. Among genomic drivers of the disease, alterations of the tumor suppressor TP53 are associated with poor outcomes. In physiological situation, once activated by oncogenic stress or DNA damage, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. Its inactivation participates to drug resistance in MM. The frequency of TP53 alterations increases along with the progression of the disease, from 5 at diagnosis to 75% at late relapses. Multiple mechanisms of regulation lead to decreased expression of p53, such as deletion 17p, TP53 mutations, specific microRNAs overexpression, TP53 promoter methylations, and MDM2 overexpression. Several therapeutic approaches aim to target the p53 pathway, either by blocking its interaction with MDM2 or by restoring the function of the altered protein. In this review, we describe the mechanism of deregulation of TP53 in MM, its role in MM progression, and the therapeutic options to interact with the TP53 pathway.

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Letermovir is the first approved drug for cytomegalovirus (CMV) infection prophylaxis in adult CMV-positive patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Since CMV infection risk varies from patient to patient, we evaluated whether a risk-based strategy could be effective. All consecutive CMV-positive adult patients (median age: 56.0 years, IQR: 43.5-64.0) who underwent allo-HCT between 2015 and 2021 (n=316) were included. Letermovir was not used in Period 1 (2015-2017, n=186), whereas during Period 2 (2018-2021, n=130), letermovir was used in high-risk patients but not in low-risk patients, except in those receiving corticosteroids. In high-risk patients, the incidence of clinically significant CMV infection (csCMVi) in Period 2 was lower as compared to Period 1 (p<0.001) by week 14: 10.5% (95% CI 4.6-19.2) vs 51.6% (41.0-61.3) and week 24: 16.9% (8.9-27.0) vs 52.7% (42.0-62.3), respectively. In low-risk patients, although only 28.6% of patients received letermovir in Period 2, csCMVi incidence was also significantly lower (p=0.003) by week 14: 7.9% (2.9-16.3) vs 29.0% (20.2-38.5) and week 24: 11.2% (4.9-20.5) vs 33.3% (23.9-43.0). Among low-risk patients who did not receive letermovir (n=45), 23 (51.1%) patients experienced transient positive CMV DNA without csCMVi by week 14, while it remained negative in 17 (37.8%) patients. In both risk groups, the two periods were comparable for CMV disease, overall survival, progression-free survival, relapse, and non-relapse mortality. We concluded that a risk-based strategy for letermovir use is an effective strategy which maintains the high efficacy of letermovir in high-risk patients but allows some low-risk patients not to use letermovir.