Introduction. Patients with TP53 dysfunction, assessed by del(17p) or TP53 mutations, respond poorly to chemo-immunotherapy and fare better with the new therapies (BCR and BCL-2 inhibitors); however, it is unclear whether their response is similar to that of patients without anomalies or whether there is currently an adequate determination of TP53 dysfunction. Area covered.A literature search was undertaken on clinical trials and real-world experience data on patients with TP53 dysfunction treated with different protocols. Moreover, data on the TP53 biological function and on the tests currently employed for its assessment were reviewed. Expert opinion.Although TP53 dysfunction has less negative influence on the new biological therapies, patients with these alterations, particularly those with biallelic inactivation of TP53, have a worst outcome with these therapies than those without alterations. At present, a determination of TP53, particularly with next generation sequencing (NGS) methodologies, may be sufficient for the identifications of the patients unsuitable for chemo-immunotherapy, although integration with del(17p) would be advisable. For the future, more extensive determinations of the TP53 status, including functional assays, may become part of the current armamentarium for a better patient stratification and treatment with newer protocols.

No abstract

No abstract

Objectives To compare the capacity of ibrutinib (IB) and idelalisib‐rituximab (IDELA‐R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only. Methods A real‐life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study. Results At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA‐R vs IB HR = 0.5, 95% CI = 0.36‐0.71) although with some limitations due to the non‐randomized and retrospective nature of the study and to the lower number of patients in the IDELA‐R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA‐R (HR = 0.67, 95% CI = 0.45‐0.98, P = .04) independent of potential confounders. Conclusions Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.

Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptideconjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased offtarget cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third-or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.