Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials.

The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton's tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3-4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.

Ferritin Metabolism Reflects Multiple Myeloma Microenvironment and Predicts Patient Outcome.

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.

Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again.

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called "smoldering" MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients' survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.

Network meta-analysis of randomized trials in multiple myeloma: Efficacy and safety in frontline therapy for patients not eligible for transplant.

The treatment scenario for newly-diagnosed transplant-ineligible multiple myeloma patients (NEMM) is quickly evolving. Currently, combinations of proteasome inhibitors and/or immunomodulatory drugs +/- the monoclonal antibody Daratumumab are used for first-line treatment, even if head-to-head comparisons are lacking. To compare efficacy and safety of these regimens, we performed a network meta-analysis of 27 phase 2/3 randomized trials including a total of 12,935 patients and 23 different schedules. Four efficacy/outcome and one safety indicators were extracted and integrated to obtain (for each treatment) the surface under the cumulative ranking-curve (SUCRA), a metric used to build a ranking chart. With a mean SUCRA of 83.8 and 80.08 respectively, VMP + Daratumumab (DrVMP) and Rd + Daratumumab (DrRd) reached the top of the chart. However, SUCRA is designed to work for single outcomes. To overcome this limitation, we undertook a dimensionality reduction approach through a principal component analysis, that unbiasedly grouped the 23 regimens into three different subgroups. On the bases of our results, we demonstrated that first line treatment for NEMM should be based on DrRd (most active, but continuous treatment), DrVMP (quite "fixed-time" treatment), or, alternatively, VRD and that, surprisingly, melphalan as well as Rd doublets still deserve a role in this setting.