Preclinical results showing synergistic activity of hLL1-DOX with PIs and IMiDs provide the biological rationale for the evaluation of this ADC in combination with other agents

Preclinical results showing synergistic activity of hLL1-DOX with PIs and IMiDs provide the biological rationale for the evaluation of this ADC in combination with other agents. 4. the front-line and relapse settings. Other antibodies targeting numerous antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a encouraging target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs?), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, AS2717638 we present an overview on mAbs currently approved for the treatment of MM and encouraging compounds under investigation. 0.001) in the Dara-Rd versus Rd arms; this benefit was also consistent AS2717638 in patients with high-risk cytogenetics (HR 0.53, = 0.09) [42]. Of notice, the addition of daratumumab to Rd did not significantly increase the rates of grade 3C4 toxicities, with the exception of neutropenia (54% vs. 39%) and infections (28.3% vs. 22.8%). These data supported the approval of Dara-Rd for the treatment of MM patients who had previously received at least 1 line of therapy. Daratumumab was then evaluated with pomalidomide and dexamethasone (Dara-Pd). In a preliminary phase II trial, this 3-drug regimen showed, in a heavily pretreated population (the median number of prior therapies was 4), ORR (60%) and median PFS (8.8 months) that compared favorably with those of Pd alone (ORR 31%, median PFS 3.8 months) despite the limitations of a cross-trial comparison [32,43]. Following the results of this study, the triplet Dara-Pd received accelerated approval by the FDA for RRMM patients who previously received both an IMiD and a PI. This combination is appealing considering that, in the near future, the majority of newly diagnosed (ND)MM patients will become refractory to continuous lenalidomide after their first line of therapy. Definitive results will come from the phase AS2717638 III trial APOLLO (“type”:”clinical-trial”,”attrs”:”text”:”NCT03180736″,”term_id”:”NCT03180736″NCT03180736) comparing Dara-Pd vs. Pd in RRMM patients. Daratumumab has also been associated with PIs. The phase III CASTOR trial compared bortezomib-dexamethasone (Vd) administered for 8 cycles to daratumumab-Vd (Dara-Vd) for 8 cycles, followed by monthly daratumumab until progression in RRMM patients [30]. The addition of daratumumab resulted in higher ORR (83% vs. 63%) and MRD negativity AS2717638 rate (12% vs. 2%, threshold 10?5), and in prolonged PFS (median, 16.7 vs. 7.1 months; HR 0.31; 0.0001) [31]. Importantly, the MRD negativity rate continued to increase over time for patients receiving Dara-Vd as compared to those receiving Vd, thus highlighting the benefit of continuous treatment with daratumumab. The PFS advantage was also consistent for patients previously exposed to bortezomib (HR 0.35, 0.001) and for patients with high-risk cytogenetic features detected by fluorescence in situ hybridization (FISH, HR 0.45, = 0.05). The triplet Dara-Vd is currently approved by the FDA and EMA for RRMM patients. A phase Ib study with carfilzomib-dexamethasone-daratumumab (KdD) induced an objective response in 84% of RRMM patients after both lenalidomide and bortezomib [33]. It was recently announced that the phase III CANDOR study (“type”:”clinical-trial”,”attrs”:”text”:”NCT03158688″,”term_id”:”NCT03158688″NCT03158688) comparing Kd to KdD met its primary endpoint, with a 37% reduction in the risk of progression or death ActRIB (HR 0.63, 95% CI 0.464C0.854, = 0.0014) in patients receiving daratumumab [44]. Because CD38 expression is higher in the early stages of the disease, and mAbs greatly rely on the immune system to exploit their anti-MM activity, it seems reasonable to expect that moving daratumumab to the first-line setting, when the immune-system of a treatment-na?ve patient is less compromised, could increase its efficacy. In older patients with newly diagnosed (ND)MM, daratumumab plus bortezomib-melphalan-prednisone (Dara-VMP), followed by daratumumab maintenance, significantly increased the MRD negativity rate as compared to the standard of care VMP (22% vs. 6%, 0.001, threshold 10?5), ultimately prolonging the median PFS (NR after a median follow-up of 17 months vs. 18.1 months, HR 0.50, .

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