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Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib-lenalidomide-dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10 -5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10 -5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free ( p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10 -5 . Altogether 95% of the patients with sustained MRD <10 -5 , 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance ( p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients.

Competing Interests: FHS: Grants or contracts from Celgene, Janssen, Oncopeptides, Sanofi, GSK Targovax. Payments or honoraria for lectures/presentations/speakers bureus/article writing or educational events: Amgen, BMS, Takeda, Abbvie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Pfizer, Daiki-Sankyo, GSK. Participation on a Data Safety Monitoring Board or Advisory Board: Abbvie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, BMS. MH: Royalties of payments for lectures: Janssen, BMS, Pfizer. EvdS: Royalties for lectures Janssen. PFY: Royalties of payments for lectures/article preparations/etc: Janssen and Amgen: participation in a company sponsored speakers’ bureau. UHM: Employment/Consultation: Advisory boards: Amgen, Sanofi, Pfizer. Royalties of payments for lectures/article preparations/etc: Lecture honoraria: Amgen, Janssen, BMS, Sanofi, GSK. NWCJvdD: Research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. PS: Consulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen Therapeutics, Pfizer. Research Funding: Janssen, Amgen, BMS/Celgene. NA: Research grant, honorarium and advisory board, Takeda. SZ: Consulting or Advisory Role: Janssen-Cilag, Takeda, Celgene/Bristol Myers Squibb, Sanofi, Oncopeptides (no personal funding). Research Funding: Janssen, Takeda. All the other authors have no conflicts of interest to disclose.

Data on the impact of long term treatment with immunomodulatory drugs (IMiD) on health-related quality of life (HRQoL) is limited. The HOVON-87/NMSG18 study was a randomized, phase 3 study in newly diagnosed transplant ineligible patients with multiple myeloma, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by maintenance therapy until progression (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed at baseline, after three and nine induction cycles and six and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for evaluation. 596 patients participated in HRQoL reporting. Patients reported clinically relevant improvement in global quality of life (QoL), future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size. In general, improvement occurred after 6-12 months of maintenance only and was independent of the World Health Organisation performance at baseline. Patients treated with MPR-R reported clinically relevant worsening of diarrhea, and patients treated with MPT-T reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least three months reported clinically meaningful improvement in global QoL and role functioning at six months, remaining stable thereafter. There were no clinically meaningful deteriorations, but patients on thalidomide reported clinically relevant worsening in neuropathy. In general, HRQoL improves both during induction and maintenance therapy with immunomodulatory drugs. The side effect profile of treatment did not negatively affect global QoL, but it was, however, clinically relevant for the patients. ( Clinicaltrials.gov identifier: NTR1630 )., (Copyright© 2020 Ferrata Storti Foundation.)

KIT is detected in a variety of cells, also in acute leukemia. Inhibition of wild-type KIT is not always satisfactory. The aim of this work was to evaluate the frequency of the most common KIT mutations in acute myeloid leukemia (AML) and determine the correlation between mutation and expression level. Samples were obtained from 75 patients with AL. CD117 presence was shown in 45 of 51 patients with AML and in 1 of 16 patients with acute lymphocytic leukemia (ALL). Asp816Val mutation was found in 3.5% of cases of AML and Val560Gly mutation in 1 sample with acute biclonal leukemia. Other genetic changes were found in 15 of 57 samples with AML: polymorphisms Met541Leu in 14% of cases, Lys546Lys in 7% and 1 case of acute biclonal leukemia, Ile798Ile in 5.3% of cases, Met541Leu in 1 acute biphenotypic leukemia and in 6.3% of ALL. Polymorphism Lys546Lys was also shown in 1 case of acute biclonal leukemia. Nonsilent genetic changes were detected in a total of 23% cases with core binding factor leukemia. There was no statistical significance between KIT expression and genetic changes. There was no correlation between the incidence and types of KIT mutations and its expression on cells in AML., (© 2014 S. Karger AG, Basel.)

We have recently reported that two typical Gs-coupled receptors, the beta2-adrenergic receptor and the receptor for prostaglandin E1, stimulate phospholipase C-epsilon (PLC-epsilon) and increase intracellular Ca2+ concentration ([Ca2+]i) in HEK-293 cells and N1E-115 neuroblastoma cells, respectively, by a pathway involving Epac1, a cAMP-activated and Rap-specific guanine nucleotide exchange factor (GEF), and the GTPase Rap2B. Here we have demonstrated that these Gs-coupled receptors use this pathway to activate H-Ras and the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Specifically, agonist activation of the receptors resulted in activation of H-Ras and ERK1/2. The latter action was suppressed by dominant negative H-Ras, but not Rap1A. The receptor actions were independent of protein kinase A but fully mimicked by an Epac-specific cAMP analog as well as by a constitutively active Rap2B mutant. On the other hand, a cAMP-binding-deficient Epac1 mutant, the Rap GTPase-activating proteinII, and a dominant negative Rap2B mutant suppressed receptor- and Epac-mediated activation of H-Ras and ERK1/2. Finally, we have demonstrated that activation of H-Ras and ERK1/2 requires the lipase activity of PLC-epsilon and the subsequent [Ca2+]i increase, suggesting that H-Ras activation is mediated by a Ca2+ -activated GEF. In line with this hypothesis, receptor-mediated activation of H-Ras and ERK1/2 was strongly enhanced by expression of RasGRP1, a Ca2+ -regulated Ras-GEF. Collectively, our data indicated that Gs-coupled receptors can activate H-Ras and subsequently the mitogen-activated protein kinases ERK1/2 by a Ca2+ -activated Ras-GEF, possibly RasGRP1, mediated by cAMP-activated Epac proteins, which then lead via Rap2B and PLC-epsilon stimulation to [Ca2+]i increase.

Receptor tyrosine kinase regulation of phospholipase C-epsilon (PLC-epsilon), which is under the control of Ras-like and Rho GTPases, was studied with HEK-293 cells endogenously expressing PLC-coupled epidermal growth factor (EGF) receptors. PLC and Ca(2+) signaling by the EGF receptor, which activated both PLC-gamma1 and PLC-epsilon, was specifically suppressed by inactivation of Ras-related GTPases with clostridial toxins and expression of dominant-negative Rap2B. EGF induced rapid and sustained GTP loading of Rap2B, binding of Rap2B to PLC-epsilon, and Rap2B-dependent translocation of PLC-epsilon to the plasma membrane. GTP loading of Rap2B by EGF was inhibited by chelation of intracellular Ca(2+) and expression of lipase-inactive PLC-gamma1 but not of PLC-epsilon. Expression of RasGRP3, a Ca(2+)/diacylglycerol-regulated guanine nucleotide exchange factor for Ras-like GTPases, but not expression of various other exchange factors enhanced GTP loading of Rap2B and PLC/Ca(2+) signaling by the EGF receptor. EGF induced tyrosine phosphorylation of RasGRP3, but not RasGRP1, apparently caused by c-Src; inhibition of c-Src interfered with EGF-induced Rap2B activation and PLC stimulation. Collectively, these data suggest that the EGF receptor triggers activation of Rap2B via PLC-gamma1 activation and tyrosine phosphorylation of RasGRP3 by c-Src, finally resulting in stimulation of PLC-epsilon.

We have previously observed that melanocytes produce nitric oxide in response to ultraviolet radiation and lipopolysaccharide and in this study have examined how these responses are affected by alpha-melanocyte-stimulating hormone. Nitric oxide production by cultured cells was measured electrochemically in real time using an ISO-nitric oxide sensor probe. B16 mouse melanoma cells released nitric oxide in response to lipopolysaccharide and the effects were enhanced in cells that had been grown in the presence of 10-11-10-9 M alpha-melanocyte-stimulating hormone prior to stimulation. At concentrations in excess of 10-9 M alpha-melanocyte-stimulating hormone decreased nitric oxide production. Preincubation with lipopolysaccharide, a well-known inducer of inducible nitric oxide synthase, also increased nitric oxide production but this response was reduced by alpha-melanocyte-stimulating hormone. alpha-Melanocyte-stimulating hormone also increased the levels of nitric oxide produced in response to ultraviolet radiation (20-100 mJ per cm2) in B16 cells. The same effect was seen in human melanocytes and as this was inhibited by aminoguanidine would appear to involve an induction of inducible nitric oxide synthase. Reverse transcription-polymerase chain reaction showed that melanocytic cells express inducible nitric oxide synthase mRNA. Western blotting analysis and immunocytochemistry confirmed the presence of inducible nitric oxide synthase protein in B16 cells and FM55 human melanoma cells and that the levels were increased in response to alpha-melanocyte-stimulating hormone. alpha-Melanocyte-stimulating hormone, however, decreased inducible nitric oxide synthase protein expression, which occurred in response to lipopolysaccharide. These results suggest that alpha-melanocyte-stimulating hormone regulates nitric oxide production in melanocytic cells by modulating the induction of inducible nitric oxide synthase. Additional experiments showed that nitric oxide increased melanin production by B16 cells and human melanocytes. This is in keeping with a melanogenic role for nitric oxide but whether its production by melanocytes in response to alpha-melanocyte-stimulating hormone is associated with such a role or whether it has some other significance relating to melanocyte differentiation or in mediating immunomodulatory actions of alpha-melanocyte-stimulating hormone remains to be seen.

The growth of solid tumors and their metastasis is dependent on the development of new blood vessels (angiogenesis). In this study, we examined the effect of the angiogenesis inhibitor TNP-470 on a fast growing melanoma in hamsters. The effect was observed both on tumor growth and metastasis. Treatment with TNP-470 caused a significant decrease in the rate of tumor growth and suppression of the development of metastasis in 63% of treated animals. Some of the hamsters treated with TNP-470 had the tumor excised and the effect of that operation on the development of metastasis was examined. In such cases the inhibitory effect of TNP-470 was weaker than in tumor bearing animals. This indicates that excision of tumor created more favourable conditions for angiogenesis and that the dose of TNP-470 should be increased to be effective in such conditions.