The multidrug resistance gene (MDR1) has been reported to be an additional prognostic factor in acute myeloid leukaemia patients. This study evaluated the prognostic role of MDR1 in the outcome of 115 multiple myeloma patients treated with DAV (dexamethasone, doxorubicin [adryamicin] and vincristine) regimen followed by autologous transplantation. In particular, when investigating the C3435T polymorphism, a prognostic value of MDR1 genotypes for overall survival (OS) was observed. Our data suggested a longer OS for patients with C/T and T/T genotypes (log‐rank test, P = 0·02) compared with patients with C/C genotype.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10⁻⁹) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10⁻⁴−5.79 × 10⁻¹⁴). Mechanistically, we found that the ULK4_rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10⁻⁴), whereas the IKBKE_rs17433804 SNP correlated with the number of transitional CD24⁺CD38⁺ B cells (p = 4.8 × 10⁻⁴) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10⁻⁴). We also found that the CD46_rs1142469 SNP correlated with numbers of CD19⁺ B cells, CD19⁺CD3⁻ B cells, CD5⁺IgD⁻ cells, IgM⁻ cells, IgD⁻IgM⁻ cells, and CD4⁻CD8⁻ PBMCs (p = 4.9 × 10⁻⁴−8.6 × 10⁻⁴) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2A_rs2811710 SNP correlated with levels of CD4⁺EMCD45RO⁺CD27⁻ cells (p = 9.3 × 10⁻⁴). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3⁻, MCP-2⁻, and IL20-dependent pathways.

Background: Maintenance treatment after autologous bone marrow transplantation in multiple myeloma improves the outcome of patients. We designed a phase II clinical trial to evaluate the treatment with IL2 and zoledronate after autologous bone marrow transplantation in myeloma patients.Methods: Patients with a histologically proven diagnosis of multiple myeloma become eligible if achieved a very good partial remission in bone marrow samples after 3 months from autologous bone marrow transplantation. IL2 was administered from day 1 to 7. In the first cycle, the daily dose was 2 × 10⁶IU, whereas, in subsequent ones the IL2 dose was progressively escalated, with +25% increases at each cycle, until evidence of toxicity or up to 8 × 10⁶IU. Four mg of zoledronic acid were infused on day 2. Flow cytometry analysis of γδ-lymphocytes was performed at days 1 and 8 of treatment cycles.Results: Forty-four patients have been enrolled between 2013 and 2016. The median time to progression was 22.5 months (95% CI 9.7–35.2). A complete remission with a negative immunofixation was obtained in 18% of patients and correlated with a significantly longer time to progression (p = 0.015). Treatment was well tolerated without G3 or 4 toxicities. After a week of treatment with IL2 and zoledronate, γδ lymphocytes, Vγ9δ2, CD57+, effector, late effector, and memory γδ increased but in subsequent cycles, there was a progressive reduction of this expansion.Conclusions: The maintenance treatment with IL2 and Zoledronate has a modest activity in myeloma patients after autologous bone marrow transplantation.EudraCT Number: 2013-001188-22.

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9); however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p < 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.

In addition to morphological and cytogenetic features, acute myeloid leukemias are characterized by mutations that can be used for target-therapy; also the minimal/measurable residual disease (MRD) could be an important prognostic factor. The purpose of this retrospective study was to investigate if somatic mutations could represent an additional prognostic value in respect of MRD alone. At baseline, 98 patients were tested for NPM1, FLT3, and for WT1 expression; 31 for ASXL1, TET2, IDH1, IDH2, N-RAS, WT1, c-KIT, RUNX1, and DNMT3A. The same genes have been also tested after induction and consolidation. Overall, 60.2% of our patients resulted mutated: 24.5% carried mutations of FLT3-ITD, 38.7% of NPM1, 48.4% of c-KIT, 25.8% of N-RAS and 19.3% of IDH2. The probability of achieving a complete response (CR) was higher for younger patients, with low ELN risk score, NPM1-mutated, with low WT1 levels, and without FLT3. The presence of additional mutations represented a poor predictive factor: only 19% of these cases achieved CR in comparison to 43% of subjects without any of it. Concerning survival, it was conditioned by a lower ELN risk score, younger age, reduction > 1 log of the NPM1 mutational burden, disappearance of FLT3 mutations and lower WT1 expression. Regarding the role of the additional mutations, they impaired the outcome of 20% of the already MRD-negative patients. Concerning the possibility of predicting relapse, we observed an increase of the NPM1 mutational burden at the time-point immediately preceding the relapse (about 2 months earlier) in 50% of subjects. Similarly concerning WT1, an increase of its expression anticipated disease recurrence in 64% of cases. We demonstrated that additional somatic mutations are able to impair outcome of the already MRD-negative subjects. About MRD, we suggest a prognostic role also for the WT1 expression. Finally, we considered as relevant the assessment of NPM1 quantity clearance instead of the presence/absence of mutations alone. Still remains in doubt the utility in terms of long-term prognosis of a baseline more complex mutational screening; we could hypothesize that it would be useful for those patients where other markers are not available or who reached the MRD negativity.