SummaryThe nephrotoxicity of tobramycin given at a dose of 4.5 mg/kg/day for a period of 12 days to a group of 90 patients with a mean age of 62.9 years was studied.Toxicity was determined on the basis of 3 main criteria (oliguria <400 ml/24 hr, serum creatinine 0.4 mg increase over a minimum basal level of 1.2 mg/100 ml, BUN 5 mg increase over a minimum of 25 mg/100 ml); and 3 minor criteria (proteinuria, microhaematuria and cylindruria). These parameters were determined before treatment at 7, 10, 14, 17, 21, and 30 days afterwards. The age and coexistence of factors such as hypertension, diabetes, anaemia, cardiac insufficiency, shock and dehydration were considered. Nephrotoxicity level ranges from 3.3 to 38'8 % depending on the criterion used, and is related to hypertension (P<0.001), age (P<0.005) and association with ampicillin (P<0-005). Nephrotoxicity was reversible spontaneously in 96.7% of the cases and no differences have been observed between patients with moderate renal insufficiency and those with normal renal function on the initiation of treatment.

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Aims: Using our large dataset from uniformly treated newly diagnosed patinets as well as relpased patient samples, we investigated the somatic alterations in the non coding genome to identify critical hotspots. Methods: We performed a deep (average coverage > 80X) whole genome sequencing (WGS) on 376 MM samples (240 newly diagnosed, 52 first relapse and 84 rrMM) as well as RNAseq to comprehensively analyze recurrent somatic alterations in non-coding regions. Results: We detected median 9,649 (Range 3,935) mutations and indels per sample with overall more than 4 M total somatic mutations. Introns (> 2.5 mutations/per Mb) and intergenic regions (> 3 mutations/per Mb) had significantly higher number of mutations per megabase compared to Exons (~2 mutations/per Mb) (p < 1e-5). Mutations in coding regions in our data was similar to published whole exome sequencing studies with increase in several driver mutations at relapse. We observed 57 [range 7 -376] structural variants (SVs) per sample with > 98% involving non-coding regions. We identified 48 SV hotspots that are targeting tumor suppressor genes or key regulatory elements such as TCF3 and TNFSF10 and these SVs were also associated with significantly altered expression of the target genes. We have detected two less defined translocations targeting MAP3K14 and NFKB1 and driving the expressions of these genes. Our data showed that ~80% of translocation breakpoints are in the close proximity of super enhancers and therefore Ig is not the only mechanism over expresses the target genes. We detected >500 single nucleotide hotspots in the con-coding genome some of which are targeting 5'UTR and introns of BCL7A, BCL6, CD93, CCND1, PAX5. Some of these hotspots were correlated with disease outcome. We also observed that overall mutational load is also associated with disease outcome. We detected chromothripsis in ~25% of newly diagnosed samples; and kataegis hotspots on chromosome 3q27-3q28 (24%), 11q13 (5.8%) and 12q24 (5.3%). Summary/Conclusion: In conclusion, this large deep whole genome sequencing data from newly-diagnosed MM patients identifies a vast majority of non-coding mutations with potentially significant functional and biological role in MM. Our integrative approach using both WGS and RNA-seq data from the patients now provides us important tools to further characterize the impact of these mutations and develop opportunities for targeted therapeutics.

The present pilot study was designed to analyse the efficacy and toxicity of the association of interferon (IFN) and dexamethasone (Dx) in 32 resistant and relapsed myeloma patients. Among the evaluable cases, 15 (68 per cent) responded to treatment (32 per cent achieved an objective response--OR--and 36 per cent a partial response--PR--), the 'remission' status lasting for more than one year in six of them. Moreover, four out of the seven OR patients showed a reduction in B.M. plasma cells to less than 5 per cent. Five out of 11 patients that were previously refractory to VBAD, that includes high dose dexamethasone (Dx), responded to IFN-Dx. The protocol was generally well tolerated with only four patients discontinuing therapy due to adverse effects. The present results show that the combination IFN + Dx is a promising therapeutic approach for patients with refractory myeloma.

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