Purpose: Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact.Experimental Design: Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data.Results: 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting.Conclusion: Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations.

Purpose Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike in other B cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been previously reported. We sought to address this using results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. Experimental Design Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences. We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. Results In diagnostic myeloma patient samples we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. Conclusions Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available.

No abstract

Background Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design.Methods The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m² subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for pati...

Summary:To assess high-dose carboplatin chemotherapy with or without paclitaxel with filgrastim mobilized peripheral blood progenitor cell (PBPC) support in a phase I/II study, a total of 21 patients with mostly chemonaive disease received four cycles of high-dose chemotherapy. Cycle 1 (cyclophosphamide, 6 g/m 2 ) was followed by two cycles of carboplatin (1600 mg/m 2 or 1800 mg/m 2 ). Cycle 4 consisted of carboplatin (1600 mg/m 2 ), etoposide (1600 mg/m 2 ), and melphalan (140 mg/m 2 ). Further chemotherapy intensification was achieved by adding paclitaxel (175 mg/m 2 ) to all cycles with a fixed carboplatin dose (1600 mg/m 2 ). Ototoxicity was dose-limiting for escalation of sequential cycles of carboplatin. Grade 2 and grade 3 ototoxicity, hearing loss not requiring a hearing aid, or hearing loss correctable with a hearing aid, was observed with carboplatin at 1800 mg/m 2 . The maximum tolerated dose (MTD) of sequential carboplatin, therefore, was identified in this study as 1600 mg/m 2 . After cycles 1, 2, 3 and 4 the median duration of leukopenia (Ͻ1.0 ؋ 10 9 /l) was 7, 4, 4 and 6 days. Severe grade 3 and 4 infections were seen in only 7% of cycles. Of the 21 patients evaluable for disease response, 57% had complete remissions and 43% experienced partial remissions resulting in an overall response rate of 100%. The median progression-free survival is 25 (15-36) months, the median overall survial 36.5 (15-38) months. Most patients were suboptimally debulked or had bulky residual disease at the start of chemotherapy. Sequential high-dose chemotherapy to a maximum dose of 1600 mg/m 2 carboplatin is effective and feasible. A randomized, prospective trial comparing sequential high-dose chemotherapy with optimal standard chemotherapy is now warranted. Keywords: sequential high-dose chemotherapy; ovarian cancer; peripheral blood stem cell; autologous transplantation; maximum tolerated dose of carboplatin The prognosis for patients with advanced ovarian cancer remains poor in spite of the fact that combination chemotherapy, including platinum compounds, yields response rates between 60% and 80%. 1,2 Long-term disease control occurs in 20% to 30% of women with stage III disease, in less than 10% of women with incompletely resected stage III disease, and in less than 5% of women with stage IV disease. 3,4 These disappointing results are presumably due to the resistance of the disease to standard chemotherapy. 5 A retrospective analysis performed by Levin and Hryniuk 6 demonstrated a significant correlation between increased dose-intensity of cisplatin, response rate, and overall survival. Several randomized trials have addressed the role of dose intensity of chemotherapy in ovarian cancer. Maximum dose intensification in these studies was twofold. The results were inconclusive and the merit of dose intensification remains unproven. 7,8 According to in vitro studies, a minimum four-fold increase in dose intensity is necessary to overcome resistance to chemotherapy. 9-11 Single high-dose chemotherapy followed by stem c...