Stewart, A. Keith

Key PointsIn a randomized phase 3 trial, overall response rates, PFS, and overall survival were similar between MPT-T and mPR-R. Toxicity with both regimens was common, but mPR-R was better tolerated, and patients on the mPR-R regimen reported better quality of life.

Abstract Purpose: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the central nervous system. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental Design: We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results: Biallelic inactivation of TOX and PRKCD was recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. In addition, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11, and translocations IgH-BCL6. Overall, B-cell receptor/Toll-like receptor/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions: In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas. Clin Cancer Res; 21(17); 3986–94. ©2015 AACR.

SummarySixty‐four transplant‐eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1–28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28‐day cycles (CYKLONE regimen). Carfilzomib was dose‐escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide‐related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression‐free survival and overall survival at 24 months was 76% and 96%, respectively (median follow‐up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.

Key Points Elderly patients with myeloma are heterogeneous and assessment strategies are needed to define the frailty profile. The proposed frailty score aims to better assess patients and provide them with more suitable therapies.

AbstractObjectivesApproximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation.MethodsAdult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2‐stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5‐days‐on/2‐days‐off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non‐responding patients, treatment could continue with the addition of low‐dose dexamethasone.ResultsIn total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non‐interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)‐positive group and 3.7 weeks in the t(4;14)‐negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)‐positive group and 34.6% in the t(4;14)‐negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%).ConclusionDovitinib showed no single‐agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)‐positive patients.

Key Points High-throughput RNAi screening identified lenalidomide sensitizer genes, including RSK2, RAB, peroxisome, and potassium channel family members. Knockdown or inhibition of RSK2 synergized with lenalidomide to induce myeloma cytotoxicity and downregulation of interferon regulatory factor 4 and MYC.

Key Points Dinaciclib is a novel cdk inhibitor that demonstrates single agent activity in myeloma. Dinaciclib has a safety profile that is easily manageable.

SummaryWe constructed a multiple myeloma (MM)‐specific gene panel for targeted sequencing and investigated 72 untreated high‐risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high‐risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.

SummaryDickkopf‐1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti‐DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma‐related bone disease and as an agent with potential anti‐myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose‐limiting toxicity (DLT) of escalating doses in combination with anti‐myeloma therapy and zoledronic acid. Twenty‐eight patients were enrolled and received BHQ880 at doses of 3–40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal‐related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti‐myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.