Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma.

Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received ≥3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ≥3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10-5 Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971.

A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus.

The analysis of patient blood transcriptional profiles offers a means to investigate the immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease data sets. Mapping changes in gene expression at the module level generated disease-specific transcriptional fingerprints that provide a stable framework for the visualization and functional interpretation of microarray data. These transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Thus, this work describes the implementation and application of a methodology designed to support systems-scale analysis of the human immune system in translational research settings.

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma.

BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2 /day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2 /day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2 /day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2 (duration of response, 5.2 to ≥21.2 months). CONCLUSIONS: The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-3335. © 2016 American Cancer Society.

Harnessing human dendritic cell subsets for medicine.

Immunity results from a complex interplay between the antigen-non-specific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. In this article, we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines.

Effect of stem cell source on outcomes after unrelated donor transplantation in severe aplastic anemia.

Outcome after unrelated donor bone marrow (BM) transplantation for severe aplastic anemia (SAA) has improved, with survival rates now approximately 75%. Increasing use of peripheral blood stem and progenitor cells (PBPCs) instead of BM as a graft source prompted us to compare outcomes of PBPC and BM transplantation for SAA. We studied 296 patients receiving either BM (n = 225) or PBPC (n = 71) from unrelated donors matched at human leukocyte antigen-A, -B, -C, -DRB1. Hematopoietic recovery was similar after PBPC and BM transplantation. Grade 2 to 4 acute graft-versus-host disease risks were higher after transplantation of PBPC compared with BM (hazard ratio = 1.68, P = .02; 48% vs 31%). Chronic graft-versus-host disease risks were not significantly different after adjusting for age at transplantation (hazard ratio = 1.39, P = .14). Mortality risks, independent of age, were higher after PBPC compared with BM transplantation (hazard ratio = 1.62, P = .04; 76% vs 61%). These data indicate that BM is the preferred graft source for unrelated donor transplantation in SAA.

Dendritic cell subsets as vectors and targets for improved cancer therapy.

Current active immunotherapy trials have shown durable tumor regressions in a fraction of patients. However, the clinical efficacy of current vaccines is limited, possibly because tumors skew the immune system by means of myeloid-derived suppressor cells, inflammatory Type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of cancer vaccines in patients with metastatic disease, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the dendritic cell (DC) system, including the existence of distinct DC subsets. Critical to the design of better vaccines is the concept of distinct DC subsets and distinct DC activation pathways, all contributing to the generation of unique adaptive immune responses. Such novel DC vaccines will be used as monotherapy in patients with resected disease and in combination with antibodies and/or drugs targeting suppressor pathways and modulation of the tumor environment in patients with metastatic disease.

Filanesib plus bortezomib and dexamethasone in relapsed/refractory t(11;14) and 1q21 gain multiple myeloma.

Filanesib is a first-in-class kinesin spindle protein inhibitor which demonstrated safety and encouraging activity in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma in a preliminary analysis of dose-escalation phase results. This multicenter study included first a dose-escalation phase to determine maximum tolerated dose of two schedules of filanesib, bortezomib, and dexamethasone and a subsequent dose-expansion phase using the maximum tolerated doses. In the dose-expansion phase, 28 patients were evaluable for safety and efficacy. The most common grade ≥3 adverse events were neutropenia (21%) and anemia (18%), which were noncumulative and reversible, and hypertension (18%). The overall response rate was 43% with median duration of response not yet reached (range, 2.8-23.7+ months) with median follow-up of 6.3 months. A post hoc analysis incorporated 29 dose-escalation phase patients who received therapeutic filanesib doses, with an overall response rate of 39% and median duration of response of 18.0 months among the 57 total patients with median progression-free survival of 8.5 months. Notably, the PFS of high risk patients was comparable at 8.5 months, driven by the patients with 1q21 gain, characterized by increased MCL-1 expression, with a PFS of 9.1 months versus 3.5 months for the remainder of high risk patients. Patients with t(11;14) also had an encouraging PFS of 15.0 months. The combination of filanesib, bortezomib, and dexamethasone continues to show safety and encouraging activity in relapsed/refractory multiple myeloma, particularly in those patients with 1q21 gain and t(11;14).

Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity.

PURPOSE: To determine the efficacy and safety of clofarabine and cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and in elderly patients with untreated AML and heart disease. PATIENTS AND METHODS: Patients with relapsed/refractory AML and older patients for whom there was a concern over toxicity from additional anthracyclines received 5 days of clofarabine, 40 mg/m(2) per day i.v. over 1 hour, followed 4 hours later by Ara-C, 1,000 mg/m(2) per day i.v. over 2 hours. RESULTS: Thirty patients were enrolled. The median age was 67 years (range, 38-82 years) and 18 (60%) had received at least one prior therapy. Eleven (37%) patients had a history of cardiovascular disease and were considered to be at high risk for anthracycline toxicity. High-risk cytogenetic abnormalities were present in 14 (47%) patients. The overall response rate (complete remission [CR] plus partial remission) was 53%, including a CR in 14 patients (47%). Responses were observed in all cytogenetic risk groups and in patients who had received up to five prior therapies. The median disease-free survival interval was 9.5 months. The 30-day mortality rate was 20% (de novo AML, 8%; relapsed/refractory AML, 28%). Of the 14 patients achieving a CR, half were able to proceed to curative hematopoietic stem cell transplantation. CONCLUSIONS: Clofarabine in combination with Ara-C is effective in both untreated and previously treated patients with AML. In addition, it represents a useful remission induction strategy to serve as a bridge to transplantation in older patients with AML.

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease.

We conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.

Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells.

Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T cells able to control tumor relapse. We have shown earlier, in 18 human histocompatibility leukocyte antigen (HLA)-A*0201 patients with metastatic melanoma, that vaccination with peptide-loaded CD34-dendritic cells (DCs) leads to expansion of melanoma-specific interferon gamma-producing CD8+ T cells in the blood. Here, we show in 9 out of 12 analyzed patients the expansion of cytolytic CD8+ T cell precursors specific for melanoma differentiation antigens. These precursors yield, upon single restimulation with melanoma peptide-pulsed DCs, cytotoxic T lymphocytes (CTLs) able to kill melanoma cells. Melanoma-specific CTLs can be grown in vitro and can be detected in three assays: (a) melanoma tetramer binding, (b) killing of melanoma peptide-pulsed T2 cells, and (c) killing of HLA-A*0201 melanoma cells. The cytolytic activity of expanded CTLs correlates with the frequency of melanoma tetramer binding CD8+ T cells. Thus, CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill melanoma antigen-expressing targets. These results justify the design of larger follow-up studies to assess the immunological and clinical response to peptide-pulsed CD34-DC vaccines.

Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma.

Although it is accepted that regulatory T cells (T regs) contribute to cancer progression, most studies in the field consider nonantigen-specific suppression. Here, we show the presence of tumor antigen-specific CD4(+) T regs in the blood of patients with metastatic melanoma. These CD4(+) T regs recognize a broad range of tumor antigens, including gp100 and TRP1 (melanoma tissue differentiation antigens), NY-ESO-1 (cancer/testis antigen) and survivin (inhibitor of apoptosis protein (IAP) family antigen). These tumor antigen-specific T regs proliferate in peripheral blood mononuclear cells (PBMC) cultures in response to specific 15-mer peptides, produce preferentially IL-10 and express high levels of FoxP3. They suppress autologous CD4(+)CD25(-) T cell responses in a cell contact-dependent manner and thus share properties of both naturally occurring regulatory T cells and type 1 regulatory T cells. Such tumor antigen-specific T regs were not detected in healthy individuals. These tumor antigen-specific T regs might thus represent another target for immunotherapy of metastatic melanoma.

Unrelated donor hematopoietic cell transplantation for non-hodgkin lymphoma: long-term outcomes.

We analyzed the outcomes of 283 patients receiving unrelated donor allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma (NHL) facilitated by the Center for International Blood and Marrow Transplant Research/National Marrow Donor Program (CIBMTR/NMDP) between 1991 and 2004. All patients received myeloablative conditioning regimens. The median follow-up of survivors is 5 years. Seventy-three (26%) patients are alive. The day 100 probability of death from all causes is estimated at 39%. The cumulative incidence of developing grade III-IV acute graft-versus-host disease (aGVHD) at day 100 is 25%. The estimated 5-year survival and failure free survival are 24% (95% confidence interval [CI]: 19-30) and 22% (95% CI: 17-28), respectively. Factors adversely associated with overall survival (OS) included increasing age, decreased performance status, and refractory disease. Follicular lymphoma (FL) and peripheral T cell lymphoma had improved survival compared to aggressive B cell lymphomas. Factors adversely associated with progression-free survival (PFS) included performance status, histology, and disease status at transplant. Long-term failure-free survival is possible following unrelated donor transplantation for NHL, although early mortality was high in this large cohort.

Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma.

BACKGROUND: Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). METHODS: 9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; n = 916), non-Hodgkin lymphoma (NHL; n = 3546) and plasma cell myeloma (PCM; n = 4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS. RESULTS: 335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR = 4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR = 2.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HR = 1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HR = 2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort. CONCLUSIONS: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Immunotherapy via dendritic cells.

The immune system evolved to protect us from microbes. The antigen (Ag)-nonspecific innate immunity and Ag-specific adaptive immunity synergize to eradicate the invading pathogen through cells, such as dendritic cells (DCZ7) and lymphocytes, and through their effector proteins including antimicrobial peptides, complement, and antibodies. Its intrinsic complexity renders the immune system prone to dysfunction including cancer, autoimmunity, chronic inflammation and allergy. DCs are unique in their capacity to induce and regulate immune responses and are therefore attractive candidates for immunotherapy. However, DCs consist of distinct subsets with common as well as unique functions that lead to distinct types of immune responses. Therefore, understanding DC heterogeneity and their role in immunopathology is critical to design better strategies for immunotherapy. Indeed, what we learn from studying autoimmunity will help us induce strong vaccine specific immunity, either protective, as in the case of microbes, or therapeutic, as in the case of tumors.

A novel vaccine for mantle cell lymphoma based on targeting cyclin D1 to dendritic cells via CD40.

BACKGROUND: Mantle cell lymphoma (MCL) is a distinct clinical pathologic subtype of B cell non-Hodgkin's lymphoma often associated with poor prognosis. New therapeutic approaches based on boosting anti-tumor immunity are needed. MCL is associated with overexpression of cyclin D1 thus rendering this molecule an interesting target for immunotherapy. METHODS: We show here a novel strategy for the development of recombinant vaccines carrying cyclin D1 cancer antigens that can be targeted to dendritic cells (DCs) via CD40. RESULTS: Healthy individuals and MCL patients have a broad repertoire of cyclin D1-specific CD4(+) and CD8(+) T cells. Cyclin D1-specific T cells secrete IFN-γ. DCs loaded with whole tumor cells or with selected peptides can elicit cyclin D1-specific CD8(+) T cells that kill MCL tumor cells. We developed a recombinant vaccine based on targeting cyclin D1 antigen to human DCs via an anti-CD40 mAb. Targeting monocyte-derived human DCs in vitro with anti-CD40-cyclin D1 fusion protein expanded a broad repertoire of cyclin D1-specific CD4(+) and CD8(+) T cells. CONCLUSIONS: This study demonstrated that cyclin D1 represents a good target for immunotherapy and targeting cyclin D1 to DCs provides a new strategy for mantle cell lymphoma vaccine.

Dendritic cells: controllers of the immune system and a new promise for immunotherapy.

Dendritic cells (DCs) can be utilized either as vectors or as targets for therapy. Patients with metastatic melanoma received CD34-DC vaccine that contains Langerhans' cells and interstitial DCs. DCs were pulsed with MART1, tyrosinase, MAGE3, gp100 and Flu-MP peptides, and KLH. DCs induced an immune response to control antigens in 16/18 patients. An enhanced immune response to 1 or more melanoma antigens (MelAgs) was seen in these 16 patients. The two patients failing to respond experienced rapid tumour progression. Six out of seven patients with immunity to two or fewer MelAgs had progressive disease 10 weeks after study entry, in contrast to tumour progression in only 1/10 patients with immunity to > two MelAgs. Since tumour immunotherapy targets autologous antigens we can learn from systemic autoimmunity such as systemic lupus erythematosus (SLE). As opposed to normal monocytes, SLE monocytes induce proliferation of allogeneic CD4+ T cells. SLE sera induce monocyte differentiation towards DCs in an IFNalpha-dependent mechanism. Spiking autologous serum with IFNalpha reproduces DC differentiation. 50% of SLE patients have high serum levels of IFNalpha, which could explain T/B lymphopenia. Yet, plasmacytoid DCs, a major IFNalpha source, are 80% decreased. pDCs and IFNalpha may play a role in SLE pathogenesis and therapy.

Dendritic cells: controllers of the immune system and a new promise for immunotherapy.

The immune system is controlled by dendritic cells (DCs). Just as lymphocytes comprise different subsets, DCs comprise several subsets that differentially control lymphocyte function. In humans, the myeloid pathway includes Langerhans cells (LCs) and interstitial DCs (intDCs). While both subsets produce IL-12, only intDCs make IL-10 and induce B cell differentiation. Another pathway includes plasmacytoid DCs, which promptly secrete large amounts of IFN-alpha/beta viral encounter. Thus, insights into in vivo DC functions are important to understand the launching and modulation of immunity.

Evaluation of the QTc prolongation potential of a monoclonal antibody, siltuximab, in patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or low-volume multiple myeloma.

PURPOSE: A phase 1 study evaluated the QTc prolongation potential of siltuximab, a chimeric, anti-interleukin-6 mAb, in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or low-volume MM. METHODS: Patients with baseline QTcF and QTcB ≤ 500 ms, QRS < 100 ms, PR < 200 ms and no significant cardiac disease received siltuximab 15 mg/kg q3w, the highest dosage used in clinical studies, for 4 cycles. Twelve-lead ECGs obtained at multiple time points pre- and post-infusion at cycles 1 and 4 were evaluated by central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of least square (LS) mean 90 % CI for QTc change from baseline at each time point was <20 ms. RESULTS: An effect on QTc prolongation was ruled out, as the upper bound of 90 % CI was <10 ms at each time point in 27 evaluable patients (13 MGUS, 13 SMM, 1 low-volume MM) with no differences between disease types. Maximum mean QTc increase from baseline occurred 3 h after cycle 1 infusion (QTcF = 3.2 [LS mean 90 % CI -0.01, 6.45] ms; QTcB = 2.7 [-0.69, 6.14] ms). At all other time points, mean QTcF and QTcB increase from baseline was ≤1.5 ms and upper bound 90 % CI was ≤5.1 ms. Twenty patients had mostly low-grade AEs, including nausea, fatigue (20 % each); thrombocytopenia, headache (each 13 %); dyspnea, leukopenia, neutropenia, paresthesia, abnormal hepatic function, URTI (each 10 %). Three MGUS patients achieved 50 % M-protein reduction. There was no association between siltuximab pharmacokinetics and QTc interval. CONCLUSIONS: Siltuximab did not affect the QTc interval. Overall safety was similar to other single-agent siltuximab studies.