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Summary Background Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit–risk of the combination at the request of the US Food and Drug Administration (FDA). Methods KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1–21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov , number NCT02579863 , and it is closed for accrual. Findings Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4–9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2–88·1) versus 85·0% (76·8–90·5; hazard ratio [HR] 1·22; 95% CI 0·67–2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). Interpretation The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).

Objectives: Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan–prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. Methods: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg ⁄ m 2 , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, days 1, 8, 22, 29, cycles 5–9, plus melphalan 9 mg ⁄ m 2 and prednisone 60 mg ⁄ m 2 , days 1–4, cycles 1–9; N = 344) or MP alone (N = 338). Results: Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P = 0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P £ 0.0001) and CR ⁄ PR (P £ 0.01). Median DKK-1 decreased with VMP by 694.4 pg ⁄ mL and increased with MP by 1273.3 pg ⁄ mL from baseline to day 4 (P = 0.0069). Available radiologic data revealed evidence of bone healing in 6 ⁄ 11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. Conclusions: These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.

Background Induction therapy in patients with multiple myeloma has evolved from chemotherapy-based to novel agents–based regimens. We compared autologous hematopoietic cell transplantation (HCT)-associated toxicity in patients induced with VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatinum, adriamycin, cyclophosphamide, and etoposide) to that of patients induced with novel agents–only therapy. Methods We reviewed medical charts of all patients with multiple myeloma who were given induction therapy and HCT. Results Between the years 2007 and 2011, 38 patients received VTD-PACE, and 31 patients received novel agents–only regimen. Mean time to neutrophil and platelets recovery was longer in patients given VTD-PACE compared with those given novel agents–only regimen (7 vs. 6 d, p = 0.0002 and 11 vs. 10 d, p = 0.04, respectively). We observed higher rates of grade 2–4 mucositis and parenteral narcotic analgesia administration in the patients given VTD-PACE (45% vs. 19%, p = 0.05 and 37% vs. 12%, p = 0.07, respectively). Progression free survival and overall survival were not statistically significantly different between the two groups. Conclusions A more intensive induction regimen was associated with slightly delayed counts recovery and a higher rate of mucositis during HCT compared with novel agents–only regimens. A longer follow-up is needed to assess long-term disease control of the two different regimens.

Introduction: Elotuzumab is an immunostimulatory monoclonal antibody (mAb) that recognizes Signaling Lymphocytic Activation Molecule F7 (SLAMF7), a protein highly expressed by myeloma and natural killer cells. Elotuzumab has a dual mechanism of action, directly activating natural killer cells and initiating antibody-dependent cell-mediated cytotoxicity targeted against myeloma cells, with minimal effect on normal tissues. In the 2-year progression-free survival (PFS) interim analysis of ELOQUENT-2, a Phase 3 study (NCT01239797) comparing elotuzumab plus lenalidomide/dexamethasone (ELd) with lenalidomide/dexamethasone (Ld), ELd resulted in a significant 30% reduction in the risk of disease progression or death vs Ld (hazard ratio 0.70 [95% CI 0.57, 0.85]; p=0.0004). Overall response rate (ORR) was 79% (95% CI 74, 83) in the ELd arm vs 66% (95% CI 60, 71) in the Ld arm (p=0.0002). Furthermore, the addition of elotuzumab to Ld was well tolerated, with minimal added toxicity.1 Elotuzumab's immunotherapeutic effect induces effective therapeutic outcomes and represents an important approach to treating multiple myeloma (MM). Here we present extended 3-year follow-up data. Methods: As previously described,1 patients (pts) with relapsed/refractory MM (RRMM) and 1-3 prior therapies were randomized 1:1 to ELd or Ld in 28-day cycles until disease progression or unacceptable toxicity. Primary endpoints were PFS and ORR. Secondary and other endpoints included overall survival (OS) and health-related quality of life. Post hoc analyses assessed Worst Pain using the Brief Pain Inventory-Short Form (BPI-SF); data were collected at screening, on Day 1 of each 28-day cycle, and at the end of treatment. Sustained improvement in pain was defined by a decrease of ≥3 points for ≥2 consecutive treatment cycles. Results: In total, 646 RRMM pts were randomized (321 to ELd, 325 to Ld). Baseline demographic factors included: median age 66 years (20% ≥75 years old); 32% of pts had del17p and 10% had t(4;14); median prior number of therapies was 2; and 35% of pts were refractory to their last therapy. At data cut-off (16 May 2015), 29% of pts treated with ELd vs 15% of pts treated with Ld remained on study therapy; discontinuation was mainly due to disease progression (46% in ELd arm, 51% in Ld arm). Grade 3-4 adverse events in ≥15% of pts included lymphopenia (78% in ELd arm, 49% in Ld arm), neutropenia (35% in ELd arm, 44% in Ld arm), anemia (20% in ELd arm, 21% in Ld arm), and thrombocytopenia (21% in ELd arm, 20% in Ld arm). Infections (any grade) occurred in 83% of pts in the ELd arm and 75% in the Ld arm. Exposure-adjusted infection rates (incidence rate/100 person-years of exposure) were 196 and 193 in the ELd and Ld arms, respectively. Infusion reactions (mostly Grade 1-2) occurred in 11% of pts treated with ELd. In total, there were 263 deaths during treatment follow-up (123 [47%] in ELd arm, 140 [53%] in Ld arm); 62% of the required 427 deaths for the OS final analysis. With regard to patient-reported pain (BPI-SF), sustained improvement in Worst Pain was observed in pts with ORR, with more pts demonstrating sustained improvement in the ELd arm (n=74) vs the Ld arm (n=56). 3-year PFS and the interim analysis of OS will be presented. Conclusions: Elotuzumab is the first immunostimulatory mAb for the treatment of MM to demonstrate a statistically significant and clinically relevant improvement in efficacy with minimal added toxicity.1 The addition of elotuzumab to Ld led to an effective and durable benefit, representing a novel approach to treating MM. The updated safety and tolerability data reported were consistent with previous findings, confirming that there are minimal incremental toxicities associated with the addition of elotuzumab. A greater proportion of ELd pts vs Ld pts with an ORR had improvement in BPI-SF Worst Pain. Three-year PFS data and the interim analysis of OS will be presented, providing insight into the long-term benefits of ELd therapy. Reference: 1. Lonial S et al. N Engl J Med 2015; Jun 2 [Epub ahead of print]. Study funding: Study funded by Bristol-Myers Squibb and AbbVie Biotherapeutics. Writing assistance was provided by S Addison, PhD, at Caudex and funded by Bristol-Myers Squibb. Disclosures Dimopoulos: Genesis: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. Off Label Use: Elotuzumab is an investigational agent being studied for the treatment of multiple myeloma. . Lonial:Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. White:Millennium: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria. Moreau:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Array BioPharma: Honoraria; Janssen-Cilag: Consultancy, Honoraria; Sanofi-Aventis: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. San Miguel:Novartis: Honoraria; Sanofi-Aventis: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Bristol-Myers Squibb: Honoraria; Millennium: Honoraria. Shpilberg:Millennium Takeda: Consultancy; Gilead: Consultancy. Spicka:Janssen-Cilag: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy. Mateos:Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy; Celgene: Consultancy, Honoraria. Reece:Amgen: Honoraria; Novartis: Honoraria, Research Funding; Otsuka: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Lundbeck: Honoraria; Millennium Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Onyx: Consultancy; Merck: Research Funding. Beksac:Novartis: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy. Bleickhardt:Bristol-Myers Squibb: Employment. Poulart:Bristol-Myers Squibb: Employment. Katz:Bristol-Myers Squibb: Employment. Singhal:Abbvie: Employment. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338). Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.

The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices. © AlphaMed Press., Advisory Board meeting supported by Janssen Pharmaceutical Companies of Johnson and Johnson in Europe, Middle East, and Africa (EMEA). Unrestricted educational grant provided by Janssen Pharmaceutical Companies of Johnson and Johnson in the EMEA to assist with editorial support.

Incorporation of novel biological agents has become the cornerstone of treatment in multiple myeloma. For the last 4 years we have adopted the more intensified approach, previously published as total therapy 3 by the Arkansas group and used it with local modifications. This study aims to evaluate the efficacy and safety of the Arkansas protocol-based treatment outside clinical trial in a tertiary medical center in Israel. We retrospectively analyzed 23 patients. Seventy-three percent of the patients achieved very good partial remission (VGPR) before autologous stem cell transplantation (ASCT). Eighty-six percent of the patients achieved at least VGPR after tandem ASCT. Two-year overall survival was estimated as 70%. Four patients died during treatment, one as a result of disease progression. We conclude that this protocol is effective and rather safe. Further clinical trials should assess which subgroups of patients would benefit most from this approach.

8508 Background: Elo, a monoclonal antibody (mAb) targeting Signaling Lymphocytic Activation Molecule F7 (SLAMF7), kills myeloma cells with minimal effect on normal tissue. Elo showed encouraging a...

Objectives Patients with malignancies have an increased prevalence of antiphospholipid antibodies (APA). The aim of this study was to determine the prevalence of IgG, IgM, and IgA anticardiolipin antibodies (aCL) and anti-beta-2 glycoprotein I antibodies (anti-beta2-GPI) in patients with non-Hodgkin's lymphoma (NHL), and to investigate their clinical and prognostic significance. Methods The study group included 86 patients with NHL. Enzyme-linked immunosorbent assay kits were used to measure the concentrations of aCL and anti-beta2-GPI, and coagulation tests, to measure lupus anticoagulant (LAC) activity. Blood was collected at diagnosis in all patients and at follow-up in 15. Median follow-up time was 1.9 yr. Results Elevated APA levels were found in 35 patients (41%) at diagnosis: one patient aCL IgG, five patients aCL IgM, five aCL IgA, one anti-beta2-GPI IgG, 14 anti-beta2-GPI IgM, and 19 anti-beta2-GPI IgA; LAC activity was found in three of 67 patients (4.5%). There was no significant correlation between elevated APA levels and patient's age or sex, disease stage or grade, bone marrow involvement, B symptoms, serum lactate dehydrogenase levels, serum beta2 microglobulin levels, International Prognostic Index (IPI) score, performance status, type of treatment, or response to treatment. There was a correlation between elevated APA and absence of extranodal disease (P = 0.045). A strong negative correlation was found between elevated APA at diagnosis and survival time. Two-year survival was 90 +/- 5% for patients without APA at diagnosis compared with 63 +/- 11% for patients with an elevated APA levels (P = 0.0025). APA added to the predictive value of IPI for event-free and overall survival. Conclusions APA are elevated in 41% of NHL patients at diagnosis and are correlated with shortened survival. Their level may serve as an independent prognostic variable in aggressive NHL.

Cancer antigen 125 (CA 125) is a glycoprotein expressed in normal tissues originally derived from coelomic epithelia such as peritoneum, pleura, pericardium, fallopian tubes and endometrium. Serum CA 125 levels are elevated in various benign and malignant conditions that involve stimulation of these tissues. Although elevated levels have been reported in patients with non-Hodgkin's lymphoma (NHL), its role as a prognostic factor remained uncertain. In this study, serum CA 125 levels were measured prospectively in 108 consecutive patients with NHL: at diagnosis in 106, in remission in 39 and at relapse in 7. Levels were elevated in 43% at diagnosis. This finding was associated with advanced disease stage, bulky tumors, bone marrow involvement, extranodal disease (in stages III and IV), occurrence of B symptoms, pleural or peritoneal effusions, high serum LDH levels, high serum beta2 microglobulin (beta2-M) levels, elevated International Prognostic Score, poor performance status and partial or no response to treatment. No difference in CA 125 level was found between the indolent and aggressive lymphomas. Serum CA 125 levels at diagnosis had strong association with event-free and overall survival (p = 0.01 and 0.003, respectively), with the patients with increased levels having worse survival. Patients with high CA 125 levels at diagnosis who achieved remission showed a significant decrease in CA 125 levels in remission. In conclusion, CA 125 is not only a reliable marker for staging and assessing tumor activity in NHL, elevated levels are also predictive of decreased survival.