ALBERT

Description: Salvage of patients with relapsed and refractory Hodgkin disease (HD) with high-dose chemoradiotherapy (HDT) and autologous stem cell transplantation (ASCT) results in event-free survival (EFS) rates from 30% to 50%. Unfortunately, the reduction in toxicity associated with modern supportive care has improved EFS by only 5% to 10% and has not reduced the relapse rate. Results of a comprehensive 2-step protocol encompassing dose-dense and dose-intense second-line chemotherapy, followed by HDT and ASCT, are reported. Sixty-five consecutive patients, 22 with primary refractory HD and 43 with relapsed HD, were treated with 2 biweekly cycles of ifosfamide, carboplatin, and etoposide (ICE). Peripheral blood progenitor cells from responding patients were collected, and the patients were given accelerated fractionation involved field radiotherapy (IFRT) followed by cyclophosphamide-etoposide and either intensive accelerated fractionation total lymphoid irradiation or carmustine and ASCT. The EFS rate at a median follow-up of 43 months, as analyzed by intent to treat, was 58%. The response rate to ICE was 88%, and the EFS rate for patients who underwent transplantation was 68%. Cox regression analysis identified 3 factors before the initiation of ICE that predicted for outcome: B symptoms, extranodal disease, and complete remission duration of less than 1 year. EFS rates were 83% for patients with 0 to 1 adverse factors, 27% for patients with 2 factors, and 10% for patients with 3 factors (P 

Description: Abstract 3971 Background: Although outcomes have improved for patients (pts) with multiple myeloma (MM), relapsed/refractory MM remains associated with short survival and constitutes an unmet medical need. Glucocorticoids (GCs) are an important component of MM therapy; however, resistance is common. In preclinical models, interleukin-6 (IL-6) promotes the proliferation and survival of MM cells in the context of the bone marrow microenvironment and protects these cells from GC-induced apoptosis. Therefore, blocking IL-6 may disrupt resistance and restore sensitivity to GCs. Here, we report the final results from a Phase 2 open-label, non-randomized study that evaluated the safety and efficacy of siltuximab (S), a monoclonal antibody targeting soluble human IL-6, in combination with high-dose dexamethasone (D) in pts with relapsed and relapsed/refractory MM. Methods: Pts with measurable, secretory disease who had received at least 2 prior lines of therapy, one of which contained bortezomib, and progressed during or after their last line of treatment were eligible. Other key eligibility criteria included a creatinine clearance ≥20 mL/min, platelets ≥50,000/mm3, and neutrophils ≥1,000/mm3. S was administered 6 mg/kg IV on days 1 and 15 of a 28-day cycle and oral D 40mg once daily, on days 1–4, 9–12, and 17–20 for a max of 4 cycles; days 1–4 for subsequent cycles. The first 14 pts received S alone for the initial 1 to 2 cycles; 10 pts had D added for progressive disease post-Cycle 1 or suboptimal response post-Cycle 2. 39 subsequent pts received S+D concurrently as none of the first 14 pts achieved ≥PR while on S monotherapy. The primary endpoint was overall response rate (ORR, CR+PR) using EBMT criteria. Secondary endpoints were time to progression (TTP), progression-free survival (PFS), overall survival (OS), and incidence of AEs and SAEs. Results: Forty-nine pts received S+D. The median age was 65 yrs (range 43–89) and 43% of pts were female. The median disease duration was 4 yrs (range 0.7–13.2). Pts were heavily pretreated, having received prior bortezomib (100%), steroids (100%), IMIDs (90%), alkylating agents (91%) and ASCT (65%). The median number of prior lines of therapy was 4 (range 2–9); 86% had disease that was refractory to the last prior line. Of the 44 pts with prior D exposure, 32 (73%) were refractory to the last D-containing regimen. The median duration of therapy was 4 cycles (99 days). Of the 47 pts evaluable for response, the ORR by EBMT criteria was 17% (0 CRs, 8 PRs); the ORR + minimal response (MR) rate was 23.4% (N=11). Using IMWG criteria, the ORR + MR rate was 27.7% (9 PRs, 4 MRs). Of the 11 pts with at least MR by EBMT criteria, 5 pts were refractory to the last D-containing regimen and 7 experienced less than MR on a prior D-containing regimen. The median duration of response was 5.9 months (181 days, 95% CI: 147, 365). Three pts had a long-lasting response of 9 months or more. For all 49 pts, the median PFS was 3.7 months (114 days, 95% CI: 84, 148) and median OS was 20.4 months (621 days, 95% CI: 347,984). AEs occurring in ≥25% of pts were thrombocytopenia, fatigue, anemia, abnormal hepatic function, neutropenia, diarrhea, peripheral edema, dyspnea and dizziness. 74% of pts experienced a grade ≥3 AE; the most frequent non-hematologic grade ≥3 AEs were fatigue (8%), abnormal hepatic function (8%), and pneumonia (6%). Grade 4 hematologic toxicities were thrombocytopenia (12%), neutropenia (4%) and anemia (2%). 25% of pts discontinued treatment due to an AE. Twenty (41%) of the 49 pts experienced ≥1 SAE. The most frequently occurring SAEs were pneumonia (8%), thrombocytopenia (6%), septic shock, anemia, and hemolytic anemia (4% each). Five pts died during the study; 3 due to progressive disease, 2 due to infection (nosocomial infection, septic shock). Conclusions: The combination of siltuximab with dexamethasone was well tolerated. Although the ORR was modest in this relapsed/refractory patient population, responses were seen in pts with MM refractory to prior dexamethasone-containing therapy, suggesting that siltuximab may be able to at least partially overcome dexamethasone resistance in some cases. Overall, these results provide a rationale for further studies of siltuximab in combination with dexamethasone-based MM therapy. Disclosures: Voorhees: MedImmune: Consultancy; Pfizer: Research Funding; Centocor Ortho Biotech: Research Funding; Celgene: Research Funding; Merck: Research Funding. Off Label Use: Siltuximab for the treatment of multiple myeloma. Manges:Centocor Ortho Biotech: Research Funding. Sonneveld:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:Merck: Honoraria; Millennium Pharmaceuticals: Honoraria; Johnson and Johnson Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Research Funding. Somlo:Onyx: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Speakers Bureau; Centocor Ortho Biotech: Research Funding. Krishnan:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau; Centocor Ortho Biotech: Research Funding. Lentzsch:Celgene: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; Centocor Ortho Biotech: Research Funding. Frank:Centocor Ortho Biotech: Research Funding. Zweegman:Centocor Ortho Biotech: Research Funding. Wijermans:Centocor Ortho Biotech Research & Development: Research Funding. Rijnbeek:Ortho Biotech Oncology Research and Development: Employment. Qin:Johnson & Johnson Pharmaceutical Research & Development, LLC: Employment. Cornfeld:Ortho Biotech Oncology Research and Development: Employment. Xie:Ortho Biotech Oncology Research & Development: Employment. Thomas:Centocor Ortho Biotech: Research Funding; Millennium Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding.