Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows ...chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R
2
-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2–8 cycles + R-CHOP (non-activated B-cell ABC subtype) or R
2
-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R
2
-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% 95% CI 50.2–82.0) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (
n
= 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP.
Summary
Interleukin‐6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid‐induced apoptosis. We therefore evaluated the efficacy and safety of ...siltuximab, an anti‐IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥2 prior lines of therapy, one of which had to be bortezomib‐based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone‐containing regimen. Suppression of serum C‐reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone‐refractory disease. The median time to progression, progression‐free survival and overall survival for combination therapy was 4·4, 3·7 and 20·4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination‐treated patients, including ≥grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid‐containing myeloma regimens is warranted, with special attention to infection‐related toxicity.
Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows ...chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R
-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2-8 cycles + R-CHOP (non-activated B-cell ABC subtype) or R
-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R
-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% 95% CI 50.2-82.0) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (n = 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP.
Abstract 129
In this US community-based, randomized, open-label, multicenter phase 3b study, we compare the safety and efficacy of three highly active bortezomib (Velcade®, Vc)-based regimens for ...multiple myeloma (MM), Vc–thalidomide–dexamethasone (VcTD), Vc–dexamethasone (VcD), and Vc–melphalan–prednisone (VcMP), in previously untreated MM patients (pts) ineligible for high-dose therapy and autologous stem cell transplantation. Use of these regimens is supported by data from phase 3 studies; only VcMP has been investigated specifically in elderly pts. Here we present data from a pre-specified interim analysis (IA) of 210 pts performed after the first 70 pts in each arm had the opportunity to complete four cycles of therapy. Pts with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD (Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 Cycles 1–4), days 1, 2, 4, 5 Cycles 5–8), VcTD (Vc 1.3 mg/m2, days 1, 4, 8, 11; T 100 mg/d, d1-21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 Cycles 1–4), days 1, 2, 4, 5 Cycles 5–8) or VcMP (Vc 1.3 mg/m2, days 1, 4, 8, 11; M 9 mg/m2 and P 60 mg/m2, day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with Vc alone (1.6 mg/m2, days 1, 8, 15, 22). Prophylactic aspirin, full dose warfarin, or low molecular weight heparin was administered to the VcTD arm unless medically contraindicated.The primary endpoint is progression-free survival; secondary endpoints include overall survival, duration of response, time to next therapy, quality of life (QoL) using the EORTC QLQ-C30 questionnaire, safety and tolerability, and efficacy (CR/nCR, VGPR, PR, and ORR). Responses were assessed by investigators using central laboratory data, applying the International Myeloma Working Group uniform criteria. An Independent Data Monitoring Committee (IDMC) assessed safety, tolerability, response rates and QoL data to determine which two of the three arms should continue enrolling pts. Pts in the VcD, VcTD, and VcMP arms had median ages of 74, 73, and 72 years, respectively; 83%, 58%, and 73% had ISS stage ll/lll and 21%, 22% and 32%, respectively, were non-Caucasian. In the VcD, VcTD, and VcMP arms, mean number of treatment cycles (for the first four cycles) and total Vc doses (16 doses for the first four cycles) were similar: 3.8, 3.6, and 3.7 cycles and 14.5, 13 and 13.8 Vc doses, respectively. The VcD arm had the lowest rate of adverse events (AEs) grade ≥3 (58% vs 71% each in the VcTD and VcMP arms, respectively), as well as the lowest rate of discontinuations due to AEs (10% vs 18% and 16% in the VcTD and VcMP arms, respectively). The VcTD arm had the highest rate of serious AEs (50% vs 39% and 36% in the VcD and VcMP arms, respectively), as well as peripheral neuropathy (PN) of any grade (48% vs 29% and 30% in the VcD and VcMP arms, respectively). PN grade ≥3 was 6%, 12% and 13% in the VcD, VcTD, and VcMP arms, respectively. The VcTD arm had higher rates of serious embolism/thrombosis (8% vs 6% and 3%) than in the VcD and VcMP arms, respectively. All three regimens demonstrated substantial activity. The overall response rate was 60%, 70%, and 52% in the VcD, VcTD, and VcMP arms, respectively (complete response (CR)/near CR: 13%, 18% and 15%; ≥very good partial response 15%, 23% and 24%, respectively). QoL functional scores improved in all arms, except for physical, role function and global health status, which worsened in the VcTD arm only. At a preplanned IA, the three Vc-based regimens were evaluated as having similar risk/benefit considerations after four cycles. The regimens were active with well-characterized and predictable toxicities. The study continues to enroll in all three arms as recommended by the IDMC. The UPFRONT trial demonstrates the feasibility of conducting a large, randomized, outpatient, phase 3b trial in community-based oncology centers in the United States.
Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc: Research Funding. Phooshkooru:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Charu:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Neuwirth:Millennium Pharmaceuticals, Inc: Employment.
Background: Bortezomib represents a significant advance in the treatment of relapsed/refractory myeloma, but its efficacy is limited by a number of resistance mechanisms including activation of the ...anti-apoptotic heat shock protein (HSP) and stress response pathways. CNTO 328 is an anti-IL-6 chimeric monoclonal antibody shown to have anti - myeloma activities in vitro. Because IL-6 signaling augments the HSP response, downregulation of IL-6 signaling may enhance bortezomib's clinical anti-myeloma activity. Pre-clinical studies demonstrated that this combination had an additive to synergistic effect in inducing apoptosis in IL-6-dependent and independent multiple myeloma cell lines (Voorhees et al., 2007, in press).
Methods: In this safety lead-in cohort of a pivotal trial (clinicaltrials.gov), CNTO 328, 6 mg/kg, was administered by IV every 2 weeks in combination with bortezomib, 1.3 mg/m2, given by IV on days 1, 4, 8, and 11 every 3 weeks. Pateints received a maximum of four, 6-week treatment cycles, after which the bortezomib schedule was reduced to four, once weekly doses in a 5-week maintenance cycle. When disease progression was documented, oral dexamethasone was added at 20 mg and given on the day of, and day after each bortezomib infusion, for a maximum of two cycles. All later cycles included 20 mg dexamethasone given only on the day of bortezomib administration.
Results: Preliminary results from the first 6 patients are available. Pateint characteristics included median age of 68 years; B2M > 3.0 mg/L, (n = 4 pateints); CRP > 3.0 mg/L (3); a median of 2 prior regimens (range 1 – 3), and prior bone marrow or peripheral blood stem cell transplantation in three patients. Using the EBMT response criteria, three patients achieved confirmed partial responses (PRs). Additionally, two patients had unconfirmed PRs. One patient discontinued prior to confirmation, while a follow up assessment for the other patient is pending. The median number of cycles administered was 3. Two of the patients ended treatment prematurely, 1 due to disease progression and 1 due to adverse events. The remaining 4 patients continue on study. Grade 3/4 adverse events (AEs) considered possibly related to CNTO 328 and bortezomib include neutropenia (2 patients), leukopenia (1), lymphopenia (1), and bloody diarrhea (1).
Conclusion: Treatment with anti-IL-6 CNTO 328 in combination with bortezomib has been evaluated for safety and efficacy in the first 6 patients of an ongoing pivotal trial for the treatment of relapsed or refractory multiple myeloma. Initial activity observed with this combination is encouraging, and enrollment is continuing to explore its full potential.
Background: CNTO 328 is an anti-interleukin (IL)-6 chimeric monoclonal antibody demonstrated to have anti-myeloma activities in vitro. Because IL-6 signaling augments the anti-apoptotic heat shock ...protein response, a potential resistance mechanism for bortezomib, downregulation of IL-6 signaling may enhance bortezomib's anti-myeloma activity. Pre-clinical studies have shown that this combination had an additive to synergistic effect in inducing apoptosis in IL-6-dependent and independent multiple myeloma cell lines.
Methods: In this open-label, safety lead-in cohort of a pivotal phase II trial, bortezomib naïve patients with relapsed/refractory multiple myeloma received CNTO 328 at 6mg/kg IV every 2 weeks in combination with 1.3 mg/m2 bortezomib IV on days 1, 4, 8, and 11 every 3 weeks. Patients received a maximum of 4, 6-week treatment cycles, after which bortezomib was reduced to 4, once weekly doses in a 5-week maintenance cycle. Dexamethasone was added to the regimen at disease progression.
Results: Twenty-one patients (median age 66, range 39–85) were treated with bortezomib + CNTO 328. The median number of prior lines of therapy was 2 (range 1–3); the median duration since diagnosis was 3.5 years (range 1–10). Eleven patients had received prior autologous stem cell transplantation; 8 patients had received prior IMiDs. Baseline β2M levels of >3.5mg/L were reported in 13 patients; median CRP was 2.21 mg/L (range 0.4 – 86.1). Utilizing EBMT criteria, 12 patients (57%) achieved either a complete response (CR) or partial response (PR): 3 CR, 9 PR (including 2 very good partial response >90% reduction and 1 unconfirmed due to discontinuation for renal insufficiency). Thirteen of twenty-one patients discontinued treatment: 5 due to disease progression, 7 adverse events (AEs), and 1 withdrawal of consent. The other 8 remain on treatment. The median number of CNTO 328 administrations was 11 (range 2–38). Median time to disease progression/death was 280 days (range 36–540+). Grade 3 and higher hematologic toxicity was common: neutropenia (15/21); thrombocytopenia (8/21); lymphopenia (6/21); leukopenia (5/21). Grade 3 and higher hematologic AEs considered to be possibly related to CNTO 328 included neutropenia (10/21), leukopenia (3/21), lymphopenia (2/21) and thrombocytopenia (1/21). Grade 3 and higher infections were reported in 5 patients (urinary tract, bacterial, and campylobacter infection, pneumococcal sepsis, and pneumonia, 1 case each, among which the urinary tract and campylobacter infections were considered to be possibly CNTO 328-related). Other common CNTO 328-related AEs (>15%) of any grade included diarrhea (5/21), fatigue (5/21), and hypercholesterolemia (4/21). No patients died during treatment. Dexamethasone was added to the treatment regimen for only 4/21 patients, and no conclusions regarding this treatment modification can be drawn at present.
Conclusion: Treatment with CNTO 328 combined with bortezomib is a promising new regimen for the treatment of relapsed/refractory multiple myeloma. Enrollment in a larger phase 2 randomized trial with bortezomib and either CNTO 328 or placebo is now ongoing to explore its full potential.
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