• No new safety signals were observed with daratumumab plus pomalidomide and dexamethasone, except for increased neutropenia.• Daratumumab plus pomalidomide and dexamethasone induced rapid, deep, and durable responses in heavily treated patients with 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 5 103) received a median (range) of 4 (1-13) prior therapies; 76% received ‡3 prior therapies. The safety profile of daratumumab plus pomdex 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 25 . 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. (Blood. 2017;130(8):974-981)

Current monoclonal antibody therapies for multiple myeloma have had limited success, perhaps due to narrow target specificity. We have previously described the ability of polyclonal rabbit antithymo-cyte globulin (rATG) to induce caspase-and cathepsin-mediated apoptosis in human B and plasma cells. We now extend this observation to myeloma cells. Complement independent cell death was measured after addition of rATG (1-1000 g/mL) to cultures of myeloma cell lines or primary CD138 isolates from patient bone marrow aspirates. rATG induced significant levels of apoptosis in my-eloma cells as assayed by caspase induction , annexin V binding, subdiploid DNA fragmentation, plasma-membrane per-meability, and loss of mitochondrial-membrane potential. Addition of complement greatly augmented myeloma-cell death. Binding of rATG to individual my-eloma cell-surface proteins, primarily CD38, CD52, CD126, and CD138, was demonstrated by competitive inhibition experiments with targeted monoclonal antibod-ies. Three pathways of cell death were identified involving caspase activation, cathepsin D, and the genistein sensitive tyrosine kinase pathway. F(ab) 2 fragments of rATG had reduced proapoptotic activity, which was restored by coincuba-tion with Fc fragments, and anti-CD32 or anti-CD64 antibodies. We conclude that rATG is an effective agent for in vitro induction of apoptosis in multiple myeloma, and that exploratory clinical trials may be warranted. (Blood. 2006;107:2895-2903)

Introduction : Daratumumab (DARA) is a human anti-CD38 IgG1κ monoclonal antibody with remarkable safety and activity as monotherapy in heavily treated relapsed and refractory (RR) multiple myeloma (MM) (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl:abstr LBA8512). DARA has demonstrated clinical activity in combination with lenalidomide (LEN) and dexamethasone (D) in relapsed or RR MM (Plesner T. Blood 2014;124(21):84). This ongoing 4-arm, multicenter, phase 1b study (NCT01998971) evaluated the safety and efficacy of DARA in combination with various backbone therapies and pomalidomide plus D (POM-D). Results in newly diagnosed patients treated with DARA and backbone therapies were previously reported (Mateos MV, et al. Haematologica 2015;100(s1):84). Methods : Patients in the DARA + POM-D arm had relapsed or RR MM with ≥2 prior lines of therapy including ≥2 consecutive cycles of LEN and bortezomib. During 28-day treatment cycles patients received DARA 16 mg/kg qw for 2 cycles, then q2w for 4 cycles, and q4w until disease progression (PD). Pomalidomide 4 mg was administered qd for 21 days with D 40 mg qw (20 mg for patients >75 years of age). The primary endpoint was safety and tolerability of DARA in combination with POM-D. Overall response rate (ORR) was a secondary endpoint. Disease responses were evaluated by an independent data safety monitoring board. Results: A total of 77 patients were enrolled into the DARA + POM-D arm. The median (range) age was 64 (35-86) years and the median number of prior therapies was 3.5 (2-10). Sixty-five percent of the patients were refractory to bortezomib, 30% to carfilzomib, 88% to lenalidomide, and 65% to both a PI and IMiD. With a median (range) duration of follow-up of 72 (1-423) days, 28 (36%) patients have discontinued treatment due to PD (15 [20%]), adverse events (AEs; 6 [8%]), death or physician's decision (3 [4%] each), and one (1%) patient withdrawal. The median (range) duration of treatment was 69 days (1-416), and the median (range) number of infusions was 7.5 (1-25). Forty-nine (64%) patients continue on study treatment and enrollment is ongoing. There was little additional toxicity when DARA was added to POM-D other than DARA-specific infusion related reactions (IRRs; 47/77 patients). Most occurred on Cycle 1 Day 1 (45/47 patients), and the most common (>10%) IRRs were chills (13%), cough (13%), and dyspnea (11%). The most common (>10%) and grade ≥3 adverse events (AEs) are presented in Table 1. Five patients died within 30 days of receiving study treatment due to AEs (4[5%]) or progressive disease (1 [1%]). In 53 patients with >1 post-baseline assessment, the ORR was 58.5%, with 3 stringent complete responses (sCR), 1 complete response (CR), 12 very good partial responses (VGPR), 15 partial responses (PR), 2 minimal responses, 18 stable disease, and 2 PD. Many responses deepened over time. Median (range) time to first response was 30 (28-92) days. After a median follow-up of 148 days, 4 out of 31 responders developed PD. Among the evaluable double refractory patients (n = 40), there was 1 sCR, 1 CR, 10 VGPRs, and 11 PRs with an ORR of 57.5%. Conclusions : The addition of DARA to POM-D was well tolerated and did not result in additional toxicities with the exception of DARA-related infusion reactions. Deep and durable responses were observed quickly, along with a high response rate. Study enrollment is ongoing and data will be updated at the meeting. Table 1. Most Common (>10%) Adverse Events (N = 77) Adverse Event, n (%) Any Grade Grade ≥3 Neutropenia 42 (54.5%) 39 (50.6%) Anemia 28 (36.4%) 16 (20.8%) Fatigue 28 (36.4%) 4 (5.2%) Cough 24 (31.2%) 0 Nausea 21 (27.3%) 0 Dyspnea 20 (26.0%) 5 (6.5%) Diarrhea 19 (24.7%) 1 (1.3%) Leukopenia 19 (24.7%) 12 (15.6%) Thrombocytopenia 17 (22.1%) 8 (10.4%) Pyrexia 16 (20.8%) 1 (1.3%) Dizziness 15 (19.5%) 0 Chills 14 (18.2%) 0 Nasal Congestion 14 (18.2%) 0 Upper Respiratory Tract Infection 14 (18.2%) 1 (1.3%) Back Pain 13 (16.9%) 2 (2.6%) Constipation 13 (16.9%) 0 Tremor 13 (16.9%) 2 (2.6%) Insomnia 12 (15.6%) 1 (1.3%) Lymphopenia 11 (14.3%) 7 (9.1%) Muscle Spasms 11 (14.3%) 0 Vomiting 11 (14.3%) 0 Arthralgia 9 (11.7%) 1 (1.3%) Pruritus 9 (11.7%) 0 Throat Irritation 9 (11.7%) 0 Anxiety 8 (10.4%) 0 Headache 8 (10.4%) 0 Hypertension 8 (10.4%) 4 (5.2%) Musculoskeletal Chest Pain 8 (10.4%) 2 (2.6%) Peripheral Edema 8 (10.4%) 1 (1.3%) Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Onyx: Consultancy, Research Funding. Lonial:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Suvannasankha:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Arnulf:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Qin:Janssen: Employment. Masterson:Janssen: Employment. Nottage:Janssen: Employment. Schecter:Janssen: Employment. Ahmadi:Janssen: Employment. Weiss:Janssen and Millennium: Consultancy; Janssen and Onclave: Research Funding. Krishnan:Millenium: Speakers Bureau; BMS: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Lentzsch:Celgene: Consultancy; Janssen: Consultancy; Axiom: Honoraria; Novartis: Consultancy; BMS: Consultancy.