Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

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][1]) 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. | 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%) | | | Nausea | 21 (27.3%) | | | 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%) | | | Chills | 14 (18.2%) | | | Nasal Congestion | 14 (18.2%) | | | Upper Respiratory Tract Infection | 14 (18.2%) | 1 (1.3%) | | Back Pain | 13 (16.9%) | 2 (2.6%) | | Constipation | 13 (16.9%) | | | 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%) | | | Vomiting | 11 (14.3%) | | | Arthralgia | 9 (11.7%) | 1 (1.3%) | | Pruritus | 9 (11.7%) | | | Throat Irritation | 9 (11.7%) | | | Anxiety | 8 (10.4%) | | | Headache | 8 (10.4%) | | | Hypertension | 8 (10.4%) | 4 (5.2%) | | Musculoskeletal Chest Pain | 8 (10.4%) | 2 (2.6%) | | Peripheral Edema | 8 (10.4%) | 1 (1.3%) | Table 1. Most Common (>10%) Adverse Events (N = 77) 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. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01998971&atom=%2Fbloodjournal%2F126%2F23%2F508.atom