Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma

Abstract

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.

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma

“…The rates of treatment discontinuation owing to adverse events were low and similar in the two groups. After the implementation of guidelines from other studies of daratumumab regarding the management of infusion-related reactions, infusion-related reactions were consistent with daratumumab monotherapy 9,10 and combination therapy, 18,19,32 were mostly of grade 1 or 2, and usually occurred during the first infusion.…”

Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma

“…[33][34][35][36] However, intertrial comparisons must be interpreted with caution because they may be biased by differences in patient populations and study design. Nevertheless, this combination may be an ideal backbone for future studies in conjunction with monoclonal antibodies such as the anti-SLAMF7 37 or the anti-CD38 monoclonal antibodies, daratumumab or isatuximab, 38,39 given its favorable safety profile and oral administration.…”

Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd‐line therapy for relapsed and refractory multiple myeloma – a phase II trial

“…In addition to lenalidomide‐based regimens, pomalidomide has also been shown to improve PFS as well as OS in patients with rrMM (San Miguel et al , ). Likewise, pomalidomide‐based three‐drug combinations with newer drugs such as carfilzomib or monoclonal antibodies have shown very encouraging efficacy in phase II trials (Chari et al , ; Shah et al , ). Whereas single agent daratumumab was associated with an overall response rate of 29–36% in early phase I and II trials, an overall response rate of 81% and 71% could be achieved in phase II trials by the combination of daratumumab with the Rd and pomalidomide/dexamethasone backbone, respectively (Chari et al , ; Lokhorst et al , ; Lonial et al , ; Plesner et al , ).…”

“…Likewise, pomalidomide‐based three‐drug combinations with newer drugs such as carfilzomib or monoclonal antibodies have shown very encouraging efficacy in phase II trials (Chari et al , ; Shah et al , ). Whereas single agent daratumumab was associated with an overall response rate of 29–36% in early phase I and II trials, an overall response rate of 81% and 71% could be achieved in phase II trials by the combination of daratumumab with the Rd and pomalidomide/dexamethasone backbone, respectively (Chari et al , ; Lokhorst et al , ; Lonial et al , ; Plesner et al , ). These results confirm the synergistic activity of immunomodulatory drugs (IMiDs) and daratumumab observed in in vitro studies and further support the concept of IMiD‐based combination therapies with monoclonal antibodies (van der Veer et al , ).…”