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

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%)