The CD38 monoclonal antibody daratumumab in combination with lenalidomide and dexamethasone proved to be safe and showed an 81% response rate in patients with relapsed or refractory multiple myeloma, according to research presented at the 2015 ASH Annual Meeting.
Torben Plesner, MD
Torben Plesner, MD
The CD38 monoclonal antibody daratumumab (Darzalex) in combination with lenalidomide and dexamethasone proved to be safe and showed an 81% response rate in patients with relapsed or refractory multiple myeloma, according to research presented at the 2015 ASH Annual Meeting.1
The updated findings from the phase I/II GEN503 study are part of a growing body of data about daratumumab presented at the conference just a few weeks after the drug became the first monoclonal antibody approved by the FDA for treating patients with the malignancy.
Torben Plesner, MD, of Vejle Hospital at the University of Southern Denmark, said the response rates achieved by the combination were “impressive.”
The efficacy combined with a favorable safety profile point to the potential for incorporating daratumumab into existing and emerging multiple myeloma regimens, Plesner indicated. “There’s no added toxicity from daratumumab,” he said. “I think the future will be to explore optimal combinations in clinical trials.”
The 81% overall response rate (ORR) among 32 patients who participated in the expansion phase of the GEN503 trial included 11 patients who achieved a complete response (34%), 9 patients with a very good partial response (28%), and 6 patients with a partial response (19%). In a further breakdown of the results, Plesner said the complete responders included 8 patients (25%) with a stringent complete response.
Additionally, Plesner said, patients responded quickly to the daratumumab-containing regimen. The median time to first response was 1.0 month (0.5-5.6 months) and the median time to best response was 5.1 months (0.5-14.4 months). The median duration of response was not yet reached.
After 18 months, the progression-free survival (PFS) rate was 72% and the overall survival (OS) rate was 90%.
Notably, there were no new safety signals by combining the three drugs, and the trial met its primary endpoint, which was to analyze the incidence of adverse events (AEs). Only 3 patients discontinued treatment due to AEs.
The most common AEs were neutropenia (84%), cough (50%), diarrhea (44%), and muscle spasms (44%). Plesner said these AEs are associated with lenalidomide and dexamethasone. Overall, 50% of the participants experienced serious AEs, but Plesner said only neutropenia (n = 3), gastroenteritis (n = 2), and pyrexia (n = 2) occurred in more than 1 patient.
Infusion-related reactions occurred in 56% of patients, but these typically were ≤2 grade severity and arose after the first infusion. They were managed with premedication or a slower infusion rate, Plesner said.
Efficacy Evidence Mounts
Plesner, who said he dosed his first patient with daratumumab in 2007, described daratumumab as a human IgG1 monoclonal antibody that targets CD38, which is highly expressed on myeloma cells. He said the agent induces tumor cell death through direct cell killing, indirect immune-mediated activity, and immunomodulation.
“There is an important immunomodulatory function of daratumumab,” said Plesner. “Daratumumab was able to eliminate regulatory T cells, B cells, and monocytes that inhibit the T-cell cytotoxic response against myeloma cells.”
On November 16, the FDA granted an accelerated approval for daratumumab as a therapy for patients who have relapsed after ≥3 prior lines including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to those therapies.
The decision was based on findings from the GEN501 and SIRIUS trials in which daratumumab was administered as monotherapy. In an updated combined analysis presented during 2015 ASH, daratumumab demonstrated a 31% ORR as monotherapy for patients with heavily pretreated multiple myeloma.2
The combined rate of complete response plus very good partial response was 13% for patients treated with daratumumab at 16 mg/kg. The 12-month PFS rate was 50% and median OS was 19.9 months.
The GEN503 study was conducted in 2 parts. The first part was a dose escalation trial involving patients with with multiple myeloma who had relapsed after receiving 2 to 4 prior lines of therapy. The second part was the expansion cohort for which Plesner reported results.
In the expansion phase, daratumumab was administered at 16 mg/kg on a 28-day cycle along with lenalidomide at 25 mg on days 1-21 and dexamethasone at 40 mg weekly.
The potential for employing daratumumab in multiple myeloma remains the subject of significant exploration, with 5 ongoing phase III trials in several clinical settings, according to Janssen Biotech, Inc, which is developing the drug.
These include 2 randomized trials evaluating the combination of daratumumab with lenalidomide/dexamethasone versus the standard of lenalidomide/dexamethasone.
The POLLUX trial is evaluating the regimens in an estimated 570 patients with relapsed or refractory multiple myeloma.3 The MAIA trial will compare the regimens in an estimated 730 newly diagnosed, previously untreated patients who are not candidates for high-dose chemotherapy or autologous stem cell transplant.4
1. Plesner T, Arkenau HT, Gimsing P, et al. Daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: updated results of a phase 1/2 study (GEN503). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 507.
2. Usmani S, Weiss B, Bahlis NJ, et al. Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 29.
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02076009.
4. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02252172.