A new class of drugs designed to attack malignant plasma cells could offer patients with multiple myeloma new treatment options, according to early clinical trials using two anti-CD38 antibodies presented at the 56th ASH Annual Meeting.
The CD38 antigen is commonly expressed on myeloma cells, and anti-CD38 antibody binding signals the patient’s immune cells to destroy the malignant cells.
There are currently three anti-CD38 antibodies being studied for multiple myeloma. Researchers at the ASH annual meeting presented early trial findings for two of the agents: daratumumab and SAR650984. Each drug met safety standards and was shown to be effective – either in combination with existing treatment regimens or as a single agent – in patients with relapsed or treatment-resistant disease.
This new class of drug could fill an unmet need in the treatment of multiple myeloma by potentially adding another highly active class of drugs to the list of treatment options, said Thomas Martin, MD, professor of clinical medicine at the University of California San Francisco, and lead author on the study evaluating SAR650984. Over the last 10 years, Dr. Martin noted, immunomodulatory agents (IMiDs) and proteasome inhibitors have resulted in improved survival in patients with myeloma. Anti-CD38 antibodies could be a third option for patients – especially for those with variations of the disease resistant to other novel agents.
“I do think these represent that next ‘blockbuster’ class of myeloma drugs that has the ability to synergize with other drugs – especially with the IMiDs,” he said.
Phase 1 Study Evaluates Safety in Daratumumab in Combination Regimens
While previous research has evaluated daratumumab as a single agent for patients relapsed or refractory to several earlier lines of therapy, the latest ongoing study is designed to evaluate the safety, tolerability, and dose regimen of daratumumab when it is administered in combination with currently approved treatments for multiple myeloma.
The phase 1b multicenter study divided patients into four treatment groups: bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). The researchers then took six patients from each treatment group and administered an additional dose of 16 mg/kg daratumumab, and planned to eventually increase the number of patients receiving daratumumab if it was found to be well tolerated in earlier cycles.
After median treatment duration of 44 days, the investigators evaluated data from 17 patients taking daratumumab and found there was no unexpected additional toxicity when the anti-CD38 antibody was added. While four patients experienced infusion-related reactions (IRR) on the first day of the first cycle, all other adverse events were consistent with the backbone therapies the patients were already receiving.
In patients with newly diagnosed multiple myeloma, 100 percent experienced an overall response to combination therapy, while half of patients in the relapsed group experience overall response.
“In the future, daratumumab will represent a key piece of the treatment of our patients with myeloma, in the upfront and relapse setting,” study author Maria-Victoria Mateos, MD, PhD, said during a press conference presenting the results.
Dose Escalation Trial of SAR650984
Another anti-CD 38 antibody may be effective in patients who have already been heavily pre-treated. In this phase 1 study, researchers led by Dr. Martin added escalating doses of SAR650984 to relapsed or treatment-resistant multiple myeloma patients receiving a standard regimen of lenalidomide and dexamethasone, in order to determine the maximum tolerated dose of the anti-CD38 antibody.
Of the 31 patients who received SAR650984, 24 ultimately received 10 mg/kg. No dose-limiting toxicities were reported and researchers found that patients had an overall response rate of 65 percent and a clinical benefit rate of 71 percent; progression-free survival was 6.2 months in patients treated with the investigational drug.
“These study results confirm the notion that SAR650984 and IMiD-based therapy work synergistically,” Dr. Martin told ASH Clinical News. “Most of the patients in this study were IMiD-refractory, with 80 percent refractory to lenalidomide. It was not that lenalidomide was providing a potent anti-myeloma effect; we think, instead, that lenalidomide was boosting up the immune system.”
Dr. Martin added that the findings from both the daratumumab and SAR650984 studies have helped propel initiation of phase 3 studies comparing various combinations with and without the antibodies to further understand the roles that anti-CD 38 antibodies can play in treatment.
- Martin TG, Baz R, Benson DM Jr., et al. “A phase Ib dose escalation trial of SAR650984 (anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma.” Abstract #83. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.
- Moreau P, Mateos M-V, Bladé J, et al. “An open-label, multicenter, phase 1b study of daratumumab in combination with backbone regimens in patients with multiple myeloma.” Abstract #176. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.