Thomas Martin, MD
Anti-CD38 monoclonal antibodies continue to demonstrate promise across a variety of settings, generating excitement that a new treatment paradigm could be on the horizon for patients with multiple myeloma.
Two studies spotlighted at the 2014 ASH Annual Meeting characterized the efficacy of these agents in the frontline setting and for patients with refractory disease. In a phase Ib trial, the human IgG1κ antibody daratumumab combined with standard frontline therapies induced a dramatic improvement in outcomes without additional toxicity for patients with multiple myeloma.1
Additionally, in a separate phase Ib study, nearly two-thirds of patients with heavily pretreated relapsed/refractory multiple myeloma responded to treatment with the humanized IgG1 monoclonal antibody SAR650984 in combination with lenalidomide and dexamethasone.2
“These therapies are going to be tested in the frontline, in the early relapsed patients, and in the multiple relapsed patients. These are some of the most exciting agents in multiple myeloma,” said the lead study author of the SAR650984 trial Thomas Martin, MD, of the University of California, San Francisco. “These CD38 therapies are blockbuster drugs.”
In May 2013, single-agent daratumumab received a breakthrough therapy designation from the FDA as a treatment for patients with multiple myeloma following two lines of therapy. In combination with lenalidomide and dexamethasone, daratumumab demonstrated an overall response rate (ORR) of 75% across the entire study, which included a dose-escalation portion. In an expansion cohort of patients who received daratumumab at the maximum-tolerated dose of 16 mg/kg (n = 13), the ORR was 92.3%.3
In the frontline setting, the four-arm phase Ib study combined daratumumab with bortezomib and dexamethasone (VD); bortezomib, thalidomide, and dexamethasone (VTD); bortezomib, melphalan, and prednisone (VMP); or pomalidomide and dexamethasone (POM-D). Patients in the VD and VTD arms were untreated and transplant eligible, patients in the VMP arm were untreated but not candidates for transplant, and those in the POM-D arm were relapsed/refractory to at least two lines of therapy.
At the time of the analysis, twenty-four patients received treatment with daratumumab at 16 mg/kg plus the backbone therapy at a standard dose. In the VD (n = 6) and VTD arms (n = 6), patients were treated for eighteen 3-week cycles or until transplantation. In the VMP arm (n = 6), treatment continued for nine 6-week cycles. In the POM-D (n = 6) arm, patients received treatment in 4-week cycles until progression.
The ORR was 100% with VD, VTD, and VMP, and 50% with POM-D. Responses comprised very good partial responses and partial responses; no patients in the frontline arms achieved a complete response (CR). In the POM-D arm, the CR rate was 17% (n = 1). Most patients responded within 30 days of receiving treatment.
“We consider that the addition of 16 mg/kg [of] daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity,” study author María-Victoria Mateos, MD, from Hospital Universitario Salamanca, Spain, said during a press briefing. “Daratumumab was associated with high rates of response in combination with the different backbones.”
Infusion-related reactions were the only added toxicity seen with daratumumab when combined with a bortezomib-containing regimen. All infusion reactions were grade 1 and resolved with supportive care. Most other side effects reported in the study could be attributed to the backbone therapy, the authors of the study wrote.
“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” lead study author Philippe Moreau, MD, University Hospital of Nantes in France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”
In addition to daratumumab, findings for SAR650984 also support the dramatic efficacy of targeting CD38 in patients with multiple myeloma. In the phase Ib study, three separate dosages of SAR650984 (3, 5, and 10 mg/kg) were administered every 2 weeks in combination with lenalidomide and dexamethasone. A total of 24 patients with relapsed/refractory multiple myeloma received the 10 mg/kg dose. In the 28-day treatment cycle, lenalidomide was administered at 25 mg on days 1 to 21, which was adjusted to 10 mg in patients with baseline creatinine clearance ≤60 mL/min. Dexamethasone was administered at 40 mg on days 1, 8, 15, and 22.