San Francisco, CA—Monoclonal antibodies may be to multiple myeloma what rituximab has been to lymphoma, according to myeloma experts who expressed enthusiasm over these emerging agents at an education session at ASH 2014.
“Monoclonal antibodies present an attractive therapeutic strategy,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston. “Monoclonal antibodies have activity in high-risk disease and represent truly novel mechanisms of action.”
“Elotuzumab is the most advanced in development, and is currently in phase 3 testing in both the upfront and relapsed/refractory settings and primarily in combination. Daratumumab and SAR650984 show promise. Numerous other potential targets in the myeloma plasma cells have been identified, and a number of other monoclonal antibodies are in development as well,” Dr Richardson said.
Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody that targets the signaling lymphocytic activation molecule F7. The regimen of elotuzumab plus lenalidomide and dexamethasone demonstrated encouraging efficacy in a phase 1b/2 study of patients with relapsed or refractory disease.
“What was particularly exciting was that we saw a remarkable response rate in this relapsed/refractory population, recognizing that they were lenalidomide-naïve,” said Dr Richardson, who presented the final results from a randomized phase 2 cohort of 73 patients. The overall response rate was 84%. A complete response (CR) or stringent CR was achieved by 14% of patients. The median duration of response was 20.8 months, which is reflected by the long progression-free survival (PFS)—29 months, and 32.5 months with the highest dose of elotuzumab.
Approximately 66% of patients had diarrhea and muscle spasms, and nearly 50% reported constipation, nausea, and upper respiratory tract infection. The most common grade 3 or 4 adverse events were neutropenia, thrombocytopenia, lymphopenia, and anemia. Infusion reactions occurred in 11% of patients.
“It’s important to judge safety in the context of the duration of treatment; patients were on therapy for a number of years,” said Dr Richardson.
Anti-CD38 Monoclonal Antibodies
The data were slightly less mature but at least as impressive for the anti-CD38 antibodies SAR650984 and daratumumab.
“These anti-CD38 monoclonal antibodies, I believe, will be blockbuster drugs and will be an important component to multiple myeloma treatment,” predicted Thomas G. Martin, III, MD, Associate Director, Myeloma Program, University of California, San Francisco.
Dr Martin led a study of SAR650984 given in combination with lenalidomide and dexamethasone in 31 heavily pretreated patients with relapsed or refractory disease. The combination produced responses in 58% of patients overall, rising to 63% in the highest-dose cohort. The median PFS was 6.2 months, but it had not been reached in the least pretreated patients.
“SAR650984 in combination with lenalidomide and dexamethasone showed encouraging activity in this heavily pretreated population,” without increasing toxicity, Dr Martin said.
The other anti-CD38 antibody, daratumumab, was evaluated in combination with standard regimens in the MMY1001 study of 18 patients with newly diagnosed disease and 7 patients with relapsed or refractory disease. Backbone regimens included bortezomib/dexamethasone (VD), bortezomib/thalidomide/dexamethasone (VTD), bortezomib/melphalan/prednisone (VMP), and pomalidomide/dexamethasone (POM-DEX).
For daratumumab combined with VD, VMP, and VTD in the upfront setting in patients with newly diagnosed myeloma, 100% of the patients responded. With POM-DEX, in patients with relapsed or refractory disease, 50% responded and 1 of these patients had a stringent CR, reported Philippe Moreau, MD, of Nantes University Hospital, France.