January 2015, Vol. 2, No. 1
Monoclonal Antibodies Poised to Be Blockbusters
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 ASH 2014.
“Monoclonal antibodies present an attractive therapeutic strategy,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, MA. “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 up-front and relapsed/refractory settings, and primarily in combination. Daratumumab and SAR650948 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,” Richardson said in his talk at an educational session.
Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody targeting the signaling lymphocytic activation molecule F7 (formerly known as CS1).
The regimen of elotuzumab plus lenalidomide and dexamethasone demonstrated encouraging efficacy in a phase 1b/2 study of patients with relapsed/refractory disease (although no previous lenalidomide treatment).
“What was particularly exciting was that we saw a remarkable response rate in this relapsed/refractory population, recognizing that they were lenalidomide naive,” said Richardson, who presented final results from a randomized phase 2 cohort of 73 patients. The overall response rate was 84%, and many of these were deep responses. 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 – 29 months overall, and 32.5 months with the highest dose.
Approximately 66% of patients experienced diarrhea and muscle spasms, and nearly 50% reported constipation, nausea, and upper respiratory tract infection. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, lymphopenia, and anemia. Infusion reactions occurred in 11% of patients.
Richardson put these in context. “It’s important to judge safety in the context of the duration of treatment; patients were on therapy for a number of years.”
Anti-CD38 Monoclonal Antibodies
The data were slightly less mature but equally impressive for the anti-CD38 antibodies SAR650948 and daratumumab. These agents target the CD38 antigen on myeloma cells, which ultimately aids the immune system in attacking the tumor.
“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.
Martin led a study of SAR650948 administered 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. A 50% response rate was observed in patients relapsed or refractory to previous treatment with immunomodulators. The median progression-free survival was 6.2 months but had not been reached in the least pretreated patients.
“SAR650948 in combination with lenalidomide and dexamethasone showed encouraging activity in this heavily pretreated population,” without increasing toxicity, 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 relapsed/refractory patients. 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 up-front setting in patients with newly diagnosed disease, 100% of patients responded. With POM-Dex in patients with relapsed/refractory disease, 50% responded, and 1 of these patients had a stringent CR, reported Philippe Moreau, MD, of Nantes University Hospital, France.
In a separate study of 45 patients with relapsed/refractory disease who received daratumumab plus lenalidomide and dexamethasone, responses were observed in 100% of patients who had 2 previous lines of therapy in the dose-escalation phase and in 87% of patients in the expansion cohort. The depth of response is expected to further improve. Infusion reactions were common, but most occurred during the first infusion only, and all but 1 patient were able to continue receiving treatment.
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