Future treatment options for multiple myeloma will include monoclonal antibodies, according to Andrzej J. Jakubowiak, MD, Professor of Medicine and Director of the Myeloma Program at the University of Chicago, IL.
Commenting on studies that were presented at the recent American Society of Clinical Oncology annual meeting for the 2 agents that are furthest along in development, Dr Jakubowiak noted that although monoclonal antibodies have become routine treatment for many tumor types, their development in patients with multiple myeloma has “lagged behind.” “But here we are now,” he said. “These immunotherapies are exciting for a variety of reasons, and we have plenty of potential targets.”
Almost a dozen monoclonal antibodies and other immunotherapy drugs are now in development for treatment of patients with myeloma.
Elotuzumab Works Best in Combination
The monoclonal antibody elotuzumab, paired with lenalidomide plus low-dose dexamethasone, achieved very high response rates and prolonged time to progression, French investigators reported (Moreau P, et al. J Clin Oncol. 2012;30[suppl]:Abstract 8020).
Elotuzumab is directed against CS-1, a molecule almost exclusively expressed on myeloma but not normal cells. It is believed that lenalidomide increases the activity of antibodies by stimulating the patient’s immune system, and combination treatment thus eliminates more myeloma cells.
In a phase 2 trial discussed by Philippe Moreau, MD, Head of Hematology at University Hospital Hôtel-Dieu in Nantes, France, the combination of elotuzumab 10 mg/kg plus lenalidomide/dexamethasone led to an overall response rate (ORR) of 92% among patients with relapsed or refractory multiple myeloma. The 10-mg/kg dose has been selected to be evaluated in phase 3 trials.
The study included 73 patients who had received 1 to 3 prior regimens. Patients received 10 mg/kg or 20 mg/kg, plus lenalidomide 25 mg/d and low-dose dexamethasone. Elotuzumab was given once weekly for the first 2 cycles and then twice per month until progression, for a median number of 17 cycles.
The ORR was 84%, including 92% for the cohort receiving 10 mg/kg and 76% for those patients receiving 20 mg/kg. Complete responses (CRs) or stringent CRs were observed in 12%, 14%, and 11% of the cohorts, respectively.
By number of prior therapies, the response rates were 100% for patients receiving 10 mg/kg and 82% for patients receiving 20 mg/kg. After 2 or more regimens, response rates were 85% and 70%, respectively. High-risk patients had an 80% response rate and a median PFS of 9 months.
“There was a rapid time to response (median, 1 month) and a long duration of response,” Dr Moreau reported. “At a median follow-up of 17 months, median progression-free survival (PFS) has not been reached in the 10-mg/kg group, and was 18.6 months in the 20-mg/kg arm.”
In a historical comparison, response rates were approximately 60% and the median PFS was approximately 11 months for lenalidomide plus high-dose dexamethasone in the pivotal trial of that combination (Dimopoulas M, et al. N Engl J Med. 2007;357:2123-2132), he pointed out.
Grade 3 or 4 adverse events were primarily hematologic, including anemia (12%), lymphopenia (19%), neutropenia (16%), and thrombocytopenia (16%).
Two phase 3 studies (Study of Lenalidomide and Dexamethasone With or Without Elotuzumab to Treat Newly Diagnosed, Previously Untreated Multiple Myeloma [ELOQUENT]) are evaluating elotuzumab plus lenalidomide and low-dose dexamethasone in previously untreated patients (ELOQUENT-1) and in relapsed/refractory patients (ELOQUENT-2).
In his discussion, Dr Jakubowiak commented that although single-agent activity for elotuzumab appears weak, the drug has robust activity in combination.
“This combination is truly promising, and it has very good tolerability in combination with lenalidomide/dexamethasone,” Dr Jakubowiak commented. “The results look very good for this patient population, especially those in very early relapse, and justify phase 3 studies.”
“We will also want to know if we can do even better by combining elotuzumab with a 3-drug regimen or other agents, and if so, is cost going to be a concern,” he added. “We also want to learn how to use elotuzumab in lenalidomide-refractory patients.”
Daratumumab: Early Results Are Impressive
Encouraging results were also reported for the anti-CD38 molecule daratumumab. Given as a single agent in doses up to 16 mg/kg, daratumumab produced responses in 11 of 29 relapsed or refractory heavily pretreated patients, and led to stable disease in another 7 patients. These observations corresponded with a marked reduction in serum M-component (Plesner T, et al. J Clin Oncol. 2012;30[suppl]:Abstract 8019).
“These numbers in a relapsed/refractory population are among the best we have,” Dr Jakubowiak noted. “The data are fairly convincing to me.”
Dose-escalation studies of daratumumab are in progress. Continuous therapy studies and combination strategies are planned, including an evaluation of benefit when paired with bortezomib or lenalidomide plus dexamethasone.
Siltuximab Study Was Negative
By contrast, the anti-interleukin 6 antibody siltuximab, combined with bortezomib, was no more effective than bortezomib alone in a phase 2 study of 286 patients (Orlowski RZ, et al. J Clin Oncol. 2012;30[suppl]:Abstract 8018).
“The study is disappointing to all of us…but it is important to pay attention to the design. It may have been underpowered, and the dose and schedule may have been suboptimal,” Dr Jakubowiak said.
Siltuximab, therefore, is not out of the picture. The next steps are to study it as a single agent in patients with smoldering myeloma and in newly diagnosed patients combined with bortezomib/melphalan/prednisone and with lenalidomide/bortezomib/dexamethasone.