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First Monoclonal Antibody for Myeloma Shows Increases in PFS and Overall Response

Carlson, Robert H.

doi: 10.1097/01.COT.0000466850.71122.d8
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Elotuzumab, a novel first-in-class antibody that targets plasma cells and also activates immune function, reduced the risk of progression or death in patients with relapsed/refractory multiple myeloma by 30 percent at two years when combined with lenalidomide-dexamethasone, compared with lenalidomide/dexamethasone alone.

Median progression-free survival was 19.4 months for the elotuzumab-lenalidomide-dexamethasone combination versus 14.9 months for controls, in the randomized Phase III open-label ELEQUENT-2 study. Interim results for 646 patients were reported in a teleconference for reporters in advance of the American Society of Clinical Oncology Annual Meeting (Abstract 8508).

“We've made much headway over the past decade in understanding and treating multiple myeloma, and this study is of an innovative approach, one that combines the precision of a targeted, immune-based therapy with traditional myeloma therapy,” said ASCO President Julie M. Vose, MD, Chair and Chief of the Oncology/Hematology Division of the University of Nebraska Medical Center. “The results are very encouraging, giving renewed hope to patients who have relapsed.”

The lead author of the study, Sagar Lonial, MD, Professor and Chief Medical Officer of Winship Cancer Institute and Executive Vice Chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine, said that while it has been fortunate in the last decade or to have several new drugs and new classes of drugs approved for multiple myeloma, many of those have been newer versions of existing classes of drugs such as immunomodulatory drugs and proteasome inhibitors.

The study's senior author is Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Center.

Currently there are no monoclonal antibodies to treat myeloma, Lonial noted. “What we have sought out for some time now is a new class that focuses more on immune-targeted approaches to killing myeloma cells.”

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SLAMF7

Elotuzumab is a monoclonal antibody that targets the signaling lymphocytic activation molecule F7 (SLAMF7) receptor on the plasma cells, killing myeloma cells with minimal effect on normal tissue. SLAMF7 is also found on the surface of natural killer (NK) cells.

“Elotuzumab appears to have a dual mechanism by which it targets the myeloma cell and also enhances the activation of natural killer cells, making the activity of elotuzumab more effective,” Lonial said.

Control patients in ELOQUENT-2, which was funded by Bristol-Myers Squibb and AbbVie, were randomly selected to receive a standard therapy consisting of oral lenalidomide at 25 mg/kg once daily on days 1-21 of a 28-day cycle, plus oral dexamethasone at 40 mg on days 1, 8, 15, and 22 (325 patients).

Study patients received the same lenalidomide/dexamethasone regimen in combination with elotuzumab at 10 mg/kg IV on days 1, 8, 15, and 22 in cycles 1 and 2, and on days 1 and 15 of cycle 3 and beyond (321 patients). The patients' median age was 66.

There were 224 study locations in the U.S., Europe, Australia, and Japan.

Study patients had relapsed/refractory myeloma but were early in their treatment and had disease progression on only one to three prior lines of therapy. “These was not an end-stage, truly refractory population, so it was reasonable to treat them with lenalidomide/dexamethasone in the control arm,” Lonial said.

Primary endpoints were progression-free survival and overall response rate, with overall response rate a secondary endpoint.

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Progression-Free Survival

Elotuzumab-lenalidomide-dexamethasone improved progression-free survival compared with lenalidomide/dexamethasone at one year—68 versus 57 percent; two-year progression-free survival rates were 41 versus 27 percent, respectively.

“Progression-free survival was improved at one year and continued to improve at two years, and what is quite striking about the progression-free survival curve is that the two curves do not appear to come back together with longer follow-up,” Lonial said. “Maintenance of benefit over time really speaks to the power of an immune-mediated approach.”

Similar maintenance of response has been seen with PD-1 inhibitors and other immune-based approaches, he added.

Overall response also improved in the elotuzumab group—79 versus 66 percent for the control group. “This improvement in clinical parameters occurred without a significant increase in toxicity or adverse events, and in fact, there was no reduction in quality of life for the group receiving the three-drug arm.”

Grade-3/4 adverse events of note were neutropenia, in 25 percent of study group and 33 percent of controls, and anemia in 15 and 16 percent, respectively.

Typical autoimmune side effects such as rash had not been seen with the monoclonal antibody, he noted. The survival data are still immature and need about six more months before they can be reported—“but there certainly are some encouraging signs in improvement in overall survival.

“Based on this Phase III trial we hope we have a new treatment option for patients with relapsed or refractory disease,” he said.

“Investigators should be aware when evaluating monoclonal antibodies in a disease where biochemical assessment is used for response, such as a serum protein electrophoresis, that the antibody may interfere with the ability to identify patients who have achieved complete remission.”

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Breakthrough Therapy Status

The Food and Drug Administration last year gave elotuzumab Breakthrough Therapy status when used in combination with lenalidomide-dexamethasone for patients with multiple myeloma who have received more than one previous treatment, based on previous studies. “These new data confirm the unique mechanism and new target as being important in the management of multiple myeloma,” Lonial concluded.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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