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Improving Treatment of Myeloma With Drug Combinations

A combination approach can improve responses through mechanisms that, "enhance immune function, enhance receptor expression, or target intracellular signaling."
BY Jason M. Broderick
PUBLISHED November 09, 2015
Optimizing outcomes with novel antibodies, such as Empliciti (elotuzumab) and daratumumab, in multiple myeloma will involve combination regimens with established agents, according to Sagar Lonial, chief medical officer at Winship Cancer Institute of Emory University.
 
A combination approach can improve responses through mechanisms that, “enhance immune function, enhance receptor expression, or target intracellular signaling,” Lonial said in a presentation last week at the 33rd Annual Chemotherapy Foundation Symposium, a meeting of over 1,000 physicians and other oncology professionals in New York City.
 
Empliciti, which targets SLAMF7, has shown efficacy in combination with several agents, according to Lonial. Early data with MuLuc63, the murine version of Empliciti, in a xenograft mouse model showed that “when you begin to combine Empliciti with Revlimid [lenalidomide] preclinically, you see pretty significant synergy over time compared to either single-agent [Empliciti] or a control,” said Lonial.
 
Under its priority review program, the FDA is currently considering an application for Empliciti for use in combination regimens in patients with multiple myeloma following the failure of one or more prior therapies. The application is primarily based on the phase 3 ELOQUENT-2 trial, in which adding Empliciti to standard Revlimid/dexamethasone reduced the risk of disease progression by 30 percent.
 
At a median follow-up of two years, progression-free survival (PFS) with the Empliciti regimen was 19.4 months versus 14.9 months with Revlimid and dexamethasone alone. The one-year PFS for the Empliciti versus control arm was 68 percent versus 57 percent, respectively, with the difference in two-year PFS rates increasing to 41 percent versus 27 percent.
 
The overall response rate was 79 percent with Empliciti and 66 percent for the control group. The overall survival (OS) data for the trial are not yet mature.
 
Lonial said the benefit of combination therapy with Empliciti “is not limited to [Revlimid] — there is also synergy identified preclinically with bortezomib [Velcade] combinations, as well. There are trials suggesting at least an additive benefit for Empliciti in combination with bortezomib.”
 
Taken together, the positive data with adding Empliciti to either [Revlimid] or bortezomib “give rise to the concept of an RVD [Revlimid, Velcade and dexamethasone] plus Empliciti approach, which is currently being tested in newly diagnosed myeloma.”
 
The anti-CD38 agent daratumumab is also currently being assessed by the FDA under its priority review process, specifically for use as a treatment for patients with multiple myeloma either following at least three lines of therapy, including both a proteasome inhibitor and an immunomodulatory agent (IMiD), or in those who are double refractory to a proteasome inhibitor and an IMiD.
 
The review is based on data from the phase 2 MMY2002 (SIRIUS) study. In this trial, daratumumab demonstrated a 65 percent one-year OS rate and a 29.2 percent overall response rate in heavily pretreated patients with double refractory multiple myeloma.
 
Responses to daratumumab consisted of stringent complete responses (2.8 percent), very good partial responses (9.4 percent) and partial responses (17 percent). The median duration of response was 7.4 months. After a median follow-up of 9.4 months, 45.2 percent of patients remained on therapy. The median was 3.7 months.
 
Lonial said data from a recently published Dutch trial (Leukemia. 2015;29[10]:2039-2049) suggest that outcomes with daratumumab can be enhanced by combining the drug with all-trans retinoic acid (ATRA).
 
"ATRA appears to increase CD-38 expression and this resulted in a higher level of myeloma cell death in vitro and in vivo models, and this is now being tested in a phase 1 clinical trial."
 
Lonial said the final piece of the antibody puzzle in myeloma will be combination regimens with checkpoint agents.
 
"The last area of development that I think is coming is the use of checkpoint inhibitors targeting CD28 and CTLA-4 — combining these with direct antitumor approaches or immune enhancement through the use of [Revlimid] or Pomalyst [pomalidomide]. And I think those combinations are coming in the future.
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