The landscape of therapeutic options for patients with myeloma at all phases of treatment has rapidly changed with the development of new drugs and targets.
Sagar Lonial, MD
Chief Medical Officer
Winship Cancer Institute of Emory University
The landscape of therapeutic options for patients with myeloma at all phases of treatment has rapidly changed with the development of new drugs and targets. While these have been focused predominantly on the proteasome inhibitors and immunomodulatory agents (IMiDS), the recent approval of the first histone deacetylase inhibitor (HDACi) panobinostat represents the first new target approved in more than a decade.
With recent data presented at 2015 ASCO and European Hematology Association meetings, this scenario is likely about to change dramatically for the better as we develop new treatment paradigms based upon the use of immune-based targeting through monoclonal antibodies. Most other areas of oncology and hematology already are reaping the benefit of targeted immune-based treatments first demonstrated through agents such as rituximab and trastuzumab, but up until recently the benefit for antibody-based treatments in myeloma had been disappointing. Now we have two agents that are likely to be ready for clinical use in the near future, and several others in development that also look very promising.
Elotuzumab Benefit Established
Elotuzumab is a humanized monoclonal antibody that targets a protein called SLAMF7 (signaling lymphocyte activating molecule F7), formerly known as CS1, which is present on plasma cells as well as natural killer (NK) cells. Though the protein is present on both NK cells and plasma cells, the effect of binding with elotuzumab is different. SLAMF7 on NK cells results in signaling through EAT2, which then activates NK cells, while plasma cells do not have EAT2, and thus no signaling is initiated when elotuzumab binds the receptor.
The net result is that elotuzumab tags tumor cells for destruction via mechanisms based on antibody-dependent cell mediated toxicity while at the same activating the NK effector cells. While having no single-agent activity, the combination of elotuzumab plus lenalidomide/dexamethasone demonstrated a higher overall response rate (ORR) and progression-free survival (PFS) when compared with lenalidomide/dexamethasone alone in early-phase development. This led to the ELOQUENT-2 randomized trial of lenalidomide/ dexamethasone with and without elotuzumab.
What was noted in the initial report at ASCO1 and in The New England Journal of Medicine paper2 published at the same time was a higher ORR and improved PFS for the elotuzumab arm compared with the standard therapy. Additionally, there appeared to be significant activity among patients with deletion of 17p (del17p), and a PFS that matched the PFS of patients who did not have del17p, suggesting that the addition of the antibody was able to overcome the negative prognostic findings associated with this very poor risk feature. Moreover, when depth of response, measured as greater than a partial response (PR) or a very good partial response (VGPR), was compared between the two arms, the duration of remission was longer when the patients received elotuzumab, suggesting that the immune component was improving not only depth of response but also durability over the long term. Additional toxicities were related only to infusion reactions, which occurred in 10% of patients, and were seen predominantly with the first dose. Thus, from this trial, the benefit of elotuzumab was seen in combination with lenalidomide/dexathemasone as it improved ORR, PFS, and was effective among high-risk subsets of myeloma as well as prolonging duration of response for all patients who achieved a PR or greater on the elotuzumab treatment arm.
Daratumumab Findings Promising
The other target of significant interest and activity is CD38, known to be present on nearly all plasma cells as well as some cells within the lymphoid and myeloid lineage. There are two antibodies targeting CD38, daratumumab and SAR690584, in mid- to advanced development.
Both have demonstrated single- agent activity of approximately 30% in early phase I studies, with good combination activity when used with bortezomib and lenalidomide.
The largest of the CD38 trials, reported at ASCO this year, showed significant activity as a single agent.3 In the Sirius trial, 106 patients with double refractory myeloma and a median of five prior lines of therapy were treated with a daratumumab dose of 16 mg/kg. Overall, 66% of the patients were refractory to three of four approved novel agents, and a significant number of patients were refractory to alkylator agents as well. The ORR was 29% with several patients achieving a stringent complete response or VGPR. Median duration of response was 7.4 months, median PFS was 3.4 months, and median projected overall survival at 1 year was 65%. Of note, 29 of the 31 responders remained alive at the time of data cutoff.
Response rates appear to be consistent across different levels of refractoriness, and responses were seen among patients with extramedullary disease as well as high-risk disease. The main added toxicity associated with daratumumab was infusion reactions, which occurred in 43% of patients, more than 90% of which occurred with the first dose of treatment. Based upon this data in a highly refractory patient population, the use of single-agent daratumumab in a refractory myeloma patient population suggests that this is a new treatment option in a setting where other treatments do not have consistent activity.
More Targets Under Study
Additional potential targets in development include antibodies targeting CD138, CD56, PD-1, and PDL-1. These all have shown some activity among patients with relapsed or refractory myeloma and, when coupled with IMIDs as we have seen with elotuzumab, the synergy for these monoclonal antibodies can be quite impressive, providing additional new options in the near future.
Based upon these data, it appears that the era of antibodies is here now for myeloma therapy and, while the studies currently have focused on a relapsed or refractory setting, it is clear that these agents will have a major impact in large part due to their novel targets and mechanisms of action, in all phases of treatment. These are very exciting data, and represent new hope and treatments for patients.