The modern use of immunomodulatory agents (such as lenalidomide and more recently pomalidomide) with proteasome inhibitors (such as bortezomib, carfilzomib, and ixazomib) has markedly improved patient outcomes for those having multiple myeloma. One example of this type of combination therapy, carfilzomib in combination with lenalidomide plus dexamethasone, was approved by the FDA in July 2015 for the treatment of multiple myeloma patients, with ixazomib in combination also achieving regulatory approval later in the same year.
Despite the important advances made with immunomodulatory/proteasome inhibitor combination therapies, multiple myeloma patients frequently have disease that is refractory or develop disease that is resistant to this treatment strategy. For those patients, their prognosis is typically poor. In one study, a median overall survival of 9 months was obtained for multiple myeloma patients that had disease resistant to the combination of bortezomib and lenalidomide or thalidomide (Leukemia 2012;26:149-157).
To address this key therapeutic need, a variety of new agents and combinations have been developed including pomalidomide and dexamethasone, approved in 2013, and panobinostat combined with bortezomib and dexamethasone, approved in 2015. The development and approval of monoclonal antibodies, specifically daratumumab (either as monotherapy or more recently in combination) and elotuzumab in combination with lenalidomide, during the same period represent major advances in the treatment of relapsed and relapsed/refractory multiple myeloma.
In this context, the novel combination of elotuzumab plus pomalidomide and dexamethasone was evaluated versus pomalidomide and dexamethasone in the randomized phase II ELOQUENT-3 study (NCT02654132)(N Engl J Med 2018;379:1811-1822). One leading clinician involved in this international study was Paul G. Richardson, MD, of the Dana-Farber Cancer Institute. “Our results have substantial implications for immune-based combination approaches in treating multiple myeloma patients with advanced disease,” he noted.
Further support for that assertion was given on Nov. 6, 2018, when the FDA granted approval for the use of elotuzumab plus pomalidomide and dexamethasone in relapsed or relapsed/refractory multiple myeloma patients who had two prior lines of therapy including lenalidomide and a proteasome inhibitor.
Signaling lymphocytic activation molecule F7 (SLAMF7) is a glycoprotein that has high surface expression on myeloma cells and on some immune system cells, such as natural killer cells, but it is not found in other tissues. This notable difference makes SLAMF7 a potentially attractive target for treating multiple myeloma, which expresses this protein.
Elotuzumab is a humanized monoclonal antibody that targets SLAMF7. The mechanism of action of elotuzumab is thought to primarily include direct activation of natural killer cells as well as natural killer cell-mediated antibody-dependent cellular cytotoxicity of SLAMF7-expressing myeloma cells (Clin Transl Sci 2018;11:261-266).
“It is also thought that elotuzumab may facilitate macrophagemediated killing of myeloma,”Richarson noted.
When asked why this particular combination was evaluated, he replied, “The clinical rationale was an extension of the elotuzumab-based triplet combination therapy with lenalidomide, but incorporated the potent immunomodulatory agent pomalidomide, which has been shown to be effective both in lenalidomide and bortezomib refractory patients, and preclinically to be a strong activator of natural killer cells.”
In the original November 2015 FDA statement, approval was granted for the use of elotuzumab plus lenalidomide and dexamethasone in multiple myeloma patients who had received 1-3 prior treatments.
Patients were randomized in a 1:1 manner to either the elotuzumab group (elotuzumab plus pomalidomide and dexamethasone) or the control group (pomalidomide and dexamethasone). Stratification was performed using the number of prior therapies (i.e., 2 or 3 vs. 4 or more) and the International Staging System disease stage at the time of trial enrollment (stage I or II vs. III).
This phase II study had the following eligibility requirements:
- adults (18 years or older);
- measurable multiple myeloma;
- disease that was refractory (disease progression while receiving treatment or within 60 days after end of treatment) or relapsed and refractory (disease progression within 6 months after end of treatment after the patient had at least a partial response) to lenalidomide and a proteasome inhibitor;
- two or more prior therapeutic regimens, including at least two consecutive cycles of the immunomodulator lenalidomide and a proteasome inhibitor alone or in combination;
- disease refractory to last therapy; and
- an ECOG performance status score of 0-2.
Among the key exclusion criteria were previous pomalidomide-based therapy, active plasma-cell leukemia, and a creatinine clearance of less than 45 mL per minute.
Investigator-assessed progression-free survival (PFS), defined as the time between randomization and first occurrence of disease progression (not including clinical deterioration) or death from any cause, whichever occurred first, was the primary endpoint. This assessment included all patients who underwent randomization (i.e., the intentto-treat population).
The secondary endpoints included were the investigator-assessed overall response rate (i.e., partial response or better, ORR) and overall survival (OS). Exploratory endpoints included the time to response (TTR), the duration of response (DOR), and safety as assessed by adverse events (AEs).
Both PFS and ORR were also assessed by an independent review committee whose members were unaware of the treatment assignments in order to confirm the results of the investigator assessment.
Therapies were administered in 28-day treatment cycles until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Patients in both the elotuzumab group and the control group received 4 mg pomalidomide orally per day on days 1 through 21 of each cycle. Patients received dexamethasone orally at 40 mg (patients 75 years or younger) or 20 mg (patients older than 75 years) per week, except on the days of elotuzumab administration, when those in the elotuzumab group received dexamethasone both orally at 28 mg (patients 75 years or younger) or 8 mg (patients older than 75 years) and intravenously (8 mg). Those in the elotuzumab group received elotuzumab intravenously at 10 mg/kg of body weight on days 1, 8, 15, and 22 during cycles 1 and 2 and 20 mg/kg on day 1 of each cycle thereafter.
Between March 2016 and April 2017, patients were enrolled at 43 sites in Australia, Europe, North America, and Japan. A total of 117 patients were randomized—60 patients to the elotuzumab group and 57 to the control group. Of these randomized patients, only two in the control group did not receive their assigned study treatment. At baseline, the characteristics for the two treatment groups were deemed to be generally well balanced. Patients had from 2 to 8 prior lines of therapy, with a median of 3 prior treatments. A total of 68 percent of the patients in the elotuzumab group and 72 percent in the control group had disease refractory to both lenalidomide and a proteasome inhibitor.
“As of February 2018, 40 percent of treated patients in the elotuzumab group, as compared with 20 percent in the control group, were continuing to receive the assigned treatment,” Richardson noted.
The median investigator-assessed PFS values for the elotuzumab and control groups were 10.3 months (95% CI: 5.6 months—not reached) and 4.7 months (95% CI: 2.8-7.2 months), affording a hazard ratio (HR) for disease progression or death of 0.54 (95% CI: 0.34-0.86; P = 0.008).
The corresponding independent review committee-assessed median PFS values in the overall population were 10.3 months (95% CI: 6.5 months—not reached) and 4.7 months (95% CI: 2.8-7.6 months) in the elotuzumab group and the control groups, respectively. This gave a HR for PFS of 0.51 (95% CI: 0.32-0.82) in favor of the elotuzumab group.
Investigator-based response assessments afforded ORR values of 53 percent (95% CI: 40-66%) and 26 percent (95% CI: 16-40) for the elotuzumab and control groups, respectively, and an odds ratio of 3.25 (95% CI: 1.49-7.11). The ORR values determined by independent committee-based analyses were: elotuzumab group—58 percent (95% CI: 45-71) and control group—25 percent (95% CI: 14-38). These figures gave an odds ratio of 4.62 (95% CI: 2.05-10.43).
Regarding the survival data, Richardson stated, “The OS data were immature at the time of the analysis; however, a clear trend favoring the elotuzumab group was observed, with a HR for death of 0.62.
“Specifically, there were 13 deaths in the elotuzumab group and 18 deaths in the control group; however, these 31 deaths were only 40 percent of the 78 deaths necessary for the final analysis of overall survival, so the data remain preliminary.” he explained.
Similar median time-to-response values were obtained for both groups: elotuzumab group—2.0 months and control group—1.9 months.
Grade 3 or 4 AEs were reported in 57 percent of the elotuzumab group and 60 percent of the control group patients respectively, with the most commonly observed events being neutropenia (13%—elotuzumab group vs. 27%—control group), anemia (10%—elotuzumab group vs. 20%—control group), and hyperglycemia (8%—elotuzumab group vs. 7%—control group).
Serious AEs were noted for 53 percent of the elotuzumab group, and 55 percent of the control group patients. The most common treatment-related AEs were neutropenia (18%—elotuzumab group vs. 20%—control group), hyperglycemia (18%—elotuzumab group vs. 11%—control group), and anemia (10%—elotuzumab group vs. 15%—control group).
AEs leading to treatment discontinuation occurred in 18 percent of the elotuzumab group patients and 24 percent of the control group patients. Importantly, no deaths in either group were deemed to be investigational treatment-related by the investigators.
Regarding the study results, Richardson noted, “In the current trial, the median PFS with elotuzumab plus pomalidomide and dexamethasone was 10.3 months and the ORR was 53 percent, which shows the superiority for that treatment over pomalidomide and dexamethasone alone, which had median PFS and ORR values of 4.7 months and 26 percent, respectively.
“The results obtained for our control group were consistent with those derived in the phase III MM-003 trial of pomalidomide and dexamethasone, where the median PFS was 4.0 months and the ORR was 31 percent (Lancet Oncol 2013;14:1055-1066), as well as other studies in similar populations.
“It is interesting to note,” Richardson commented, “in a noncomparative phase Ib trial, in which the use of daratumumab plus pomalidomide and dexamethasone was evaluated in relapsed, refractory multiple myeloma patients who had received a median of four prior lines of therapy, the median PFS was 8.8 months and an ORR of 60 percent (Blood 2017;130:974-981), suggesting both approaches are highly active.”
Efficacy was observed for elotuzumab across several subgroups, including those who had received at least four prior therapies, with a median PFS of 10.3 months as compared with 4.3 months obtained for similar patients in the control group, affording a HR for disease progression or death of 0.51.
“We were pleased to see that there were no additive effects for AEs with the triplet combination, as elotuzumab plus pomalidomide and dexamethasone was associated with a 57 percent rate of grade 3 or 4 AEs, which was similar to the 60 percent observed for pomalidomide and dexamethasone alone; as a consequence, no new safety signals were identified beyond the findings previously reported with other elotuzumab and pomalidomide regimens,” Richardson explained.
“One important observation was that, despite the elotuzumab group having a longer duration of exposure to study drugs than the control group, the incidence of AEs that led to treatment discontinuation was lower in the elotuzumab group than in the control group.”
As a further observation, Richardson said, “When we adjusted for exposure to study drugs, infections appeared less common in the elotuzumab group than in the control group, which was not expected but perhaps relates to better disease control, as myeloma itself drives infection itself.
“Our study has important implications for how combination therapy and, in particular, how therapeutic monoclonal antibodies can safely be applied for the treatment of relapsed, refractory multiple myeloma in combination with other agents, such as pomalidomide.
“Finally, this trial demonstrated the value of a randomized phase II design in assessing new treatments for advanced multiple myeloma, as was also highlighted by Drs. Gormley and Pazdur in their excellent perspective article which accompanied our paper (N Engl J Med 2018;379:1791-1794).”
Richard Simoneaux is a contributing writer.