STUDY DESIGN AND OVERSIGHT

This multicenter, randomized, open-label, phase 2 trial was designed by the sponsors (Bristol-Myers Squibb and AbbVie Biotherapeutics) and investigators. The trial was conducted in accordance with International Conference on Harmonisation Good Clinical Practice guidelines. The protocol, which was approved by the institutional review board or independent ethics committee at each participating trial center before the start of the trial, is available with the full text of this article at NEJM.org. All the patients provided written informed consent. The investigators collected the data, which were maintained by the sponsors. The manuscript was prepared with assistance from professional medical writers who were funded by Bristol-Myers Squibb. The authors contributed to the development of the manuscript, approved the final version, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

PATIENTS

Eligible patients were 18 years of age or older and had measurable multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 to 2 (on a 5-point scale, with higher numbers indicating greater disability). Patients had received two or more previous lines of therapy, including at least two consecutive cycles of lenalidomide and a proteasome inhibitor alone or in combination. Eligible patients had multiple myeloma that was refractory (disease progressed while the patient was receiving treatment or within 60 days after treatment discontinuation) or relapsed and refractory (disease progressed within 6 months after treatment discontinuation after the patient had at least a partial response) to lenalidomide and a proteasome inhibitor. In addition, all patients had multiple myeloma that was refractory to their last therapy. Key exclusion criteria were previous treatment with pomalidomide, active plasma-cell leukemia, and a creatinine clearance of less than 45 ml per minute. Further details regarding the inclusion and exclusion criteria can be found in the Supplementary Appendix, available at NEJM.org.

RANDOMIZATION AND TREATMENT

Patients were randomly assigned, in a 1:1 ratio, to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone (control group) (Fig. S1 in the Supplementary Appendix). Randomization was stratified according to the number of previous lines of therapy (2 or 3 vs. ?4) and the International Staging System disease stage at the time of trial enrollment (stage I or II vs. III, with higher stages indicating more severe disease). Additional details are provided in the Supplementary Appendix.

Treatment was administered in 28-day cycles until disease progression, development of unacceptable toxic effects, or withdrawal of consent (Fig. S1 in the Supplementary Appendix). Patients in the elotuzumab group received intravenous elotuzumab at a dose of 10 mg per kilogram of body weight on days 1, 8, 15, and 22 during cycles 1 and 2 and 20 mg per kilogram on day 1 of each cycle thereafter. Patients in both the elotuzumab group and the control group received oral pomalidomide at a dose of 4 mg per day on days 1 through 21 of each cycle. Patients received oral dexamethasone at a dose of 40 mg (patients ?75 years) or 20 mg (patients >75 years) per week, except on the days of elotuzumab administration, when patients in the elotuzumab group received dexamethasone both orally (28 mg in patients ?75 years or 8 mg in patients >75 years) and intravenously (8 mg).

Prophylaxis against thromboembolism was required for all patients according to institutional guidelines or at the discretion of the investigator. Patients in the elotuzumab group received the following medications 45 to 90 minutes before each dose of elotuzumab: diphenhydramine at a dose of 25 to 50 mg or equivalent, ranitidine at a dose of 50 mg or equivalent, and acetaminophen at a dose of 650 to 1000 mg.Assignment: Dexamethasone for allergic disorders, skin conditions

END POINTS AND ASSESSMENTS

The primary end point was investigator-assessed progression-free survival, which was defined as the time from randomization to the first occurrence of disease progression (not including clinical deterioration) or death from any cause, whichever occurred first. The analysis was based on the intention-to-treat population, which included all patients who underwent randomization. Secondary end points were the overall response rate (partial response or better), as assessed by the investigators, and overall survival. Exploratory end points included the time to response, the duration of response, and safety (end points are described in detail in the Supplementary Appendix). An independent review committee whose members were unaware of the treatment assignments also assessed progression-free survival and overall response rate to confirm the results of the investigator assessment. Response assessments were based on International Myeloma Working Group consensus criteria,^25-27 except for assessment of minor (minimal) response, which was derived from European Society for Blood and Marrow Transplantation criteria (see the Supplementary Appendix).²⁸

STATISTICAL ANALYSIS

For the final analysis of progression-free survival, we calculated that 114 patients would have to undergo randomization and 71 events (disease progression or death) would have to occur to provide the trial with 85% power to detect a hazard ratio for disease progression or death of 0.57 in the elotuzumab group as compared with the control group, using a log-rank test with a two-sided experiment-wise alpha of 0.2 (additional details are provided in the Supplementary Appendix). Progression-free survival and its associated median were estimated by the Kaplan–Meier method. Progression-free survival was compared with the use of a two-sided stratified log-rank test, and the hazard ratio of the elotuzumab group to the control group was estimated with a stratified Cox proportional-hazards model, with treatment as the single covariate. Subgroup analyses of progression-free survival were also performed.

The overall response rate in the two groups (final analysis) was compared with the use of a Cochran–Mantel–Haenszel test and its corresponding estimate of treatment odds ratio. Preliminary overall survival was estimated by the Kaplan–Meier method; a preliminary hazard ratio was estimated with the use of a stratified Cox proportional-hazards model, with treatment as the single covariate.

PATIENTS AND TREATMENT

Table 1.Characteristics of the Patients at Baseline.

Patients were enrolled from March 2016 through April 2017 at 43 sites in Europe, North America, Japan, and Australia. Overall, 60 patients were randomly assigned to the elotuzumab group and 57 to the control group; all but 2 patients (both in the control group) received their assigned treatment (Fig. S2 in the Supplementary Appendix). The characteristics of the two treatment groups were generally well balanced at baseline (Table 1). The median number of previous lines of therapy was 3 (range, 2 to 8) in both groups. In all, 68% of the patients in the elotuzumab group and 72% in the control group had multiple myeloma that was refractory to both lenalidomide and a proteasome inhibitor.

At the time of the database lock (February 2018), after a minimum follow-up period of 9.1 months, 40% of treated patients in the elotuzumab group, as compared with 20% in the control group, were continuing to receive the assigned treatment (Fig. S2 in the Supplementary Appendix). The main reason for discontinuation of the trial treatment was disease progression (43% of the treated patients in the elotuzumab group and 56% of the treated patients in the control group). The median number of treatment cycles was 9 (interquartile range, 4 to 13) in the elotuzumab group and 5 (interquartile range, 3 to 10) in the control group.

A total of 55% of the patients in the elotuzumab group and 53% in the control group received at least 90% of the planned doses of pomalidomide. Pomalidomide dose reductions occurred in 20% of the patients in each treatment group. Elotuzumab dose reductions were not permitted, but dose delays occurred in 33% of the patients in the elotuzumab group.

EFFICACY

Figure 1.Progression-free Survival.

The median investigator-assessed progression-free survival was 10.3 months (95% confidence interval [CI], 5.6 to not reached) in the elotuzumab group and 4.7 months (95% CI, 2.8 to 7.2) in the control group. The hazard ratio for disease progression or death was 0.54 (95% CI, 0.34 to 0.86; P=0.008), which represents a risk of progression or death that was 46% lower in the elotuzumab group than in the control group (Figure 1A). The corresponding Kaplan–Meier curves of progression-free survival showed early separation that was sustained over time. Thus, the progression-free survival benefit of elotuzumab plus pomalidomide and dexamethasone was significant not only at the prespecified alpha level of 0.2 that the trial was powered to detect but also at the more stringent significance level of 0.05.

The progression-free survival benefit of elotuzumab was consistently observed across key patient subgroups that were defined according to baseline characteristics, including patients whose disease was refractory to both lenalidomide and a proteasome inhibitor, patients who were assessed as having high-risk disease on the basis of International Myeloma Working Group criteria, and patients with at least one cytogenetic abnormality (chromosome 17p deletion, t[4;14] translocation, or t[14;16] translocation) or at least one of the aforementioned cytogenetic abnormalities or a high lactate dehydrogenase level (Figure 1B, and Fig. S3 in the Supplementary Appendix). The benefit of elotuzumab was also seen in patients who had received at least four previous lines of therapy; the median progression-free survival among these patients was 10.3 months (95% CI, 3.7 to not reached) in the elotuzumab group and 4.3 months (95% CI, 1.9 to 9.3) in the control group (hazard ratio, 0.51; 95% CI, 0.24 to 1.08). Assignment: Dexamethasone for allergic disorders, skin conditions

The median progression-free survival in the overall population as assessed by the independent review committee was 10.3 months (95% CI, 6.5 to not reached) in the elotuzumab group and 4.7 months (95% CI, 2.8 to 7.6) in the control group; the hazard ratio for progression-free survival was 0.51 (95% CI, 0.32 to 0.82) in favor of the elotuzumab group. Concordance between investigator assessments and independent review committee assessments of progression-free survival was 85%.

Table 2.Investigator-Assessed Treatment Response.

According to investigator assessments, 20% of the patients in the elotuzumab group and 9% in the control group had a very good partial response or better. The overall response rate was higher in the elotuzumab group (53%; 95% CI, 40 to 66) than in the control group (26%; 95% CI, 16 to 40), with an odds ratio of 3.25 (95% CI, 1.49 to 7.11) (Table 2). The overall response rate as assessed by the independent review committee was 58% (95% CI, 45 to 71) in the elotuzumab group as compared with 25% (95% CI, 14 to 38) in the control group, with an odds ratio of 4.62 (95% CI, 2.05 to 10.43). Concordance between investigator assessments and independent review committee assessments of overall response rate was 91%. Assignment: Dexamethasone for allergic disorders, skin conditions

Figure 2.Preliminary Overall Survival.

Overall survival data were immature at the time of the analysis; however, a trend favoring the elotuzumab group was observed (hazard ratio for death, 0.62; 95% CI, 0.30 to 1.28) (Figure 2). There were 13 deaths (22%) in the elotuzumab group and 18 deaths (32%) in the control group; these 31 deaths represented 40% of the 78 deaths that would need to occur for the final analysis of overall survival. Disease progression was the main cause of death in both groups (13% of the treated patients in the elotuzumab group and 25% of the treated patients in the control group).

The median time to response was similar in the two groups: 2.0 months in the elotuzumab group and 1.9 months in the control group. The median duration of response was not reached (95% CI, 8.3 to not reached) in the elotuzumab group and was 8.3 months (95% CI, 4.6 to not reached) in the control group (Fig. S4 in the Supplementary Appendix).

SAFETY

Table 3.Adverse Events (All Treated Patients).

Adverse events of any cause that were reported in at least 10% of the patients in either treatment group and adverse events of special interest are shown in Table 3. Grade 3 or 4 adverse events were reported in 57% of the patients in the elotuzumab group and in 60% in the control group; the most common events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). Infections of any grade were reported in 65% of the patients in each of the two groups, with grade 3 or 4 infections occurring in 13% of the patients in the elotuzumab group and in 22% in the control group. When we adjusted for exposure to the trial medication, the rate of infection was 182 events per 100 patient-years in the elotuzumab group and 230 events per 100 patient-years in the control group (Table S1 in the Supplementary Appendix).

The incidence of serious adverse events was 53% in the elotuzumab group and 55% in the control group. One patient in the control group had a second primary cancer (grade 4 invasive breast carcinoma) that resulted in discontinuation of treatment. The most common treatment-related adverse events were neutropenia (18% in the elotuzumab group vs. 20% in the control group), hyperglycemia (18% vs. 11%), and anemia (10% vs. 15%) (Table S2 in the Supplementary Appendix).

Adverse events that led to discontinuation of treatment occurred in 18% of the patients in the elotuzumab group and in 24% of the patients in the control group; infections led to discontinuation in 7% of the patients in the elotuzumab group and in 5% in the control group. No deaths in either group were considered by the investigators to be due to the trial medication. Assignment: Dexamethasone for allergic disorders, skin conditions

At the time of the database lock, a total of 816 infusions of elotuzumab had been administered; three infusion reactions had occurred (deafness, chest discomfort, and an unspecified infusion-related reaction occurred in one patient each). All the infusion reactions were grade 1 or 2, and all resolved.

The findings from this randomized trial showed that the addition of the monoclonal antibody elotuzumab to pomalidomide and dexamethasone resulted in a significant improvement over pomalidomide and dexamethasone alone in treatment outcomes of relapsed or refractory multiple myeloma. Specifically, the Kaplan–Meier curves for progression-free survival showed early separation that was sustained over time, with a risk of progression or death that was 46% lower in the elotuzumab group than in the control group. In addition, the odds ratio for the overall response rate showed that patients in the elotuzumab group were 3.25 times as likely to have a response to treatment as patients in the control group. These clinical data confirm the findings of preclinical studies in mice, which showed that elotuzumab, pomalidomide, and dexamethasone synergize to kill myeloma cells (Fig. S5 in the Supplementary Appendix).

Therapies approved for patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor include pomalidomide and dexamethasone, daratumumab monotherapy, and daratumumab plus pomalidomide and dexamethasone.^16,19 In the phase 3 trial (MM-003) of pomalidomide and dexamethasone, the median progression-free survival was 4.0 months and the overall response rate was 31%,¹⁸ findings that are consistent with those reported in the control group in our trial (4.7 months and 26%, respectively). In the current trial, the median progression-free survival with elotuzumab plus pomalidomide and dexamethasone was 10.3 months and the overall response rate was 53%, which shows the superiority of that treatment over pomalidomide and dexamethasone alone. In a noncomparative phase 1b trial that evaluated daratumumab plus pomalidomide and dexamethasone in 103 patients who had received a median of four previous lines of therapy, the median progression-free survival was 8.8 months and the overall response rate was 60%.²⁰ In our trial, the treatment effect of elotuzumab was observed across several subgroups, including patients who had received at least four previous lines of therapy, with a median progression-free survival of 10.3 months as compared with 4.3 months in the control group, and a hazard ratio for disease progression or death of 0.51. The benefit of combining a third agent with pomalidomide and dexamethasone has also been shown in a randomized, phase 2 trial of pomalidomide and dexamethasone with or without cyclophosphamide, in which the overall response rate was 1.7 times as high in the cyclophosphamide group as in the control group.²⁹ In the current trial, the overall response rate in the elotuzumab group was twice as high as the rate in the control group. Collectively, these data suggest that elotuzumab plus pomalidomide and dexamethasone is an effective combination and represents an alternative treatment option to other pomalidomide and dexamethasone–based regimens. However, caution is warranted when comparing results across trials. Assignment: Dexamethasone for allergic disorders, skin conditions

Elotuzumab plus pomalidomide and dexamethasone was associated with a rate of grade 3 or 4 adverse events (57%) that was similar to that observed with pomalidomide and dexamethasone alone (60%); no new safety signals were identified beyond the findings reported with other elotuzumab and pomalidomide regimens.^{11,12,17,18,23} Despite a longer duration of exposure to the trial medication in the elotuzumab group than in the control group, the incidence of adverse events that led to discontinuation of treatment was lower in the elotuzumab group than in the control group. When we adjusted for exposure to the trial medication, infections were less common in the elotuzumab group than in the control group. The occurrence of infusion reactions was minimal, a finding that is consistent with that in other elotuzumab trials.^11,23 Treatment with pomalidomide and dexamethasone has been reported to be associated with neutropenia, a risk that may be increased with the addition of daratumumab.²⁰ In contrast, the addition of elotuzumab did not result in a higher rate of treatment-related neutropenia than that without elotuzumab (18% in the elotuzumab group and 20% in the control group). Neutropenia and anemia of any cause were less common in the elotuzumab group than in the control group, even though the dose intensity of pomalidomide in the two groups was balanced. In addition, the similarity of the dose intensity of pomalidomide in the two groups suggests that elotuzumab does not affect pomalidomide dosing. Overall, these results support the initial findings of an ongoing noncomparative, phase 2 trial,²⁴ which suggests that elotuzumab plus pomalidomide and dexamethasone has a safety profile that is similar to that of elotuzumab plus lenalidomide and dexamethasone and that elotuzumab is not associated with a higher rate of toxic effects than pomalidomide and dexamethasone alone.^17,18

This trial, which was specifically designed to detect a large treatment effect in a relatively small sample, showed a significant benefit of elotuzumab plus pomalidomide and dexamethasone with respect to the primary end point of progression-free survival. Furthermore, the progression-free survival results, as assessed by the investigators, were confirmed by blinded, independent central review. Monthly administration of elotuzumab starting in cycle 3 was effective and provided a potentially more convenient dosing schedule for patients than the approved dosing schedule of every other week.^3,4The results thus far are encouraging, but extended follow-up is warranted to determine long-term efficacy and safety outcomes, including the final analysis of overall survival. This trial showed the therapeutic potential of a second elotuzumab-based combination therapy for relapsed or refractory multiple myeloma. Elotuzumab plus lenalidomide and dexamethasone is approved for multiple myeloma after treatment with at least one previous therapy^3,4 on the basis of the results of the phase 3 ELOQUENT-2 trial, in which most patients had not received lenalidomide.¹¹ In contrast, patients in the current trial had multiple myeloma that was refractory or relapsed and refractory to lenalidomide.

In conclusion, among patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor, the combination of elotuzumab plus pomalidomide and dexamethasone resulted in significantly longer progression-free survival and a higher overall response rate than pomalidomide and dexamethasone alone. The previously reported safety profile of this regimen was confirmed and was similar to that of pomalidomide and dexamethasone alone.