Elotuzumab therapy for relapsed or refractory MM

In August 2015, Lonial S., Dimopoulos M.D. and colleagues reported results from the open-label, multi-center ELOQUENT-2 trial in The New England Journal of Medicine. This was the pivotal phase 3 study leading to approval of elotuzumab for the treatment of patients with relapsed and/or refractory Multiple Myeloma (RRMM). They enrolled 646 patients (between June 2011 and November 2012 at 168 sites globally) who had received one to three prior therapies, and who had relapsed following their most recent therapy. Patients were randomly assigned into two treatment groups, receiving either elotuzumab (321 patients) or placebo (control) (325 patients) on a background of a combined regimen of lenalidomide plus dexamethasone. Primary endpoints were Progression Free Survival (PFS) and Overall Response Rate (ORR).

Treatment

• Intravenous elotuzumab (10 mg/kg of body weight) was administered on days 1, 8, 15 and 22, during cycle 1 and 2, then on day 1 and 15 in cycle 3
• Oral lenalidomide (25 mg per day) was administered from day 1 –day 21 of each cycle
• Oral dexamethasone (40 mg) was administered during the week without elotuzumab and intravenously at a dose of 8 mg, plus 28 mg orally on the day of elotuzumab treatment (days 1, 8, 15 and 21)
• Control group received the same regimen, minus elotuzumab
• Pre-medication (H1 blocker, H2 blocker, and acetaminophen) were administered prior to elotuzumab infusion
• Only 10% of patients that received previous lenalidomide treatment were allowed to enrol

Key Findings:

• Median follow-up = 24.5 months
• 35% (113 of 321 pts) in the elotuzumab group and 20% in the control group (66 of 325 pts) were still receiving treatment at the cut-off date for interim analysis
• The rate of PFS:
  • 1 year: elotuzumab group = 68%; placebo group = 57%
  • 2 years: elotuzumab group = 41%; placebo group = 27%
• Median PFS:
  • elotuzumab = 19.4 months (95% CI, 16.6 to 22.2)
  • placebo = 14.9 months (95% CI, 12.1 to 17.2)

(HR: 0.70; 95% CI, 0.57 to 0.85; P<0.001)

• Relative reduction in the risk of disease progression or death = 30%
• Safety data set: elotuzumab = 318 patients and placebo = 317 patients
• ITT population: 32% relative reduction in the risk of disease progression in the elotuzumab group (HR, 0.68; 95% CI, 0.56 to 0.83)
• ORR: elotuzumab group = 79% (95% CI, 74 to 83); placebo group = 66% (95% CI, 60 to 71) (odds ratio for elotuzumab vs placebo = 95% CI, 0.44 to 0.70; P<0.001)
• Durable responses - elotuzumab group: 21 months (95% CI, 18 to 27) and placebo: 17 months (95% CI, 15 to 19)
• Grade 3 or 4 AE’s were: lymphocytopenia, neutropenia, fatigue and pneumonia
• Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients
• Patients continued treatment until the development of unacceptable toxicity or due to disease progression

Conclusion

Patients receiving elotuzumab, on a background of the combined regimen of lenalidomide plus dexamethasone, had a 30% reduction in the risk of disease progression or death. This trial was pivotal in driving the approval of elotuzumab by the US FDA, for use in combination with two other therapies, to treat people with MM who have received one to three prior medications. Following this trial, elotuzumab was granted marketing approval by the EMA in April 2016.

Abstract

Background:

Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma.

Methods:

In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival.

Results:

Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients.

Conclusions:

Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).