The European Commission ( EC ) has approved Empliciti ( Elotuzumab ) plus Pomalidomide and low-dose Dexamethasone ( EPd ) for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies, including Lenalidomide and a proteasome inhibitor, and have demonstrated disease progression on the last therapy.
This approval is based on data from the ELOQUENT-3 trial in which EPd doubled both median progression-free survival ( PFS ) and overall response rate ( ORR ) among patients with relapsed and refractory multiple myeloma versus Pomalidomide and low-dose Dexamethasone ( Pd ) alone.
EPd is the first triplet combination approved in European Union based on a randomized clinical trial using the standard of care, Pd, as a comparator.
Results from ELOQUENT-3 have demonstrated that the addition of Empliciti to Pd can significantly prolong survival without disease progression among heavily pretreated patients with multiple myeloma regardless of the number of prior therapies received.
Investigator-assessed progression-free survival, the study’s primary endpoint, was 10.25 months ( 95% CI: 5.59 to not-estimable ) among patients randomized to EPd compared with 4.67 months ( 95% CI: 2.83 to 7.16 ) among patients treated with Pd alone, indicating a 46% reduction in risk of disease progression ( hazard ratio, HR 0.54; 95% CI: 0.34 to 0.86; p=0.0078 ) between EPd and Pd arms after a minimum follow-up of 9.1 months.
A secondary endpoint of the study, ORR, was 53.3% ( 95% CI: 40.0 to 66.3 ) compared with 26.3% ( 95% CI: 15.5 to 39.7; p=0.0029 ) among patients receiving EPd or Pd, respectively.
Data from the ELOQUENT-3 trial were first presented at the 23rd Congress of the European Hematology Association ( EHA ) in 2018.
Updated efficacy results with a minimum follow-up of 18.3 months were presented at the 24th Congress of the EHA this year. In this exploratory analysis, a total of 40 ( 67% ) patients were alive in the EPd arm and 29 ( 51% ) patients were alive in the Pd arm ( HR 0.54; 95% CI: 0.30 to 0.96 ). Median OS was not reached for the EPd treatment arm.
Treatment-related grade 3-4 adverse events were comparable between EPd and Pd groups.
Any-grade infections occurred in 65% of patients in both arms.
Rates of the most commonly occurring grade 3-4 hematologic adverse effects, neutropenia and anemia, were 13% and 10%, respectively, for patients receiving EPd and 27% and 20%, respectively, for patients receiving Pd, despite longer exposure within the EPd arm and similar dose intensity of Pomalidomide between arms.
Adverse effects led to discontinuation in 18% of patients in the EPd arm, compared with 24% of patients in the Pd arm.
The phase 2 ELOQUENT-3 trial randomized 117 patients with relapsed and refractory multiple myeloma to treatment with EPd ( n=60 ) or Pd ( n=57 ) in 28-day cycles until disease progression or unacceptable toxicity.
In the EPd arm, Elotuzumab was administered intravenously at the dose of 10 mg/kg each week for the first 2 cycles and 20 mg/kg every four week thereafter. The median number of treatment cycles was nine for the EPd arm and five for the Pd arm.
Elotuzumab is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 ( SLAMF7 ), a cell-surface glycoprotein.
SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities.
SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.
Elotuzumab has a dual mechanism of action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Elotuzumab also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.
Empliciti was initially approved by the FDA ( Food and Drug Administration ) in 2015 in combination with Lenalidomide and Dexamethasone ( ELd ) for the treatment of patients with multiple myeloma who have received one to three prior therapies.
In 2018, Empliciti was approved by the FDA in a new combination, with Pomalidomide and Dexamethasone, for the treatment of patients with multiple myeloma who have received at least two prior therapies, including Lenalidomide and a proteasome inhibitor.
The ELd and EPd indications were subsequently approved by the European Commission in 2016 and 2019, respectively. ( Xagena )
Source: Bristol-Myers Squibb, 2019