EMA CHMP recommends elotuzumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma 

The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the approval of elotuzumab (E) in combination with pomalidomide (P) and low-dose dexamethasone (d, EPd) for patients with relapsed/refractory multiple myeloma (RRMM).^1,2

The recommendation is for the treatment of patients who have received ≥ two prior lines of therapy, including lenalidomide and a proteasome inhibitor (PI), and who progressed with their last therapy.¹ This is based on the ELOQUENT-3 study, which showed EPd reduced the risk of progression or death by 46% compared with Pd in patients with RRMM.³

Elotuzumab was originally approved by the EMA in combination with lenalidomide and dexamethasone for patients with RRMM who received at least one prior line of therapy.⁴ The United States (US) Food & Drug Administration (FDA) have already approved the EPd triplet in patients with RRMM in November 2018.⁵

Background²

Elotuzumab specifically targets the signaling lymphocyte activation molecule family member 7 (SLAMF7) which is a cell surface glycoprotein expressed on MM cells as well as natural killer (NK) cells, plasma cells, and in low-levels on other hematopoietic cells. Therefore, elotuzumab has a dual mechanism of action:

1. Activates the immune system via NK cells by the SLAMF7 pathway
2. Direct targeting of SLAMF7 on MM cells, tagging them for NK-cell-mediated destruction by antibody-dependent cellular toxicity

Elotuzumab is administered as an intravenous (IV) injection.

ELOQUENT-3 trial^2,3,6

ELOQUENT-3 (NCT02654132) is a randomized, open-label, phase II trial, of EPd versus Pd in patients with RRMM. The results of the ELOQUENT-3 trial were presented by Professor Meletios A. Dimopoulos at the European Hematology Association (EHA) congress in June 2018.³

Data given as EPd versus Pd unless otherwise stated

• Patients (N= 117) were randomized to either EPd (n= 60) or Pd (n= 57)
• IV E: 10mg/kg weekly for the first two 28-day cycles, then 20mg/kg every four weeks
• Oral P: 4mg daily on days 1–21 of each 28-day cycle
• d: 40mg weekly
  • Reduced to 20mg for patients >75 years old
• Administered until disease progression (PD) or unacceptable toxicity
• Primary endpoint: investigator-assessed progression-free survival (PFS)
• Secondary endpoints: overall response rate (ORR) and overall survival (OS)
• Median age: 67 years
• Median prior lines of treatment: 3 (2–8)
• 87% of patients were refractory to lenalidomide, 80% to a PI, and 70% to both
• At the time of datacut (21^st February 2018), with a minimum follow up of 9.1 months, 40% (24/60) patients remained on EPd and 20% (11/55) on Pd
• Main reason for discontinuation was PD (EPd 43% vs Pd 56%)

In the trial, EPd doubled the median PFS and ORR compared to Pd (Table 1). Whilst survival data was not mature, there was a positive trend for EPd compared to Pd. Safety data showed the EPd regimen was well-tolerated (Table 2) and a low rate of infusion-related reactions in the EPd arm (3.3%).

Table 1. Efficacy data from ELOQUENT-3 trial^2,6

* Minimum follow-up of 9.1 months. EPd, elotuzumab, pomalidomide and dexamethasone; HR, hazard ratio; NE,, not estimable; OR, odds ratio; ORR, overall response rate; PFS, progression free survival;
	EPd (n=60)	Pd (n=57)	Statistics	p value
Median PFS*	10.25 months 95% CI 5.59 NE	4.67 months 95% CI 2.83–7.16	HR 0.54 95% CI 0.34–0.86	0.0078
ORR	53.3% 95% CI 40.0–66.3	26.3% 95% CI 15.5–39.7	OR 3.25 95% CI 1.49–7.11	0.0029

Table 2. Safety data from the ELOQUENT-3 trial^2,6

* with a ≥10% incidence in EPd arm, and ≥5% incidence in Pd arm. EPd, elotuzumab, pomalidomide and dexamethasone; SAEs, serious adverse events
	EPd (n=60)	Pd (n=55)
SAEs	22%	15%
Most common SAEs
Pneumonia	13%	11%
Respiratory tract infection	7%	3.6%
AEs*
Constipation	22%	11%
Hyperglycemia	20%	15%
Pneumonia	18%	13%
Diarrhea	18%	9%
Respiratory tract infection	17%	9%
Bone pain	15%	9%
Dyspnea	15%	7%
Muscle spasms	13%	5%
Peripheral edema	13%	7%
Lymphopenia	10%	1.8%