Relapsed/refractory patients

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 trial2,3,6

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 (21st 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 trial2,6

 

EPd

(n=60)

Pd

(n=57)

Statistics

p value

Median PFS*

 

10.25 months

95% CI

5.59–not estimable (NE)

4.67 months

95% CI

2.83–7.16

Hazard ratio (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

Odds ratio (OR)

3.25

95% CI

1.49–7.11

0.0029

* Minimum follow-up of 9.1 months

Table 2. Safety data from the ELOQUENT-3 trial2,6

 

EPd

(n=60)

Pd

(n=55)

Serious adverse events (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%

* with a ≥10% incidence in EPd arm, and ≥5% incidence in Pd arm

References
  1. European Medicines Agency: Empliciti, Opinion. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/empliciti [accessed 2019 Jul 29]
  2. Bristol-Myers Squibb Receives Positive CHMP Opinion Recommending Approval of Empliciti (elotuzumab) Plus Pomalidomide and Low-Dose Dexamethasone for Treatment of Patients with Relapsed and Refractory Multiple Myeloma. https://www.biospace.com/article/releases/bristol-myers-squibb-receives-positive-chmp-opinion-recommending-approval-of-empliciti-elotuzumab-plus-pomalidomide-and-low-dose-dexamethasone-for-treatment-of-patients-with-relapsed-and-refractory-multiple-myeloma/ [accessed 2019 Jul 29]
  3. Dimopoulos M.A. et al. 23rd Congress of the European Hematology Association; 2018 June 14–17; Stockholm, SE. Abstract #LB2606.
  4. Summary of product characteristics: Empliciti. https://www.ema.europa.eu/en/documents/product-information/empliciti-epar-product-information_en.pdf [accessed 2019 Jul 29]
  5. Targeted Oncology online. Elotuzumab Triplet Approved by FDA for Treatment of Myeloma. https://www.targetedonc.com/news/elotuzumab-triplet-approved-by-fda-for-treatment-of-myeloma. [Assessed November 08 2018]
  6. BMS: U.S. Food and Drug Administration Approves Empliciti® (elotuzumab) Plus Pomalidomide and Dexamethasone, a New Immunotherapy Combination for Certain Patients with Relapsed or Refractory Multiple Myeloma. https://news.bms.com/press-release/bristolmyers/us-food-and-drug-administration-approves-empliciti-elotuzumab-plus-pomali [accessed 2019 Jul 29]

Expert Opinion

"This combination was very well tolerated and maybe the treatment of choice for elderly patients for whom carfilzomib-based therapies maybe contraindicated. The trend for survival advantage is very encouraging."

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