Relapsed/refractory patients

IMW 2019 | ELOQUENT-2: Final overall survival results

During the XVII International Myeloma Workshop (IMW) in Boston, US, Professor (Prof.) Meletios Dimopoulos presented the final overall survival (OS) results from the phase III ELOQUENT-2 study.1

  • ELOQUENT-2 was an international, open-label, randomized trial (NCT01239797) comparing elotuzumab (E), lenalidomide (R) and dexamethasone (d, ERd, n= 321) to Rd alone (n= 325)
  • Patients had relapsed/refractory multiple myeloma (RRMM) following one to three prior lines of therapy
  • Patients were stratified by β2 microglobulin level, number of prior lines of therapy, and prior exposure to immunomodulatory drugs
  • Dosing schedule:
    • Intravenous E: 10mg/kg, weekly in cycles one and two, and every other week from cycle three onwards
    • Oral R: 25mg, on days 1­-21
    • Oral d: 40mg, weekly
  • Treatment continued until disease progression (PD), unacceptable toxicity or withdrawal of consent
  • Endpoints:
    • The co-primary endpoints were Independent Review Committee (IRC)-assessed progression-free survival (PFS) and overall response rate (ORR)
    • The secondary endpoint was OS
    • Safety was an exploratory endpoint

The co-primary endpoint results were previously reported by Sagar Lonial, Meletios Dimopoulos, and colleagues in the New England Journal of Medicine in 20152

  • One-year PFS (ERd vs Rd): 68% vs 57%
  • Two-year PFS: (ERd vs Rd): 41% vs 27%
  • Median PFS: 19.4 vs 14.9 months
  • ORR (ERd vs Rd): 79% vs 66%
  • In the intention to treat (ITT) population, ERd gave a 32% reduction in the risk of PD

Read the full report of the primary endpoint analysis on the MM Hub here

Final OS analysis1

At a data cutoff of 3rd October 2018, 437 deaths had occurred, with 10% of patients remaining on treatment in the ERd arm compared to 4% in the Rd arm (Table 1). The two-sided alpha value for final OS analysis was determined to be 0.046.

Table 1. Treatment adherence and reason for discontinuations

Disposition

ERd (n= 321, %)

Rd (n= 325, %)

Treated

319 (99)

316 (97)

Remain on treatment

33 (10)

14 (4)

Reason for discontinuation

 

 

PD

180 (56)

181 (57)

Study drug toxicity

38 (12)

45 (14)

Patient request/withdrawal of consent

32 (10)

27 (8)

Adverse event (AE) unrelated to study treatment

29 (9)

37 (12)

Other

7 (2)

12 (4)

Exposure

 ERd (n= 318, %)

Rd (n= 317, %)

Median number of cycles

19 (9-42)

14 (6-25)

  • The hazard ratio (HR) for ERd vs Rd was 0.82 (95.4% CI, 0.68-1.00, p= 0.0408)
    • ERd gave a 18% reduction in the risk of death compared to Rd alone and prolonged median OS by 8.7 months (Table 2)
    • The p-value of 0.0408 was less than the alpha value of 0.046
    • Therefore, ERd gave a statistically significant and clinically meaningful benefit in OS compared to Rd
  • Predefined subgroup analysis showed a consistent benefit of ERd across most patient subsets
  • Subsequent therapy given to:
    • ERd group: 60% of patients
    • Rd: 66% of patients

Table 2. Final OS analysis at a minimum follow-up of 71 months

 

ERd (n= 321, %)

Rd (n= 325, %)

Median OS (months, 95% CI)

48.3 (40.3-51.9)

39.6 (33.3-45.3)

1-year OS

91%

83%

2-year OS

73%

69%

3-year OS

60%

53%

4-year OS

50%

43%

5-year OS

40%

33%

  • Less deaths occurred in the ERd arm (Table 3)
    • Deaths (ERd vs Rd): 67% vs 71%
  • The safety analysis was consistent with the primary analysis:
    • In total, grade 3-4 serious AEs (ERd vs Rd): 53% vs 40% (Table 4)
    • Grade 3-4 AEs leading to discontinuation (ERd vs Rd): 21% vs 20%
    • Secondary primary malignancy of any grade (ERd vs Rd): 12% vs 9%
    • Infusion reactions in ERd arm: 11%
      • Most (9%) were grade 1-2

Table 3. Summary of deaths

 

ERd (n= 318, %)

Rd (n= 317, %)

Disease

131 (41)

142 (45)

Infection

28 (9)

20 (6)

Cardiovascular disease

12 (4)

16 (5)

Malignancy/neoplasm

9 (3)

6 (2)

Study drug toxicity

7 (2)

7 (2)

Bleeding

2 (1)

6 (2)

Other/unknown

23 (7)

28 (9)

Table 4. Most common grade 3-4 AEs occurring in >2% of patients

 

ERd (n= 318, %)

Rd (n= 317, %)

Diarrhea

24 (8)

17 (5)

Fatigue

32 (10)

27 (9)

Anemia

57 (18)

53 (17)

Pyrexia

11 (3)

11 (3)

Neutropenia

86 (27)

109 (34)

Back pain

19 (6)

17 (5)

Infection

112 (35)

85 (27)

Conclusion

Prof. Dimopoulos and colleagues concluded that ERd provided an 18% reduction in the risk of death compared to Rd alone in patients with RRMM who received between one and three prior lines of therapy, at a minimum follow-up of five years with a consistent safety profile across the five-years.

References
  1. Dimopoulos M. et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed/refractory multiple myeloma: Final overall survival results from the phase 3 ELOQUENT-2 trial. XVII International Myeloma Workshop (IMW). 2019 Sep 13. Abstract #OAB-021 and oral presentation.
  2. Lonial S, Dimopoulos M. et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015 Aug 13. 373(7):621-631. DOI: 10.1056/NEJMoa1505654
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