Relapsed/refractory patients

EHA 2019 | Results of the phase III BELLINI trial: VenBd for RRMM

On Sunday 16 June at the 24th Congress of the European Hematology Association (EHA), Shaji Kumar, Mayo Clinic, Rochester, MN, US, presented the results of the phase III BELLINI trial (NCT02755597), which investigated the efficacy and safety of venetoclax in patients with relapsed or refractory multiple myeloma (RRMM).1

Venetoclax (Ven) is a first-in-class, selective inhibitor of the anti-apoptotic protein BCL2, and thus can induce myeloma cell death. It has shown promising clinical activity and manageable safety both alone,2 and in combination with bortezomib (B) and dexamethasone3 (d) in phase I studies for RRMM.

This multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of venetoclax addition to bortezomib and dexamethasone (VenBd) in patients with RRMM. Patients were randomized to Bd or VenBd, with progression-free survival (PFS) by independent review committee (IRC) as the primary endpoint. Secondary endpoints included, overall response rate (ORR), overall survival (OS), ≥ very good partial response (VGPR), and quality of life (QoL) based on patient reported outcomes (PRO).

Study design & baseline characteristics
  • N=291 patients with RRMM, who had received 1–3 prior lines and were sensitive or naïve to proteasome inhibitors
  • Patients were randomized 2:1 to VenBd (n=194) or Bd (n=97) until disease progression (PD) or unacceptable toxicity
  • Dosing schedule (21-day cycles):
    • VenBd:
      • Ven: 800mg daily
      • B: 1.3mg/m2 on Days 1, 4, 8, 11 of cycles 1–8 and on Days 1, 8, 15, 22 of cycles 9+
      • d: 20mg on days 1, 2, 4, 5, 8, 9, 11, 12 of cycles 1–8 and on Days 1, 2, 8, 9, 15, 16, 22, 23 of cycles 9+
    • Placebo+Bd:
      • B and d: as above
    • Table 1. Key baseline characteristics:

 

VenBd (n=194)

Placebo+Bd (n=97)

Median age (range)

≥65 years old

66 (36–87)

56%

65 (44–83)

54%

MM International Staging System (ISS):

Stage 1

Stage 2

Stage 3

 

 

42%

36%

20%

 

 

50%

33%

14%

Number of prior lines:

1

2–3

 

47%

53%

 

45%

55%

Cytogenetics:

High-risk [t(4;14) or t(14;16) or del(17p)]

Standard risk

Unknown

 

17%

78%

5%

 

19%

77%

4%

t(11;14) status:

Positive

Negative

Unknown

 

11%

84%

5%

 

16%

79%

5%

BCL2 expression (immunohistochemistry):

High

Low

 

78%

22%

 

81%

19%

  • Median treatment exposure (range):
    • VenBd: 9.9 (0.1–24.7) months
    • Placebo+Bd: 10.5 (0.1–25.4) months
  • Median follow-up for OS (range):
    • VenBd: 19.0 (0.2–24.8) months
    • Placebo+Bd: 18.3 (0.0–26.5) months
Key findings
  • Median PFS:
    • VenBd: 22.4 months
    • Placebo+Bd: 11.5 months
    • Comparison: p=0.010; HR=0.630 (95% CI, 0.443–0.897)
  • Median OS:
    • VenBd: not reached (41 events)
    • Placebo+Bd: not reached (11 events)
    • Comparison: p=0.034; HR=2.027 (95% CI, 1.042–3.945)
  • Table 2. Response outcomes:

 

VenBd (n=194)

Placebo+Bd (n=97)

p value

ORR

82%

68%

0.008

≥CR

26%

5%

<0.001

≥VGPR

59%

36%

<0.001

MRD<10-4

19%

3%

<0.001

MRD<10-5

13%

1%

<0.001

MRd<10-6

7%

1%

0.026

Safety
  • Most common Grade 3–4 adverse events (AEs) in both arms were:
    • Thrombocytopenia
    • Anemia
    • Neutropenia
    • Diarrhea
  • Infection-related AEs of any grade occurred in:
    • VenBd: 80%
    • Placebo+Bd: 77%
  • Table 3. Causes of death summary:

Safety population

VenBd (n=193)

Placebo+Bd (n=96)

All deaths

Infection

PD

Other

21%

7%

9%

5%

11%

2%

8%

1%

Deaths occurring within 30 days of last dose:

Infection

PD

Other

 

7%

4%

1%

2%

 

1%

0

1%

0

Deaths occurring after 30 days of last dose:

Infection

PD

Other

 

14%

3%

8%

3%

 

10%

2%

7%

1%

Subgroup analysis

The investigators of the trial performed a PFS subgroup analysis to identify potential patient populations that benefit the most from venetoclax treatment without the serious infection adverse events identified in the total cohort

  • Patients with positive t(11;14) status (n=35) benefited the most from VenBd treatment with:
    • Median PFS:
      • VenBd: not reached
      • Placebo+Bd: 9.5 months
      • Comparison: p=0.002; HR=0.110 (95% CI, 0.022–0.560)
    • Median OS:
      • VenBd: not reached (1 event)
      • Placebo+Bd: not reached (2 events)
      • Comparison: p=0.363; HR=0.343 (95% CI, 0.031–3.842)
Conclusions
  • Despite the increased PFS and response rates seen with VenBd, an increased risk of death (lower OS) accompanied the treatment. This led to an FDA hold on patient enrollment for this trial and any other involving venetoclax treatment for MM patients
  • More deaths were reported in the VenBd arm, which were mainly due to treatment-emergent infections
  • Subgroup analysis revealed that patients with positive t(11;14) status benefited the most from VenBd without the associated treatment toxicity, thus the investigators proposed that VenBd should be further developed and implemented on this particular patient subpopulation
References
  1. Kumar S. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Abstract LB2601. 24th Congress of EHA, Amsterdam, NL
  2. Kumar S. et al. 2017. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 130, 2401–2409. DOI: 10.1182/blood-2017-06-788786
  3. Moreau P. et al. 2017. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood 130, 2392–2400. DOI: 10.1182/blood-2017-06-788323

Expert Opinion

Prof. Shaji Kumar provided a summary of the safety signals that were associated with venetoclax in this trial:

‘We observed increased numbers of deaths in the venetoclax arm, even though the rates of the adverse events, including those for serious adverse events were similar between the groups. The increased deaths were primarily related to infections, especially in the setting of disease progression. No specific organisms have been identified, though bacterial was most common. When subgroups were examined, the increased risk of death seemed to be particularly evident in patients without t(11;14), those with high-risk cytogenetics, and in those with low expression of BCL-2. In contrast, patients with t(11;14) had a significant improvement in progression-free survival without any deleterious impact. The immediate future focus will be to better define the role of the drug in this subgroup, along with development of any applicable biomarkers. Subsequently, various combinations will be explored in the other subgroups.’

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