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Venetoclax, bortezomib, and dexamethasone in MM: Updated results from BELLINI trial and t(11;14) subgroup analysis

Dec 24, 2020
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The phase III BELLINI trial (NCT02755597) was set up to investigate the efficacy of venetoclax, a Bcl-2 inhibitor, combined with bortezomib and dexamethasone (Vd) in patients with relapsed/refractory multiple myeloma (MM). However, it was put on hold by the U.S. Food and Drug Administration (FDA) in March 2019, after a decrease in overall survival (OS) due to infections was recorded in the venetoclax + Vd group compared with the placebo arm. Subsequent analysis of the data found that a subgroup of patients, those with chromosomal translocation t(11;14), showed an improved progression-free survival (PFS) and OS compared to the rest of the cohort. Shaji Kumar and colleagues have since published updated results analyzing the impact on different subsets, which have been published in The Lancet Oncology.1

The study design, baseline patient characteristics, and initial results in the intention-to-treat population and in a subset of patients harboring t(11;14) have been reported on by the Multiple Myeloma Hub previously, and can be found here.

Key points

The median PFS was not reached for patients treated with venetoclax bearing t(11;14), whereas the placebo group had a PFS of 9.5 months. The overall response rate (ORR) was higher in the venetoclax + Vd group compared with placebo + Vd across all subgroups, with the patients with t(11;14) reaching 90% (Table 1). Rates of measurable residual disease (MRD) negativity were also higher in all venetoclax + Vd treatment groups, with the t(11;14) subgroup showing the greatest improvement. Patients with high BCL2 expression also achieved superior outcomes than the intention-to-treat population.

Table 1. Response rates and MRD in different patient populations1

MR, minimal response; MRD, measurable residual disease; ORR, overall response rate; PD, disease progression; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

MRD was assessed by next-generation sequencing in patients with suspected CR or a sCR.

 

Intention-to-treat population

t(11;14) subgroup

High BCL2 subgroup

 

Venetoclax + Vd, %
(n = 194)

Placebo + Vd, %
(n = 97)

p value

Venetoclax + Vd, %
(n = 20)

Placebo + Vd, %
(n = 15)

Venetoclax + Vd, %
(n = 66)

Placebo + Vd, %
(n = 32)

Response criteria

sCR

8

2

0.054

20

-

8

-

CR

19

3

< 0.001

25

7

29

-

VGPR

32

31

0.800

25

20

35

28

PR

23

32

0.112

20

20

14

47

MR

2

10

< 0.001

-

27

-

13

SD

7

10

0.381

-

20

5

6

PD

5

5

0.990

-

-

3

-

ORR

82

68

0.0081

90

47

85

75

≥ VGPR

59

36

< 0.001

70

27

71

28

MRD negativity at given threshold

10-4

19

3

< 0.001

40

-

27

3

10-5

13

1

< 0.001

25

-

18

-

10-6

7

1

0.026

20

-

9

-

Outcomes according to BCL2 expression

Median PFS in the high BCL2 group was:

  • 22.4 months (95% CI, 22.4–not estimable) with venetoclax + Vd
  • 9.9 months (95% CI, 9.0–14.0) with placebo + Vd
  • In terms of PFS events, 16 occurred in the venetoclax + Vd group and 22 in the placebo (HR, 0.24; 95% CI, 0.12–0.48; p < 0.0001).

OS was not reached in either group.

Overall, 114 patients had either high BCL2 expression or t(11;14), and 19 patients had both markers. In this subset, the median PFS was not reached vs 9.9 months, after 16 PFS events occurred in the venetoclax + Vd group vs 28 in the placebo group (HR, 0.21; 95% CI, 0.11–0.41; p < 0.0001).

The median PFS for the 164 patients with low BCL2 expression and no translocation t(11;14) did not significantly differ between the two treatment groups:

  • Venetoclax + Vd, 15.3 months (95% CI, 10.9–not estimable)
  • Placebo + Vd, 12.2 months (95% CI, 9.6−17.2)
    • HR, 0.81; 95% CI, 0.52–1.27; p = 0.36

Discussion

Irene Ghobrial added her insightful thoughts regarding the trial in a commentary piece, also published in The Lancet Oncology.2 In her opinion, this result heralds a new era of precision medicine for the management of MM. An age when specific genetic alterations such as t(11;14) can be targeted and produce improved clinical responses in this subset of patients. Ghobrial thinks this will be the start of many such advances within the field of myeloma treatment.

In addition, she points out that many questions remain. The BELLINI trial did not define the mechanism by which patients with t(11;14) benefitted from venetoclax. As the decrease in OS in the intention-to-treat venetoclax + Vd cohort was associated with an increased rate of infection, the immune microenvironment should be investigated as part of exploratory studies looking into the mechanism. It is also true that the BELLINI trial analysis only examined the effect on patients with high BCL2 expression or the presence of t(11;14). Patients with other mutations or cytogenetic aberrations may also benefit from venetoclax combinations. Several ongoing studies evaluate venetoclax treatment in this subset of patients with high BCL2 expression or the presence of t(11;14) to confirm the BELLINI trial results (Table 2).

Table 2. Ongoing trials in MM with venetoclax3

MM, multiple myeloma; R/R, relapsed/refractory.

Trial name

Description

NCT number

M15-538

This phase II, open-label, dose-escalation study evaluates the safety and efficacy of venetoclax in combination with carfilzomib + dexamethasone in patients with R/R MM who have received 1–3 prior lines of therapy

NCT02899052

CANOVA

A phase III study designed to evaluate the safety and efficacy of venetoclax plus dexamethasone compared with pomalidomide plus dexamethasone in patients with t(11;14) R/R MM

NCT03539744

M15-654

Phase II study of venetoclax, daratumumab, and dexamethasone with and without bortezomib in participants with R/R MM. Select parts of the trial include only patients with t(11;14)

NCT03314181

MyDRUG

Precision medicine trial to treat patients with drugs targeted to affect specific genes that are mutated as part of the disease. Patients with a > 30% mutation in several genes including t(11;14) can be enrolled in the treatment arm evaluating venetoclax combined with ixazomib + pomalidomide + dexamethasone.

NCT03732703

Conclusion

As Irene Ghobrial comments, “Serendipity seems to play a role in the development of myeloma therapy.” The BELLINI trial did not set out to target a specific subset of patients but found that biomarker assessment prior to treatment can significantly impact the survival of patients with MM. Further investigation is required to identify if any other mutations or translocations confer a survival benefit for patients treated with the venetoclax + Vd combination. Despite the FDA hold, the BELLINI trial has made great strides forward in MM treatment.

  1. Shaji KK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1630-1642. DOI: 1016/S1470-2045(20)30525-8
  2. Irene Ghobrial. BELLINI: a renaissance for an era of precision therapy in multiple myeloma. Lancet Oncol. 2020;21(12):1547–1549. DOI: 1016/S1470-2045(20)30587-8
  3. NIH U.S. National Library of Medicine. Clinicaltrials.gov. https://clinicaltrials.gov/. Accessed Dec 15, 2020.

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