. 2022 Jun 3;15:75. doi: 10.1186/s13045-022-01295-3

Table 5.

Studies of BH3-mimetics in multiple myeloma

Study	Cohort	Design	ORR/ ≥ VGPR	PFS/OS	III/IV toxicity (> 10%)	Note
Phase I/II
Kumar et al.[122] NCT01794520	n = 66 R/R myeloma, median 5 prior lines of therapy 46% t(11;14)	Phase 1 dose escalation venetoclax monotherapy 300-1200 mg daily	ORR 21% ≥ VGPR 15% t(11;14): ORR 40% ≥ VGPR 27%	Median TTP 2.6 months t(11;14) median TTP 6.6 months	Thrombocytopenia 26% Neutropenia 21% Anemia 14% Lymphopenia 15%
Kaufman et al. [123] NCT01794520	Phase 1: n = 20 (median 3 prior lines of therapy) Phase 2: n = 31 (median 5 prior lines of therapy) RR myeloma with t(11;14)	Phase 1/2 study of venetoclax 800 mg daily plus 20-40 mg dexamethasone on D1, 8 and 15	Phase 1: ORR 60% ≥ VGPR 30% Phase 2: ORR 48% ≥ VGPR 36%	Phase 1: Median TTP 12.4 months Phase 2: Median TTP 10.8 months	Lymphopenia 20% Anemia 12% Neutropenia 10% Thrombocytopenia 10%
Moreau et al. [124] NCT01794507	n = 66 R/R myeloma Median of 3 prior lines of therapy 14% t(11;14)	Phase 1b study of venetoclax 50-1200 mg daily plus bortezomib and dexamethasone	ORR 67% ≥ VGPR 42%	Median TTP 9.5 months	Thrombocytopenia 29% Anemia 15% Neutropenia 14%	RP2D in combination with bortezomib and dexamethasone 800 mg daily
Bahlis et al. [126] NCT03314181	Part 1: R/R myeloma with t(11;14), n = 24 Part 2: RR myeloma (cytogenetically unselected), n = 24	Phase 1 study of venetoclax 400-800 mg daily plus: Part 1: Daratumumab plus dexamethasone Part 2: Daratumumab, bortezomib and dexamethasone	Part 1: ORR 96% ≥ VGPR 96% Part 2:ORR 92% ≥ VGPR 79%	Part 1: 18-month PFS 91% Part 2: 18-month PFS 67%	Part 1: Neutropenia (21%) Hypertension (17%) Part 2: Thrombocytopenia (17%) Lymphopenia (13%) Insomnia 25%	One death due to sepsis in part 2 (in context of progressive disease)
Costa et al.[125] NCT02899052	n = 49 R/R myeloma (median 1 prior line of therapy)	Phase 2 study of venetoclax 400 or 800 mg plus carfilzomib and dexamethasone	ORR 80% ≥ VGPR 65% t(11;14) ORR 92% ≥ VGPR 85%	Median PFS 27 months	Lymphopenia 31% Hypertension 16% Pneumonia 12% Neutropenia 12% Hypophosphatemia 10% Diarrhea 10% Insomnia 10%
Phase III
BELLINI [130, 131] NCT02755597	R/R myeloma, 1–3 prior therapies n = 97	Phase III randomized controlled trial of bortezomib and dexamethasone plus: Placebo	ORR 68% ≥ VGPR 36% t(11;14) ORR 47% ≥ VGPR 27%	Median PFS 12 months 36 (37%) deaths at median follow up 46 months	Diarrhea 11% Thrombocytopenia 30% Anemia 15%	Increased mortality in venetoclax arm, predominantly due to infections
	n = 194	Venetoclax 800 mg daily	ORR 82% ≥ VGPR 59% t(11;14) ORR 90% ≥ VGPR 70%	Median PFS 23 months 78 (40%) deaths at median follow up 46 months	Pneumonia 16% Diarrhea 15% Thrombocytopenia 15% Anemia 15% Neutropenia 18%

Study

Cohort

Design

ORR/ ≥ VGPR

PFS/OS

III/IV toxicity (> 10%)

Note

Phase I/II

Kumar et al.[122]

NCT01794520

n = 66

R/R myeloma, median 5 prior lines of therapy

46% t(11;14)

Phase 1 dose escalation venetoclax monotherapy 300-1200 mg daily

ORR 21% ≥ VGPR 15%

t(11;14): ORR 40% ≥ VGPR 27%

Median TTP 2.6 months

t(11;14) median TTP 6.6 months

Thrombocytopenia 26%

Neutropenia 21%

Anemia 14%

Lymphopenia 15%

Kaufman et al. [123]

NCT01794520

Phase 1: n = 20 (median 3 prior lines of therapy)

Phase 2: n = 31 (median 5 prior lines of therapy)

RR myeloma with t(11;14)

Phase 1/2 study of venetoclax 800 mg daily plus 20-40 mg dexamethasone on D1, 8 and 15

Phase 1: ORR 60% ≥ VGPR 30%

Phase 2: ORR 48% ≥ VGPR 36%

Phase 1: Median TTP 12.4 months

Phase 2: Median TTP 10.8 months

Lymphopenia 20%

Anemia 12%

Neutropenia 10%

Thrombocytopenia 10%

Moreau et al. [124]

NCT01794507

n = 66

R/R myeloma

Median of 3 prior lines of therapy

14% t(11;14)

Phase 1b study of venetoclax 50-1200 mg daily plus bortezomib and dexamethasone

ORR 67% ≥ VGPR 42%

Median TTP 9.5 months

Thrombocytopenia 29%

Anemia 15%

Neutropenia 14%

RP2D in combination with bortezomib and dexamethasone 800 mg daily

Bahlis et al. [126]

NCT03314181

Part 1: R/R myeloma with t(11;14), n = 24

Part 2: RR myeloma (cytogenetically unselected), n = 24

Phase 1 study of venetoclax 400-800 mg daily plus:

Part 1: Daratumumab plus dexamethasone

Part 2: Daratumumab, bortezomib and dexamethasone

Part 1: ORR 96% ≥ VGPR 96%

Part 2:ORR 92% ≥ VGPR 79%

Part 1: 18-month PFS 91%

Part 2: 18-month PFS 67%

Part 1:

Neutropenia (21%)

Hypertension (17%)

Part 2:

Thrombocytopenia (17%)

Lymphopenia (13%)

Insomnia 25%

One death due to sepsis in part 2 (in context of progressive disease)

Costa et al.[125]

NCT02899052

n = 49

R/R myeloma (median 1 prior line of therapy)

Phase 2 study of venetoclax 400 or 800 mg plus carfilzomib and dexamethasone

ORR 80% ≥ VGPR 65%

t(11;14) ORR 92% ≥ VGPR 85%

Median PFS 27 months

Lymphopenia 31%

Hypertension 16%

Pneumonia 12%

Neutropenia 12%

Hypophosphatemia 10%

Diarrhea 10%

Insomnia 10%

Phase III

BELLINI

[130, 131]

NCT02755597

R/R myeloma, 1–3 prior therapies

n = 97

Phase III randomized controlled trial of bortezomib and dexamethasone plus:

Placebo

ORR 68% ≥ VGPR 36%

t(11;14) ORR 47% ≥ VGPR 27%

Median PFS 12 months

36 (37%) deaths at median follow up 46 months

Diarrhea 11%

Thrombocytopenia 30%

Anemia 15%

Increased mortality in venetoclax arm, predominantly due to infections

n = 194

Venetoclax 800 mg daily

ORR 82% ≥ VGPR 59%

t(11;14) ORR 90% ≥ VGPR 70%

Median PFS 23 months

78 (40%) deaths at median follow up 46 months

Pneumonia 16%

Diarrhea 15%

Thrombocytopenia 15%

Anemia 15%

Neutropenia 18%