J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Review

Volume 10, Number 3, June 2021, pages 89-97

Role of Venetoclax in the Treatment of Relapsed and Refractory Multiple Myeloma

Figure 1. Mechanism of action of venetoclax in apoptosis. (a) Excessive BCL-2 production by cancer cells sequesters proapoptotic protein and evades apoptosis. (b) Venetoclax, a selective BCL-2 inhibitor, binds to BCL-2 and releases the proapoptotic protein, initiating the apoptosis cascade. BCL-2: B-cell lymphoma-2; BIM: BCL-2 interacting mediator; BAX: BCL-2 associated X protein; BAK: BCL-2 antagonist/killer protein.

**Table 1.** Study Characteristics of the Included Articles
Author, year	Study type	Number of patients	Prior lines of therapy, median (range)	Cytogenetics t (11;14)	Regimens
VEN: venetoclax; PI: proteasome inhibitor; V: bortezomib; K: carfilzomib; D: daratumumab; Dex: dexamethasone; Pbo: placebo; IMiDs: immunomodulatory drugs.
Kumar et al, 2017 [12]	Phase I	66	5 (1 - 15)	46%	VEN
Moreau et al, 2017 [14]	Phase Ib	66	3 (1 - 13)	14%	VEN + V + Dex
Costa et al, 2018 [16]	Phase II	42	1 (1 - 3)	23%	VEN + K + Dex
Kaufman et al, 2019 [13]	Phase I/II	Phase I: 20	Phase I: 2.5 (1 - 7)	Phase I: 100%	VEN + Dex
		Phase II: 31	Phase II: 5 (1 - 9)
Sidiqi et al, 2019 [18]	Retrospective	56	6 (1 - 15)	75%	VEN ± Dex
					VEN + Dex + PI ± IMiDs
Basali et al, 2020 [20]	Prospective	10	6 (2 - 19)	100%	VEN + V + Dex
Kaufman et al, 2020 [17]	Phase I/II	Part 1: 24	Part 1: ≥ 1	Part 1: 100%	VEN + D + Dex ± V
		Part 2: 24	Part 2: (1 - 3)	Part 2: 25%
Kambhampati et al, 2020 [19]	Retrospective	43	7 (2 - 13)	38%	A: VEN + PI
					B: VEN + PI + Dex
Kumar et al (BELLINI trial), 2020 [15]	Phase III	VEN: 194	(1 - 3)	11%	VEN + V + Dex
		Pbo: 97

Table 1. Study Characteristics of the Included Articles

Author, year

Study type

Number of patients

Prior lines of therapy, median (range)

Cytogenetics t (11;14)

Regimens

VEN: venetoclax; PI: proteasome inhibitor; V: bortezomib; K: carfilzomib; D: daratumumab; Dex: dexamethasone; Pbo: placebo; IMiDs: immunomodulatory drugs.

Kumar et al, 2017 [12]

Phase I

5 (1 - 15)

46%

VEN

Moreau et al, 2017 [14]

Phase Ib

3 (1 - 13)

14%

VEN + V + Dex

Costa et al, 2018 [16]

Phase II

1 (1 - 3)

23%

VEN + K + Dex

Kaufman et al, 2019 [13]

Phase I/II

Phase I: 20

Phase I: 2.5 (1 - 7)

Phase I: 100%

VEN + Dex

Phase II: 31

Phase II: 5 (1 - 9)

Sidiqi et al, 2019 [18]

Retrospective

6 (1 - 15)

75%

VEN ± Dex

VEN + Dex + PI ± IMiDs

Basali et al, 2020 [20]

Prospective

6 (2 - 19)

100%

VEN + V + Dex

Kaufman et al, 2020 [17]

Phase I/II

Part 1: 24

Part 1: ≥ 1

Part 1: 100%

VEN + D + Dex ± V

Part 2: 24

Part 2: (1 - 3)

Part 2: 25%

Kambhampati et al, 2020 [19]

Retrospective

7 (2 - 13)

38%

A: VEN + PI

B: VEN + PI + Dex

Kumar et al (BELLINI trial), 2020 [15]

Phase III

VEN: 194

(1 - 3)

11%

VEN + V + Dex

Pbo: 97

**Table 2.** Efficacy of Venetoclax-Based Regimens in the Treatment of Multiple Myeloma
Author, year	Number of patients	HR t (11;14) (%)	Overall, vs. high-risk t (11;14) subgroup efficacy
^aVGPR or better. ^bsCR = 7% in all patients and 14% in t (11:14) subgroup. ORR: overall response rate; CR: complete response; sCR: stringent complete response; VGPR: very good partial response; PR: partial response; SD: stable disease; PD: progressive disease; OS: overall survival; PFS: progression-free survival; HR: high-risk t (11:14) subgroup; VEN: venetoclax; NR: not reached.
Kumar et al, 2017 [12]	66	46%	21	40	4	10	15^a	27^a	-	-	-	-	-	-	-	-	-	-
Moreau et al, 2017 [14]	66	14%	67	-	-	-	42^a	-	-	-	9	-	14	-	-	-	-	-
Costa et al, 2018 [16]	42	23%	83	100	17^b	29^b	57	43	27	14	-	-	-	-	-	-	-	-
Sidiqi et al, 2019 [18]	56	75%	44	49	21	-	8	-	15	-	-	-	-	-	-	-	5.6	-
Kaufman et al, 2019 [13]	Phase I: 20	100%	65	-	-	-	30^a	-	35	-	20	-	-	-	-	-	12.4	-
	Phase II: 31		45	-	-	-	26^a	-	13	-	26	-	-	-	57	-	71	-
Basali et al, 2020 [20]	10	100%	-	78	-	10	-	10	-	40	-	-	-	-	-	77	-	28
Kambhampati et al, 2020 [19]	46	38%	39	71	4	-	13	24	22	47	9	12	51	7.5	15.6	NR	2.1	5.8
Kumar et al (BELLINI trial), 2020 [15]	VEN: 194	11%	-	-	-	-	-	-	-	-	-	-	-	-	33.5	-	23.2	-
	Placebo: 97
Kaufman et al, 2020 [17]	Part 1: 24	100%	96	-	-	-	96	-	-	-	-	-	-	-	-	-	-	-
	Part 2: 24	25%	92	-	-	-	97^a	-	-	-	-	-	-	-	-	-	-	-

Table 2. Efficacy of Venetoclax-Based Regimens in the Treatment of Multiple Myeloma

Author, year

Number of patients

HR t (11;14) (%)

Overall, vs. high-risk t (11;14) subgroup efficacy

ORR (%)

CR (%)

VGPR (%)

PR (%)

SD (%)

PD (%)

Median OS (months)

Median PFS (months)

All

^aVGPR or better. ^bsCR = 7% in all patients and 14% in t (11:14) subgroup. ORR: overall response rate; CR: complete response; sCR: stringent complete response; VGPR: very good partial response; PR: partial response; SD: stable disease; PD: progressive disease; OS: overall survival; PFS: progression-free survival; HR: high-risk t (11:14) subgroup; VEN: venetoclax; NR: not reached.

Kumar et al, 2017 [12]

46%

15^a

27^a

Moreau et al, 2017 [14]

14%

42^a

Costa et al, 2018 [16]

23%

100

17^b

29^b

Sidiqi et al, 2019 [18]

75%

5.6

Kaufman et al, 2019 [13]

Phase I: 20

100%

30^a

12.4

Phase II: 31

26^a

Basali et al, 2020 [20]

100%

Kambhampati et al, 2020 [19]

38%

7.5

15.6

2.1

5.8

Kumar et al (BELLINI trial), 2020 [15]

VEN: 194

11%

33.5

23.2

Placebo: 97

Kaufman et al, 2020 [17]

Part 1: 24

100%

Part 2: 24

25%

97^a

**Table 3.** Safety of Venetoclax-Based Regimens in the Treatment of Multiple Myeloma
Author, year	Number of patients	Regimens	Grade ≥ 3	Grade ≥ 3
N: sample size; AEs: adverse events; VEN: venetoclax; PI: proteasome inhibitor; V: bortezomib; D: daratumumab; K: carfilzomib; Dex: dexamethasone; IMiDs: immunomodulatory drugs.
Kumar et al, 2017 [12]	66	VEN	Nausea: 2 (3%)	Thrombocytopenia: 17 (26%)
			Diarrhea: 2 (3%)	Neutropenia: 14 (21%)
			Fatigue: 3 (5%)	Anemia: 9 (14%)
			Back pain: 5 (8%)	Leukopenia: 9 (14%)
			Vomiting: 2 (3%)	Lymphopenia: 10 (15%)
Moreau et al, 2017 [14]	66	VEN + V + Dex	Diarrhea: 4 (6%)	Thrombocytopenia: 19 (29%)
			Nausea: 3 (5%)	Anemia: 10 (15%)
				Neutropenia: 9 (14%)
Costa et al, 2018 [16]	42	VEN + K + Dex	Hypertension: 5 (12%)	Leukopenia: 11 (26%)
				Neutropenia: 6 (14%)
Kaufman et al, 2019 [13]	Phase I: 20	VEN + Dex	Hypophosphatemia: 4 (20%)	Leukopenia: 6 (29%)
				Neutropenia: 4 (21%)
	Phase II: 30		Hypertension: 3 (10%)	Leukopenia: 6 (32%)
				Thrombocytopenia: 2 (11%)
Sidiqi et al, 2019 [18]	56	VEN ± Dex	Infection: 3 (5%)	-
		VEN + Dex + PI ± IMiDs
Basali et al, 2020 [20]	10	VEN + V + Dex	-	-
Kaufman et al, 2020 [17]	Part 1: 24	VEN + D + Dex ± V	-	Neutropenia: 17%
	Part 2: 24
Kambhampati et al, 2020 [19]	43	A: VEN + PI	Diarrhea: 12 (30%)	Leukopenia: 14 (32%)
		B: VEN + PI + Dex	Nausea/vomiting: 15 (35%)	Neutropenia: 14 (32%)
			Infections: 11 (26%)	Thrombocytopenia: 12 (30%)
			Fatigue: 23 (53%)
Kumar et al. (BELLINI trial), 2020 [15]	VEN: 194	VEN + V + Dex	VEN/placebo	VEN/placebo
	Placebo: 97		Diarrhea: 29/12 (15%/12%)	Nausea: 41/8 (21%/8%)
			Pneumonia: 35/13 (18%/13%)	Thrombocytopenia: 29/29 (15%/30%)
				Anemia: 31/15 (16%/15%)

Table 3. Safety of Venetoclax-Based Regimens in the Treatment of Multiple Myeloma

Author, year

Number of patients

Regimens

Grade ≥ 3

Non-hematological AEs, n (%)

Hematological AEs, n (%)

N: sample size; AEs: adverse events; VEN: venetoclax; PI: proteasome inhibitor; V: bortezomib; D: daratumumab; K: carfilzomib; Dex: dexamethasone; IMiDs: immunomodulatory drugs.

Kumar et al, 2017 [12]

VEN

Nausea: 2 (3%)

Thrombocytopenia: 17 (26%)

Diarrhea: 2 (3%)

Neutropenia: 14 (21%)

Fatigue: 3 (5%)

Anemia: 9 (14%)

Back pain: 5 (8%)

Leukopenia: 9 (14%)

Vomiting: 2 (3%)

Lymphopenia: 10 (15%)

Moreau et al, 2017 [14]

VEN + V + Dex

Diarrhea: 4 (6%)

Thrombocytopenia: 19 (29%)

Nausea: 3 (5%)

Anemia: 10 (15%)

Neutropenia: 9 (14%)

Costa et al, 2018 [16]

VEN + K + Dex

Hypertension: 5 (12%)

Leukopenia: 11 (26%)

Neutropenia: 6 (14%)

Kaufman et al, 2019 [13]

Phase I: 20

VEN + Dex

Hypophosphatemia: 4 (20%)

Leukopenia: 6 (29%)

Neutropenia: 4 (21%)

Phase II: 30

Hypertension: 3 (10%)

Leukopenia: 6 (32%)

Thrombocytopenia: 2 (11%)

Sidiqi et al, 2019 [18]

VEN ± Dex

Infection: 3 (5%)

VEN + Dex + PI ± IMiDs

Basali et al, 2020 [20]

VEN + V + Dex

Kaufman et al, 2020 [17]

Part 1: 24

VEN + D + Dex ± V

Neutropenia: 17%

Part 2: 24

Kambhampati et al, 2020 [19]

A: VEN + PI

Diarrhea: 12 (30%)

Leukopenia: 14 (32%)

B: VEN + PI + Dex

Nausea/vomiting: 15 (35%)

Neutropenia: 14 (32%)

Infections: 11 (26%)

Thrombocytopenia: 12 (30%)

Fatigue: 23 (53%)

Kumar et al. (BELLINI trial), 2020 [15]

VEN: 194

VEN + V + Dex

VEN/placebo

Placebo: 97

Diarrhea: 29/12 (15%/12%)

Nausea: 41/8 (21%/8%)

Pneumonia: 35/13 (18%/13%)

Thrombocytopenia: 29/29 (15%/30%)

Anemia: 31/15 (16%/15%)

**Table 4.** Ongoing Clinical Trials of Venetoclax-Based Regimens in Relapsed Refractory Multiple Myeloma^a
NCT ID	Phase	Population	Regimen	Estimated completion
^aOnly clinical trials registered on https://clinicaltrials.gov/ are listed. RRMM: relapsed refractory multiple myeloma; VEN: venetoclax; NCT: national clinical trial.
NCT02899052	II	RRMM	VEN + carfilzomib + dexamethasone	2025
NCT03539744	III	t (11;14)-positive RRMM	VEN + dexamethasone vs. pomalidomide + dexamethasone	2022
NCT03312530	I/II	RRMM	VEN + cobimetinib ± atezolizumab	2020
NCT03567616	II	RRMM	VEN + pomalidomide + dexamethasone	2020
NCT03314181	II	t (11;14)-positive RRMM	VEN + daratumumab + dexamethasone ± bortezomib	2024
NCT01794520	I/II	t (11;14)-positive RRMM	VEN + dexamethasone	2021
NCT02265731	I/II	RRMM	VEN	2021
NCT03732703	I/II	t (11;14)-positive RRMM	VEN + ixazomib + pomalidomide + dexamethasone	2022

Table 4. Ongoing Clinical Trials of Venetoclax-Based Regimens in Relapsed Refractory Multiple Myeloma^a

NCT ID

Phase

Population

Regimen

Estimated completion

^aOnly clinical trials registered on https://clinicaltrials.gov/ are listed. RRMM: relapsed refractory multiple myeloma; VEN: venetoclax; NCT: national clinical trial.

NCT02899052

RRMM

VEN + carfilzomib + dexamethasone

2025

NCT03539744

III

t (11;14)-positive RRMM

VEN + dexamethasone vs. pomalidomide + dexamethasone

2022

NCT03312530

I/II

RRMM

VEN + cobimetinib ± atezolizumab

2020

NCT03567616

RRMM

VEN + pomalidomide + dexamethasone

2020

NCT03314181

t (11;14)-positive RRMM

VEN + daratumumab + dexamethasone ± bortezomib

2024

NCT01794520

I/II

t (11;14)-positive RRMM

VEN + dexamethasone

2021

NCT02265731

I/II

RRMM

VEN

2021

NCT03732703

I/II

t (11;14)-positive RRMM

VEN + ixazomib + pomalidomide + dexamethasone

2022